Biohacking Bible - A Neuropharmacology Encyclopedia

Biohacking Bible - A Neuropharmacology Encycloped…

by ryderlefeg on Discord and editors
Revised by Meso aka Deya Rabbie Neuropharmacology, B.Sc. † RIP
Last updated on 26-08-2025

Check out the GPT bot Biohacker (beta version).
And don’t forget to check out r/prefrontal as well.

---------------------------------------

If you want to download or print this book, it can be purchased on Gumroad. If you want to donate and support me, my PayPal (paste your email in the message) and crypto addresses (most preferred) are:

SOL: 516mqdwzZkerw1PT64X7PaKWT13hSrT6W2fGWjBpe4gh
ERC-20: 0xDaa1cad37f4da58B841365d96d140eD949f56E49
BTC: bc1qjwsr82d8slz06hexzus2kw47r94xe3y38hh7wf
LTC: ltc1qz6hkcwdh4us0nu6hzclkcgtvrsgjgpxmsc5j3j
XMR: 48qYHKaDDGFExz4hSAiZTi8Z623y5ehiC8kDxLNWRWCGZRQc5Nuby1G5edDz9BskD7L9CYhZXytkY5ip8XZ6qy1w2LL6k3r

---------------------------------------

This is an overview of various drugs ranging from antidepressants to psychedelics in light of pharmacological and neuroscientific research. I focus on the substances I think would be of most help to the hypodopaminergic phenotype of neuropsychiatric disorders (ie. anhedonia, depression/anxiety, PSSD, DPDR and ADHD).

Depression, poor motivation and focus are often attributed to low dopamine and norepinephrine but low acetylcholine activity is also a factor. Acetylcholine is needed to sustain attention, and a lack of acetylcholine due to low dietary choline can contribute to ADHD symptoms; make sure you eat enough choline-rich food like eggs, or supplement with CDP-choline/alpha-GPC. MAOIs increase both dopamine and norepinephrine concentrations which is why they are highly regarded.

One of the main reasons behind hypodopaminergic symptoms such as anhedonia, social withdrawal, short attention span and sexual dysfunction is supersensitivity to serotonin or excessive serotonergic signaling. Serotonin acts as a counterbalance to dopamine in the brain for the most part (it is brain region specific; cortical 5-HT2A increases dopamine release to the NAc, while hypothalamic 5-HT1A increases dopamine , β-endorphin, oxytocin there), so one of the best ways to resolve this is to block specific serotonin receptors.

---------------------------------------

NOTE: none of this is medical advice. These are mainly notes I’ve written after years of research. Some of the material mentioned in this ebook is experimental and is marked as such. Be sure to consult a licensed physician before attempting to self-medicate.

It is NOT advisable to dabble with nootropics until you first adopt a healthy lifestyle by getting your gut, immune system, blood levels, hormones in the best shape possible, and adopting a healthy diet (including drinking filtered water).

Remember to also get thyroid and blood panels done. Ideally test for all vitamins, minerals and hormones but if you can’t get your doctor to refer you for those tests, then get lab tests done yourself at a Spectracell lab or order an Idealabs kit (easiest and cheapest method).

You can also stack hepatoprotectors like black seed oil, NAC, TUDCA, Na-R-ALA/R-ALA, curcumin (with bioperine ideally), schisandra and/or milk thistle to reduce the burden on your liver and protect from any hepatotoxic chemicals, including in your food. Safety note - never take TUDCA before alcohol as the combination is very toxic to the liver; and never take NAC after alcohol as the combination is, once again, toxic.

This ebook is regularly updated, so I recommend checking in once a month or so for new material. And feel free to use the comment feature if you want to give feedback. If you have questions, add me on Discord and message me.

If any link is down, just use the archived mirror.

For information on potential health risks with medication and nootropics, you can purchase a DNA kit by AncestryDNA (or Nebula Genomics deep sequencing with the “SAVE50” coupon if you can afford it), preferably from Amazon or a third-party for privacy; this is strongly recommended in order to identify potential genetic predispositions to PSSD and other complications.

My ranking of DNA kits would be Nebula/Dante Labs/Sequencing.com > AncestryDNA > 23&Me. Also, Americans can participate in the All of Us Research Program for whole-genome sequencing. See this page regarding privacy of the program participants: Participant Privacy Protections.

US members, get your whole genome sequenced for free

If you have MTHFR/COMT/MAOA/MTR/MTRR/VDR/BHMT/GNMT/CBS/ACAT gene mutations, make sure to insert your DNA data into Genetic Genie, Promethease or Strategene to get a detailed list of mutations and respective supplements to counteract the effects of the mutations. Check out r/MTHFR for more details. As an under-methylator or over-methylator, it’s recommended to get your methylation status in check before experimenting with pharmaceuticals or nootropics.

---------------------------------------

Cannabis-induced anhedonia requires a slightly different approach. Highly recommend BDNFan’s guide to recover from cannabis-induced anhedonia.
---------------------------------------

Join my Discord server for discussing community-funded synths, neuropharmacology and more.

---------------------------------------

Pharmaceuticals & Nootropics

Antidepressants

SSRIs

These can be good for OCD, GAD and mild depression (rarely moderate or major). Fluvoxamine is the most effective out of all the SSRIs due to the decent safety profile and pro cognitive effect from sigma-1 agonism, but their use is not recommended as anything but a last-resort due to the risk of developing PSSD and also potential cognitive impairment.

As for alternative herbal antidepressants, mesembrine takes the cake. MX-16 extract by UltraKanna is unmatched and is a vastly superior option compared to pharmaceutical antidepressants for most people. Most and not all because some would still find they get better responses to pharmaceuticals.

Why Are SSRI Antidepressants So Harmful?

SJW Ze 117/Perika is also another good alternative to SSRIs. Certain σ1 agonist SSRIs like fluoxetine and fluvoxamine increase neurosteroid production at microdoses, which can be nootropic. Fluvoxamine also inhibits weight gain which can be a plus for a lot of people. Another thing worth noting is that it seems to work at least partially through ERα.

SSRIs used for OCD are sometimes dosed way higher than the recommended limit. For example, fluvoxamine can be dosed up to 450 mg/day for treatment-resistant OCD patients, while the recommended limit for depression is only 300 mg.

Treatment Resistance in Obsessive-Compulsive Disorder: Risk Factors, Biology, and Management

SNRIs

SNRIs work for OCD, GAD, mild to moderate depression marked by lack of focus, and comorbid ADHD. Venlafaxine may be helpful for ADHD, but it’s not recommended as it can cause PSSD just like SSRIs; although its classification as an SNRI is questionable. They are similar to SSRIs, but inhibit the reuptake of norepinephrine as well, which indirectly potentiates dopaminergic transmission, and are thus more effective for depressive disorders (usually).

TCAs

This group is an umbrella that is too vague as they are all vastly different. If we break them down into groups:

Imipramine, amitriptyline, amoxapine, trimipramine – especially effective against anxiety and melancholic depression. Imipramine cannot be taken with MAOIs.
Clomipramine – the only one that's labeled for OCD out of all the TCAs (doesn't necessarily mean the others don't work). It is the OCD gold standard. As for the anxiety/depression gold standard, it’s a toss-up between it and amitriptyline. Clomipramine also cannot be taken with MAOIs.
Nortriptyline and desipramine – great for depression marked by lethargy, and great for ADHD/sluggish cognitive tempo. They are safe adjuncts to MAOIs like tranylcypromine.
Non-monoaminergic TCAs like tianeptine and opipramol – quite weak for anything other than mild depression/anxiety. Also safe as adjuncts to MAOIs.

TCAs ranked by efficacy against depression: clomipramine = amitriptyline = imipramine > amoxapine = trimipramine > doxepin > nortriptyline > desipramine > tianeptine > opipramol and the others.

For OCD/anxiety disorders: clomipramine > amitriptyline = imipramine > amoxapine = doxepin > trimipramine > the others.

Atypical depression marked by mood-reactive anhedonia, hypersomnia, rejection sensitivity (guanfacine helps), leaden paralysis (heavy feeling in the arms or legs) and weight gain responds well to MAOIs. They also work for mild depression and general anxiety. Tranylcypromine is the gold-standard MAOI for atypical depression, but phenelzine is used instead when the patient cannot tolerate tranylcypromine for any reason (ie. too anxiogenic) or has severe GAD/social anxiety/certain eating disorders.

Both TCAs and SSRIs have been reported to cause PSSD in many cases due to DNMT inhibition and potent serotonin reuptake inhibition that alters the epigenome long-term (for genetically susceptible individuals, especially those with VDR +/+ and MTHFR +/+). A new study also just dropped proving that PSSD and PFS implicate dysfunctional gut-brain axis, high serotonin and low dopamine. Citalopram and escitalopram are notorious for triggering severe PSSD yet they don't alter allopregnanolone whatsoever, so I don’t agree with the point about lowered allopregnanolone levels necessarily being a direct cause of PSSD and not merely a downstream effect of the cascade of epigenetic changes done to the body.

MAOIs

On the other hand, these do not cause PSSD. They do not work as well as TCAs for melancholic depression though since they tend to be pretty anxiogenic/stimulating in most cases. Excellent responders are usually of the atypical depression subtype or poor responders to TCAs and SSRIs. Excellent responders to tranylcypromine also usually tend to have MDD without major anxiety features; while phenelzine is especially helpful for social anxiety and GAD. Neither of them generally help with other specialized anxiety disorders like OCD, although sometimes they do work.

Tranylcypromine is a semi-irreversible MAO inhibitor that inhibits the breakdown of serotonin, dopamine, norepinephrine and provides neuroprotection from dopamine’s neurotoxic metabolite precursor MPTP due to irreversible MAOB inhibition. As a result, it is a very potent drug that increases concentrations of all monoamines considerably making it far superior to SSRIs and SNRIs. It also happens to possess remarkable anti-inflammatory properties. Interestingly enough, as an LSD1 inhibitor it demethylates the genome and protects against noise-induced hearing-loss. RG108, another DNMT inhibitor (genome demethylation agent) does the same thing.

Combining MAOIs together is also safe, and dietary concerns are very overblown. It is advisable to follow Dr. Gillman’s diet guide and check out his other blog posts on MAOIs.

Phenelzine sulfate, another irreversible inhibitor of both MAOA and MAOB , could also be a good drug for social anxiety due to its GABA-T inhibitor metabolite PEH, although side effects are much worse than tranylcypromine’s. The dose range is 15 to 105 mg. Combining a MAOI like tranylcypromine or 9-methyl-β-carboline with lemon balm (contains rosmarinic acid, a potent GABA-T inhibitor) mimics phenelzine with fewer side effects. Combining MAOIs together is completely safe and sometimes beneficial for MAOI-independent effects, although can be majorly redundant, as potent irreversible inhibitors like phenelzine (or tranylcypromine to a lesser extent since it is a “semi-irreversible inhibitor”) knock out all MAOA and MAOB for weeks.

Moclobemide, a reversible inhibitor of MAO, may be used at doses ranging from 900 to 1650 mg per day. The commonly recommended daily dosage of 150-600 mg is considered somewhat conservative.

"Although it has been estimated that a single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase-A (MAOA) and 20-30% of MAOB, studies evaluating brain occupancy of MAOA enzymes have shown dosages of 600 mg to only inhibit 74% of MAOA enzymes and dosages in the 900–1200 mg range to inhibit slightly less MAOA than phenelzine at 45–60 mg; subsequently, it is highly plausible that reports of lower efficacy could be largely or entirely the consequence of conservative dosage guidelines rather than the pharmacological properties of the drug."

Instead combine MAOIs with other nootropics or perhaps a TCA (except imipramine and clomipramine as those can induce serotonin syndrome with a MAOI) like desipramine, nortriptyline (generally the best adjunct), trimipramine, amoxapine, doxepin or amitriptyline if you are treatment-resistant (although this combo has not proven to be more effective than either of them alone in this study). Be aware that irreversible MAO inhibition lasts for 14-30 days so do not take any SRI of ANY sort until 14-30 days have passed after stopping phenelzine. With tranylcypromine on the other hand, you can usually get away with only ~10-21 days theoretically depending on how fast your MAO recovers (differs from person to person).

Safinamide is another (reversible) MAOB inhibitor that also happens to be a DAT, NET reuptake inhibitor and a σ1 antagonist (bad for cognition and mood). It blocks voltage-gated sodium and calcium channels, which possibly causes severe adverse events.

Tisolagiline (KDS-2010) is a potent, highly selective, reversible, and orally active MAOB inhibitor with anti-neuroinflammatory effects in the presence of Parkinson-inducing monoaminergic neurotoxin precursor MPTP. It is a phase 2 drug for Alzheimer's disease and obesity, being therapeutically superior to irreversible MAOB inhibitors like selegiline. Tisolagiline is highly bioavailable (>100%) and BBB permeable. It also reduces reactive astrocytosis and ROS in the spinal cord.

Bifemelane is a reversible MAOA and a weak irreversible MAOB inhibitor. The regular dosage typically ranges from 150-300 mg per day, divided into 2-3 doses.

Tetrahydroharmine/Harmaline/Harmine are decent options for reversible MAOA and MAOB inhibition. They are reversible MAO inhibitors with interesting properties. THH is also an SRI at higher doses ironically, which makes it unique. Other β-carbolines are used to model essential tremor in humans. Harmane levels are higher in those with ET, and the tremor effect of β-carbolines is dose-dependent. It's not yet certain whether chronic and/or high-dose intake of β-carboline causes physical changes in the cerebellum.

Rasagiline/Selegiline (propargylamines) - selegiline is a selective and irreversible MAOB inhibitor at lower dosage and MAOA inhibitor at higher dosage. Rasagiline is similar to selegiline pharmacologically in being a selective MAOB inhibitor. However, rasagiline doesn’t produce any amphetamine metabolite. Both of them have propargylamine moiety which gives them benefits independent of MAO inhibition which causes Nrf2 induction, increased expression of neurotrophins like BDNF, GDNF and NGF, increased protein synthesis and decreased apoptosis. Other propargylamines are ladostigil (which is also a MAO inhibitor), clorgyline (also a MAO inhibitor), HLA20 and M30. Additionally, selegiline is also a catecholamine enhancer.

Rapid treatment of depression with selegiline-phenylalanine combination

NOTE: while there's a common belief that MAO-Is are entirely contraindicated with psychostimulant treatment, they can be used cautiously. Methylphenidate is considered a lower-risk alternative to amphetamines in such scenarios. This combination is to be reserved for cases that prove to be particularly treatment resistant to either one in isolation.

Do not combine MAOIs with kanna, potent SRIs or serotonin releasers (ie. MDMA). You could probably get away with microdoses of MDMA with a MAOI in some cases, but it is extremely inadvisable.

Other Pharmaceuticals

Lamotrigine

A calcium channel modulator used for bipolar disorder and other mood disorders that also happens to work for anhedonia in rare cases. It inhibits voltage-gated sodium channels, which are responsible for the rapid depolarization phase of action potentials in neurons. By stabilizing the inactivated state of these channels, lamotrigine reduces the excitability of neurons, thereby preventing the excessive firing that can lead to seizures and mania.

Lamotrigine also inhibits certain types of voltage-gated calcium channels, particularly the N-type and P/Q-type channels. This inhibition decreases the release of excitatory neurotransmitters like glutamate and aspartate, contributing to its anticonvulsant effects. Excessive glutamate release is associated with neuronal excitability and seizures, so its reduction helps to stabilize neuronal activity. Since it reduces glutamate, it is also likely that it modulates GABAergic neurotransmission (possibly increasing it).

The overall effect of lamotrigine’s action on sodium and calcium channels is the stabilization of neuronal membranes. This stabilization helps to prevent the abnormal firing of neurons that can lead to seizures.

Some studies also suggest it has action on 5-HT receptors. It blocks 5-HT3 receptors with decent affinity, and has unclear actions on 5-HT1A (most likely as a presynaptic agonist).

Modulation of the antidepressant-like effects of sustained administration of carisbamate and lamotrigine on monoaminergic systems: electrophysiological studies in the rat brain

Surprisingly, it can help depersonalization/derealization disorder too despite the fact that antiglutamatergic agents usually worsen it.

Unfortunately however, it can also cause a deadly rash in rare cases, so it is not recommended unless absolutely necessary. Titrate slowly to reduce the risk of getting the rash and stop immediately if you notice signs of a serious rash. Mild itching is usually not a concern.

IN Deferoxamine

Deferoxamine is a very experimental fortuitous compound for treating anhedonia and TRD. For one, it does concentrate very well in the brain when administered intranasally, with manifold concentrations compared to IV deferoxamine. But more than that, it also has other neuroprotective effects that are separate from simple relief of iron accumulation.

It interacts with prolyl hydroxylase enzymes to increase the expression of HIF-1α and REDD1. This basically allows it to act both as a very strong hypoxia mimetic, which can increase autophagy by inhibiting mTOR, and increase VEGF expression. HIF-1α also increases vascular permeability as well as mediating other cellular benefits seen in hypoxia. Dose range is around 10-50 mg intranasally for 7 days.

You should stack it with IN NAC for protection against mucormycosis. There is also a risk of developing anemia if you take too much.

VLD Amisulpride

Selective antagonist of D2 and D3 autoreceptors. Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, very-low-dose amisulpride has also been used to treat dysthymia. Do not exceed 25-50 mg.

The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. Subjective effects include significantly increased hedonic tone, improved focus/cognition, enhanced color vividness, improved symptoms of social anxiety, enhanced physical coordination and responsiveness, etc. It starts working very fast and usually without side effects other than maybe prolactin increase if you are particularly sensitive. This can be counteracted with anti-prolactin drugs like metergoline, bromocriptine or pramipexole.

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers

Dextroamphetamine

Exerts its behavioral effects by increasing the signaling activity of neurotransmitters norepinephrine (NE) and dopamine (DA) in the reward and executive function pathways of the brain. The reinforcing and motivational effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway. Dextroamphetamine is a potent full agonist of the trace amine-associated receptor 1 (TAAR1) and interacts with vesicular monoamine transporter 2 (VMAT2). Combined action on TAAR1 and VMAT2 results in increased concentrations of dopamine and norepinephrine in the synapses, which stimulates neuronal activity.

Can be neurotoxic even at therapeutic doses so this should only be taken if necessary.

VLD Buprenorphine

It is a partial agonist at μ-receptors, an antagonist of kappa (κ) receptors, and also displays affinity for delta (δ) opioid receptors. Buprenorphine has a favorable safety profile with low risk of respiratory depression, and the pharmacokinetics are not affected by advanced age or renal dysfunction, supporting its use in both mid-life and older adults with TRD. The combination of μ-receptor agonism and κ-antagonism produces less dysphoria than methadone, and animal studies suggest that κ-antagonism may exert antidepressant effects. Additionally, buprenorphine being ORL agonist, is hypothesized to be responsible for bell shaped dose response and have ceiling effects.

Buprenorphine may also interact with serotonergic systems and the hypothalamic-pituitary-adrenal axis. Rapid improvement in mood has been observed in both younger non-opioid abusing patients with TRD and opioid-dependent patients treated with buprenorphine. Of particular relevance for TRD, especially in older adults in which cognitive impairment is often comorbid with depression, is that the effects of buprenorphine on cognition may be minimal. The unique mechanism of action, potential for early effect, and acceptable safety profile make buprenorphine an intriguing molecule to test in older adults with TRD.

Safety, Tolerability, and Clinical Effect of Low-Dose Buprenorphine for Treatment-Resistant Depression in Mid-Life and Older Adults

Metformin

Antiglycemic medication with antidepressant, anxiolytic and neuroprotective qualities. It has broad mechanisms of actions (complex I inhibition, AMPK activation) however there are some undiscovered mechanisms as well. Mainly AMPK activation, GDF15 increase and increase in irisin release (through increased FNDC5 gene expression) are common mechanisms known. GDF15 promotes survival of dopaminergic neurons and has profound neurotrophic effects.

Its broad mechanism leads to upregulation of neurotrophins like GDNF, BDNF (increasing TH downstream), NGF and NT-3. Its effect on GABA also produces anxiolytic effects. It also reduces nicotine withdrawal both in rats and humans and cocaine addiction somewhat. When using chronically, use B12 supplement to prevent deficiency as metformin impairs B12 absorption through gut changes in the long run.

Anecdotally, it was one of few substances out of hundred different substances that prevented a neuropharma researcher suffering from severe DAWS from suicide. Side note, valproate also seems to help with DAWS according to a few case reports

Metformin: An Alternative to SSRIs [71 studies] by Deya Rabbie (neuropharmacologist)

Tianeptine

Acts as a μ-opioid receptor (MOR) agonist along with its active MC5-metabolite, and to a lesser extent on the δ-opioid receptors without affecting the κ-opioid receptor. Other mechanisms of actions include AMPA activation downstream of NMDA antagonism, HDAC inhibition and increase in SERT activity (PAM) as opposed to SSRIs which inhibit it.

A noteworthy fact is that tianeptine, despite its affinity for these receptors, does not cause tolerance, as it does not lose its efficacy after continued treatment, or physical dependence, as after suppression or administration of naloxone no withdrawal syndrome was observed. These two characteristics clearly differentiate tianeptine from the other opioids, such as morphine.

Despite acting on the μ-opioid receptor, it triggers mechanisms of neuronal transduction that are different to those induced by morphine and other opioids, since these cause tolerance and withdrawal syndrome after they are discontinued. This differential fact has raised the possibility that antidepressants could be developed that act on the transduction mechanisms modified by tianeptine. On the other hand, we should point out that the potency of tianeptine on μ-opioid receptors is 6 times less than that of morphine, and that addiction to the antidepressant has been limited to a few isolated cases, essentially polydrug-dependent individuals.

In fact, tianeptine does not cause tolerance or withdrawal syndrome if used responsibly, two inescapable characteristics of opioids that cause dependence. Furthermore, along the same lines, it has been demonstrated that supratherapeutic doses of tianeptine showed low (but not zero) potential for abuse. Thus, tianeptine significantly decreased morphine tolerance and suppressed the withdrawal syndrome caused by the administration of naloxone in the mouse, and therefore it can be claimed that tianeptine, despite having affinity for the opioid receptors, behaves as an inhibitor of morphine tolerance and dependence. In fact, these authors point out that the administration of tianeptine could benefit patients who require prolonged administration of morphine. Tianeptine reducing morphine tolerance would be partially mediated through NLRP3/TLR4 inhibition since other TLR4 antagonists reduce morphine tolerance in animal models. Nor-BNI side effects should also be reduced through weak μ-opioid agonism and TLR4 inhibition.

These pharmacological properties of tianeptine have aroused great interest, not only for the treatment of depression, but also for the potential development of μ-opioid receptor agonists that modify transduction mechanisms in a similar way to tianeptine, in order to obtain analgesics that cause less dependence than the classic opioids. Dose range is 25-50 mg orally. Above 50 mg gets you into abuse territory, which will make you liable for addiction.

Credit to u/Kiraxes and u/Jaded-Wafer-6499

Ezogabine/XEN-1101/BHV-7000

KCNQ2/3 type of potassium channels opener which disinhibits release of dopamine downstream, but side-effects are severe. Not recommended as anything but a last resort if you suffer from treatment-resistant ADHD/depression/anhedonia. Also helps lower tinnitus.

Pre-clinical work demonstrates that increased activity of KCNQ type potassium channels reverses depressive phenotypes following chronic social defeat stress (Krishnan et al. 2007; Friedman et al. 2014; Friedman et al. 2016). Mice resilient to depression and anhedonia exhibit increased KCNQ channel activity within the ventral tegmental area (VTA) of the reward system, dampening the hyperexcitability of the dopamine neurons that is associated with depressive/anhedonia phenotypes observed in the susceptible mice. This susceptible phenotype can be reversed through (a) overexpression of KCNQ channels in the VTA dopamine neurons, (b) direct intra-VTA injection of small molecule KCNQ channel openers, or (c) systemic injection of KCNQ channel openers. Repeated peripheral daily administration of ezogabine, an earlier-generation KCNQ potassium channel modulator, completely reversed the depressive/anhedonic phenotype in the susceptible mice.

In addition to an open label study, statistically significant clinical results were generated from a randomized, placebo-controlled clinical trial that explored the targeting of KCNQ channels as a treatment for MDD and anhedonia using ezogabine (Costi et al. 2021). XEN1101, a next-generation KCNQ channel opener, has been studied in a Phase 2b clinical trial in adult patients with focal onset seizures, and demonstrated compelling efficacy results, with a statistically significant and dose-dependent reduction from baseline in monthly focal seizure frequency when compared to placebo (monotonic dose response; p≤0.001).

UPDATE: it sadly failed clinical trials for depression. Although clinical trials are known to have a very strong placebo and thus should be taken with a grain of salt.

Zuranolone

Zuranolone is an orally bioavailable allopregnanolone analog that is approved for treating postpartum depression. It also works for major depression, anhedonia and anxiety according to new research. It has been found that allopregnanolone levels especially are altered in PFS and PSSD (in rare cases it's high but those are outliers). Either way, when levels are out of range (too low or too high), problems arise. Allopregnanolone is an endogenous GABAA PAM which is a substance that enhances the function of a receptor’s endogenous ligand, instead of activating it directly and downregulating it. In most PSSD/PFS cases, this neurosteroid is in very low amounts, which leads to the GABA/glutamate ratio being out of balance - favoring glutamate (the excitatory neurotransmitter). The problem with glutamate being too high is that it acts against dopamine and GABA in high amounts, which makes it anti-cognitive, anti-sexual and pro-depressive.

Not only is allopregnanolone useful for the CNS, it also mediates many functions in the body systemically including lowering inflammation and keeping the gut microbiome in check through PPAR. Recent evidence obtained in male rats, that treatment with ALLO can counteract gut inflammation induced by finasteride withdrawal.

Nootropics

Mesembrine

Mesembrine is the most notable psychoactive alkaloid present in kanna. Mesembrine acts as a VMAT2 upregulator, moderately potent serotonin reuptake inhibitor, weak PDE4 inhibitor, weak MAOA inhibitor, and a weakly reversible AChE inhibitor. There is no other known VMAT2 upregulator.

Basically VMAT2 is like the train that carries neurotransmitters like dopamine. Mesembrine somewhat increases the total amount of neurotransmitters being transported between neurons. This is a unique mechanism not shared with any other chemical, and on paper is a safe way to try treating anhedonia with low risk of side effects.

The only problem with mesembrine is that it is also an SRI which can worsen PSSD or even induce it theoretically. However, there is no report of PSSD being induced by mesembrine. This is purely theoretical but is a cause for concern nonetheless.

PDE4 inhibition is also interesting because this decreases the rate of breakdown of cAMP which is another neurotransmitter that is downregulated in depressive disorders. Though it is not very potent at inhibiting PDE4.

Finally, it is a weak MAOA inhibitor which decreases the breakdown of dopamine. This is obviously a plus when it comes to treating ADHD, depression and anhedonia.

Kanna is worth a try for those who don't respond to conventional antidepressants. Best extract seems to be UltraKanna’s MX-16.

It is worth noting that it does not work at all with SRIs and can be dangerous with MAOIs however.

Saint John’s Wort

SJW has been reported to work for anhedonia/depression. Hyperforin in hypericum perforatum is a potent reuptake inhibitor of serotonin, dopamine, noradrenaline, GABA and glutamate. It also stimulates capillary blood flow. Hypericin is a weak MAOA and MAOB inhibitor at high levels (not possible to obtain through normal doses). Hypericin also has affinity for the σ1 receptor as an agonist. However, it is an antagonist at adenosine, benzodiazepine, GABAA and GABAB and inositol triphosphate.

SJW has been shown to decrease the release of corticotropin-releasing hormone in the paraventricular nucleus of hypothalamus (in vitro), and decreased plasma levels of adrenocorticotropic hormone and corticosterone (in vitro). Due to the flavonoid content, it modulates the HPA function, downregulates β-adrenergic receptors, upregulates 5-HT1A and 5-HT2 receptors (although one study apparently found that SJW downregulates the former). Furthermore, some of the components of SJW have been found to bind very weakly to various receptors. Major depression has elevated ACTH and cortisol, and SJW downregulates them. It also antagonizes 5-HT6 and 5-HT7, which is antidepressant. The primary liver enzymes induced by SJW include:

CYP1A2: there is evidence that St. John's Wort may induce this enzyme as well, impacting the metabolism of drugs like clozapine (an antipsychotic) and some antidepressants.

CYP3A4: perhaps the most significantly induced enzyme by St. John's Wort. This enzyme metabolizes a large number of drugs, including statins (for cholesterol), some calcium channel blockers, certain antidepressants, DXM, and many others.

CYP2C9: St. John's Wort also induces this enzyme, affecting the metabolism of drugs like warfarin (a blood thinner), some NSAIDs (non-steroidal anti-inflammatory drugs), and sulfonylureas (used in diabetes treatment).

CYP2C19: St. John's Wort may also significantly increase this enzyme, which is involved in the metabolism of certain proton pump inhibitors (used for acid reflux) and some antidepressants.

P-Glycoprotein (P-gp): besides the CYP enzymes, St. John's Wort also induces P-glycoprotein, a transporter protein that affects the absorption and elimination of many drugs, including immunosuppressants and antiretrovirals.

Mechanism of Action of St John’s Wort in Depression:

“The hydroalcoholic extract of Hypericum perforatum L. is an effective antidepressant, although its mechanism of action is still unknown. It inhibits the synaptosomal uptake of serotonin (5-HT), dopamine and norepinephrine, suggesting a biochemical mechanism similar to the synthetic standard antidepressants. In the present study, further investigating this hypothesis, we confirmed that a hydromethanolic extract of H. perforatum inhibited [3H]5-HT accumulation in rat brain cortical synaptosomes with an IC50 value of 7.9 µg/ml. The IC50 of pure hyperforin was 1.8 µg/ml, so the activity of the total extract is not related only to its hyperforin content ( ≤5%). This inhibitory effect, however, is not due to a direct interaction with, and blockade of, the 5-HT transporters since the extract, like hyperforin , did not inhibit [3H]citalopram binding (IC50≥100 µg/ml and 10 µg/ml, respectively). We also found that 3–10 µg/ml of the extract, or 0.3–1 µg/ml hyperforin , induced marked tritium release from superfused synaptosomes previously loaded with [3H]5-HT. The releasing effect of the extract resembles the releasing effect of a reserpine-like compound (Ro 04-1284), i.e. it was slightly delayed and was 5-HT carrier- and calcium-independent. These data suggest that the hydromethanolic extract of H. perforatum, similarly to Ro 04-1284, rapidly depletes storage vesicles, raising the cytoplasmic concentration of 5-HT, and this increase is presumably responsible for the apparent inhibition of [3H]5-HT uptake. Therefore, our in vitro data do not confirm that the hydromethanolic extract of H. perforatum acts as a classical 5-HT uptake inhibitor but indicate reserpine-like properties. However, the concentrations of the active component(s) effective in vitro as reserpine-like agent(s) (i.e. corresponding to ≥3 µg/ml of the hydromethanolic extract) do not seem to be achieved in the brain after pharmacologically effective doses of the extract, as indicated by the finding that there were no significant changes of rat brain 5-HT and 5-hydroxyindoleacetic acid levels after a schedule of treatment (3×300 mg/kg day, orally) active in an animal model predictive of antidepressant-like activity. These data also suggest that the antidepressant effect of H. perforatum extracts is unlikely to be associated with interaction with GABA, benzodiazepine and 5-HT1 receptors since, in receptor binding studies, we found IC50 values higher than 5 µg/ml. Therefore other, still unknown, mechanisms are possibly involved in H. perforatum antidepressant effects.”

There are multiple extracts of H. perforatum (SJW) available:

LI 160 contains 0.3% hypericin derivatives, hyperforin 1-4%.

Ze 117 is a 50% ethanolic extract with an herb-to-extract ratio of 4:1-7:1; hyperforin ≤0.2% and up to 0.3% hypericin. Definitely the best extract overall due to NE:DA:5-HT uptake inhibition ratio of 30:7:1. If you live outside of Australia, get it from this Ebay seller.

WS 5570 Perika is an 80% ethanolic extract of St. John's Wort with a plant-to-extract ratio of 3:1-7:1; 5-6% hyperforin and 0.12-0.28% hypericin. Second best after Ze 117.

STEI 300 contains 0.2-0.3% hypericin and pseudohypericin, and 2-3% hyperforin.

Hyperforin may worsen or cause PSSD in very rare cases theoretically as it is an SRI. But pure hypericin extracts (Ze 117) have reports of curing PSSD.

9-Methyl-β-Carboline

9-methyl-β-carboline is an under-research compound for reversing Parkinsonism and depression/anhedonia, particularly in alleviating the symptoms of drug-induced anhedonia. Check out this subreddit about beta carbolines, and the many preliminary anecdotes. And here is another notable anecdote.

Other β-carbolines (not 9-methyl-β-carboline) are used to model essential tremor in humans. Harmane levels are higher in those with ET, and the tremor effect of β-carbolines is dose-dependent. It's not yet certain whether chronic and/or high-dose intake β-carboline causes physical changes in the cerebellum.

Mechanisms of Action

Decreases inflammation, preventing microglia proliferation and chemokine release
Protects against lipopolysaccharide toxicity and reducing LDH (lactate dehydrogenase) reduces α-synuclein, the aggregation of which form insoluble fibrils (like lewy bodies), one of the causes of some neurodegenerative disorders, like PD and AD (alzheimer's disease)
Increase ATP synthesis, leading to greater cognitive function
Significant restorative effects on the dopamine system. 9-methyl-β-carboline acts as a cognitive enhancer in a hippocampus-dependent task, and that the behavioral effects may be associated with a stimulatory impact on hippocampal dopamine levels and dendritic and synaptic proliferation
Displays potential to increase euphoria and orgasm strength, by virtue of possibly suppressing prolactin. Dopamine and prolactin have an inverse relationship
Up-regulates, differentiates and protects dopaminergic neurons, dendrites and synapses, especially in the substantia nigra of the midbrain and in the hippocampus
Increases dopamine synthesis, unlike caffeine and other stimulants, which deplete dopamine through excessive release and firing
Increases neurotrophins/neurotrophic factors (NGF, BDNF, CDNF, GDNF, SHH and decreases apoptotic signals like caspase-3) and Nurr1. These can significantly enhance executive functioning, alertness and motivation
Increase TH (tyrosine hydroxylase) expression and its transcription factors, and interacts with tyrosine kinases/TH converts L-tyrosine to L-dopa, needed for the synthesis of the catecholamines, especially dopamine, which can lead to dramatic increases in motivation and goal oriented behavior
MAOA (1 nM) and MAOB (15 nM) inhibition, preventing the formation of neurotoxic substances, like DOPAC (from the dopamine metabolization), 6-OH-DA (oxidopamine), and MPDP⁺/MPP⁺ (from MPTP), the major cause of dopaminergic neuron death
Increases/protects/recovers the NADH dehydrogenase (or "complex I" which catalyzes the transfer of electrons between NADH and CoQ10), enhancing the mitochondrial respiratory chain
Probably a κ-opioid (KOR) agonist too (downregulates with chronic usage, which disinhibits dopamine release downstream in the long-term)
Related beta-carbolines happen to be 5-HT2A and 5-HT2C antagonists

9-methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurons in primary mesencephalic culture

Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

The exceptional properties of 9‐methyl‐β‐carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti‐inflammatory effects

9-methyl-β-carboline-induced cognitive enhancement is associated with elevated hippocampal dopamine levels and dendritic and synaptic proliferation

Singlet excited state pyridinic deprotonation of the 9-methyl beta carboline cations in aqueous sodium hydroxide solutions

Ground and singlet excited state pyridinic protonation of 9-methyl beta carboline in water-N,N-dimethylformamide mixtures

The exceptional properties of 9-methyl-beta-carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti-inflammatory effects

β-carboline-independent antidepressant-like effect of the standardized extract of the barks of Mimosa tenuiflora (Willd) Poir. occurs via 5-HT2A/5-HT2C receptors in mice

Binding of beta-carbolines at 5-HT2 serotonin receptors

9-methyl-Fascaplysin exerts anti-ischemic stroke neuroprotective effects via the inhibition of neuroinflammation and oxidative stress in rats

Dose range is between 10-30 mg sublingually for about 90-360 days, because neurogenesis takes a long time. Tread with caution, and remember to stay away from sunlight and stack with astaxanthin to reduce UV-induced DNA damage from photosensitivity (ideally taken in the winter). Consider stacking it with 5-amino-1MQ/nicotinic acid as well to inhibit breakdown into neurotoxic metabolites. If it is too anxiogenic, stack with GABAergics like gotu kala, kavalactones, nigella sativa and agmatine sulfate.

After the 9-methyl-β-carboline cycle, consider replacing with 20-40 mg of MX-16 kanna extract daily for VMAT2 upregulation, indirect monoamine releasing action and PDE4 inhibition or SJW Ze 117. Kanna can be a great natural replacement for pharmaceutical antidepressants.

Do NOT combine kanna with MAOIs like 9-methyl-β-carboline or SRIs.

Credit to Lucas Aoun for the information on 9-Me-BC

Rhodiola

It acts as a natural reversible inhibitor of both MAOA and MAOB. Saffron + rhodiola may be of interest for PSSD and anhedonia/depression. Shockingly, this combination doesn’t appear to cause serotonin syndrome, despite saffron being considered to be an SRI and rhodiola is a MAOI. Combining saffron with any other SRI or MAOI is not recommended due to the non-zero risk of serotonin syndrome (a risk that is seemingly absent with rhodiola).

BPN14770

BPN14770, AKA PBIO-4D or D159797 is a NAM (Negative Allosteric Modulator) of the phosphodiesterase 4 (PDE4) Enzyme with preferential selectivity for the PDE4D isoform. It achieves this selectivity by binding to a phenylalanine residue in the N-terminal region of the PDE4 gene that is only found in the PDE4D isoform in primates. In a mouse with a humanized version of the PDE4 gene, BPN14770 was 46-fold more potent, and 730-fold more selective towards PDE4D relative to PDE4B, the other major PDE4 isoform in the brain.

BPN14770 has specific affinities for long-form variants PDE4D3 and PDE4D7. It avoids emesis caused by similar PDE4i's by avoiding other PDE4 targets and by avoiding the isoform PDE4D5.

Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice

BPN14770 is the successor to D159687, and has improved potency, half-life (10-12+ hours?) and pharmacokinetics in general [4].

BPN14770 was generally found to have a good pharmacokinetic profile with a high oral bioavailability of 70-80%. Intranasal ROA may carry higher efficacy.

BPN14770 has a superior effect profile to rolipram [4], which is a commonly tested PDE4 inhibitor used in studies. Rolipram is not selective for the PDE4D subunit, and in addition, it is not a NAM, meaning it can have full inhibition which is less desirable and could cause emetogenic side effects and other issues.

BPN14770 is well tolerated, and has a much better side effect profile than most other PDE4D modulators. It receives a substantial level of partial inhibition of PDE4D (Imax ∼80–90%).

Subjective reports have found it very effective as a spatial cognitive enhancer. It also has been found to be anxiolytic and somewhat antidepressant. Effects can take multiple weeks to compound to become efficacious.

“BPN14770 (3 mg/kg/day orally for 2 weeks) was found to improve behavioral phenotypes in a mouse model of Fragile X (male fmr1-/-). This was accompanied by changes to dendritic spine density and maturation in the cortex. Notably, the behavioral improvements persisted following a two-week washout period, suggesting that the drug has long-lasting effects. However, the improvements did weaken over time, indicating that the changes were reversible, and continuous use would likely be necessary for sustained benefit in a clinical setting.”

Bacopa Monnieri

Bacopa is a GABA upregulator; other bacopa mechanisms are explained in this overview. The primary ACh-boosting mechanism of BM is not AChE inhibition but choline acetyltransferase activation (synthesis of ACh), and that up-regulated AChE expression is a response to heightened ACh tone.

Mucuna Pruriens

This herb can be used occasionally safely. Best extract is either Nutricost’s or LiftMode’s. The alkaloids in Mucuna happen to be very useful in mitigating L-DOPA’s neurotoxicity. Mucuna is superior to pharmaceutical L-DOPA and is not comparable due to the alkaloids present in Mucuna.

The neurotoxicity associated with pharma L-DOPA usage does not apply to Mucuna. Fun fact: it also happens to contain trace amounts of DMT and other tryptamines as well.

Do not take it with phenethylamines, stimulants or MAOIs because they can cause a hypertensive crisis due to slowed breakdown. It is safe with SRIs however.

Agmatine Sulfate

Can be taken daily for a multitude of benefits including positive modulation of GABA and dopamine transmission, NMDA antagonism, imidazoline receptor agonism, modulation of nitric oxide synthesis, modulation of polyamine metabolism, and more. It’s better taken intranasally to avoid gut side effects by feeding candida species. Solubility in water is 50 mg/ml. Ideal dose is between 100 and 3000 mg.

NA-Semax Amidate

Semax is an ACTH analog, which is one of the stress hormones in the body. Its mechanisms include enkephalin breakdown inhibition, dopamine increase downstream and melanocortin antagonism. Overall effects include a mood lift, cognitive enhancement and reduction in stress (ironically) through blocking MC4. It is a potent BDNF, phasic dopamine and glutamate releaser as well which makes it a potent neurotrophic agent. It also upregulates trkB receptors which means it should not build tolerance over time.

Ideal dose is between 400 and 1000 mcg. Semax is ideally administered intranasally for enhanced CNS bioavailability. Out of all the semax forms, amidate is the best since it is the most bioavailable in the CNS. NA-semax is a close second. Regular semax is not very bioavailable so most people probably wouldn’t feel it.

Guanfacine

An atypical stimulant that acts by activating the α2A adrenoceptor which in turn reduces hypofrontality by increasing blood flow to the PFC, and enhancing the connectivity. The prefrontal cortex is responsible for executive functions such as planning, decision-making, and impulse control.

It also lowers blood pressure and thus reduces emotional reactivity to stimulus, which is useful for treating ADHD as rejection sensitivity dysphoria is a common symptom. As a result, it also calms down the sympathetic nervous system, which means the fight or flight response should be reduced as well. It is also a TAAR1 agonist similar to amphetamine/methamphetamine.

Bromantane

Upregulates tyrosine hydroxylase in the long-term through multiple complex mechanisms (including potassium channel modulation). Amantadine is a good alternative as well (same chemical family) that modulates the release of dopamine and induces tyrosine hydroxylase upregulation as well.

Bromantane (Ladasten) and amantadine share an adamantane backbone but take very different routes in the brain. The paper lays out bromantane as an atypical stimulant-anxiolytic “actoprotector” that enhances performance without hyperstimulation or dependence, then contrasts it with amantadine, an older antiparkinsonian/antiviral, to map where their mechanisms diverge.

Bromantane’s MOA is genomic: it upregulates the dopamine-synthesizing enzymes tyrosine hydroxylase (TH) and AADC, driving a sustained rise in dopamine (microdialysis shows ~8 h striatal elevation) without amphetamine-like crash or tolerance. The onset is gradual (~1.5–2 h), the action long (8–12 h), and the profile notably calm for a stimulant. Mechanistically it looks like an indirect dopamine agonist/neuroadaptive agent that also boosts inhibitory tone (via reduced GABA reuptake), and engages neurotrophic, antioxidant, and immune pathways. Pharmacokinetically: ~42% oral bioavailability, t½ ≈ 11–12 h, hepatic metabolism with urinary metabolites detectable up to two weeks.

Amantadine is multi-target and more “acute”: modestly increases dopamine availability (release + weak reuptake block) and layers on sigma-1 receptor agonism, weak NMDA antagonism, nicotinic modulation, and some PDE inhibition—yielding dopaminergic, glutamatergic, and cholinergic effects in concert. Clinically that cocktail underwrites benefits in Parkinson’s (including dyskinesia reduction) and as an influenza-A antiviral; it’s also used for MS-related fatigue and TBI recovery. PK contrasts are stark: high oral bioavailability (~86–90%), minimal metabolism, renal clearance of ~85–95% unchanged, t½ ≈ 15 h but days if kidneys are impaired. Amantadine is one of the few treatments to possibly claim parity of effectiveness with methylphenidate according to one study. However, with two other open label studies (Mattes, 1980; Donfrancesco et al., 2007) not reporting similar efficacy between amantadine and methylphenidate, Mohammadi’s study needs to be replicated, with a placebo group if possible, to better appreciate the impact of each drug. Despite these unique properties, nobody seems to talk about it much. Bromantane is ideally administered intranasally for enhanced CNS bioavailability. Alternatively, you can also go for 5-30 mg memantine (if you are fine with NMDA antagonism, and 5-HT3 antagonism).

MIF1

First identified in the 1960s, MIF-1 is a tripeptide composed of the amino acids proline, leucine, and glycine. It was initially studied for its effects on melanocyte-stimulating hormone (MSH) but has since garnered interest for its role in modulating neurotransmitter systems involved in mood regulation. It is derived from a cleavage of the hormone oxytocin and is known to block alpha-MSH (alpha-Melanocyte-stimulating hormone) which is a full agonist of melanocortin receptors MC1, MC3, MC4 and MC5 (there are five receptors in total). Since it functions as a melanocortin antagonist that way, it can be good for anhedonia and stress.

The melanocortin pathway is deeply involved in the brain's reward circuitry. Studies in the past have suggested that chronic stress leads to an increase of the melanocortin hormone in the brain in addition to an increase of melanocortin receptors in the nucleus accumbens (region involving reward and motivation).

This study has shown that anhedonia from chronic stress requires specifically MC4 receptor-mediated synaptic adaptations in nucleus accumbens. Such 'synaptic adaptations' occur due to the increase of melanocortin hormones i.e. alpha-MSH and since MIF-1 blocks alpha-MSH, MIF-1 would block "MC4 receptor-mediated synaptic adaptations" and thus the ability of stress to cause anhedonia.

It also functions as a D2 and D4 PAM, opioid receptor antagonist and increases oxytocin downstream which can be prosocial behavior. MIF1 should be administered subcutaneously ideally, although intranasally can work as well . Ideal dose is between 1 and 10 mg once a week as the half life is 5 days long and if it accumulates too much it becomes pro-anhedonic since the dose response curve is U-shaped (too much or too little is not ideal).

MIF-1 Report (Novel Antidepressant Peptide)

Metergoline

It is the most potent serotonin antagonist available. Also a D2 agonist which, in moderation, should help with enhancing dopaminergic transmission, and reduces prolactin in the long-term. Do not go above 5 mg and do not use it for longer than a few months (unless necessary) as it is a dopamine agonist which can cause DAWS in rare cases if taken for too long.

10-MeO-Harmalan

D2 agonism, 5-HT1 + 5-HT2 antagonism, MAO inhibition at high doses, and neurogenesis.

A general pro-dopaminergic effect is shown with many β-carbolines. Ideal dose seems to be around 100 to 300 mcg.

Nor-BNI

Norbinaltorphimine is a κ-opioid antagonist that functions as a partial agonist with mostly antagonist properties; receptor density doesn't appear to be significantly altered like other opioid receptors. And it has been deemed to have something called "collateral agonist efficiency" in that it pseudo-permanently traps κ-opioid receptor receptors in a state of antagonism for a few weeks after exposure.

A good way to put it is that some ligands are able to interface with only part of a receptor's elements, which can produce the desired effects, while being devoid of the expected homeostatic response, an example of non-linear biology. And nor-BNI appears to be classified under this for the time being. Seemingly an off-target effect that causes persistent κ-opioid receptor depression following exposure. Meaning, they activate JNK like a κ-opioid agonist does. It was not found in all κ-opioid antagonists, like with buprenorphine

Kappa opioid receptor in nucleus accumbens regulates depressive-like behaviors following prolonged morphine withdrawal in mice

Further, they state that JNK modulates κ-opioid receptors, like allosteric drugs typically do, and doesn't appear to play a role in receptor density. However they don't really understand the exact mechanism of nor-BNI desensitizing κ-opioid receptors like an antagonist that would distinguish it from other antagonists beyond this much. One thing is clear though because we see this with a lot of drugs, receptor density is not always parallel to activation or deactivation. Feedback to ligand binding appears to be determined by the ligand's selectivity and not the receptor complex as a whole.

Unlike typical κ-opioid receptor antagonists, nor-BNI carries properties of typical μ-opioid/κ-opioid agonists causing JNK phosphorylation. This causes inactivation of GPCR causing long lasting analgesia and KOR inactivation, but somehow since it carries some of κ-opioid receptor agonists like effect, it also somehow is inducing M1 NAM activity like dynorphins.

There is evidence to suggest that κ-opioid receptor agonists may cause a downregulation in the receptor. However, there doesn't seem to be any evidence of an upregulation with nor-BNI, which may have to do with it being an antagonist or an atypical one at that. For example, while it is a κ-opioid receptor antagonist, it acts like a partial agonist in a small portion of the receptor, which allows for JNK to build up within the receptor, which traps it in a desensitized state for an even longer duration, lasting up to 28 days before the effects completely dissipate, even though nor-BNI itself stops binding at 8 days, which is why pretreatment with a JNK inhibitor halted the effects at that stage. This abnormal mechanism might prevent the receptor from upregulating in response.

This means you may need to go easy on the dosing, as you may not realize the full effects from a single dose right away. 100-300 mcg/wk intranasally should be enough.

κ-opioid activation leads to increased NR2B signaling in the hippocampus which increased RAC1 activity and depressive behavior, which could not be counteracted with an SSRI but could be counteracted with an NMDA NR2B selective antagonist, as well as κ-opioid antagonism with nor-BNI.

κ-opioid activation itself should downregulate SERT leading to more serotonin, κ-opioid receptor antagonism upregulates/neutral effect on SERT usually. Since it's biased, even looking at p38 MAPKs and c-JNKs doesn't give much insight. P38 MAPK, but not ERKs or JNKs, is involved in the downregulation of native SERT, while it blocks p38 in certain conditions like drug withdrawal.

κ-opioid antagonism, too, prevents endocytosis of AMPA receptors and therefore helps to maintain excitatory transmission onto parvalbumin expressing fast spiking interneurons, which help to maintain impulse control, and this may be partly why it has no hedonistic or compulsive effects and why in other studies its shown to reduce cocaine or ethanol intake (anti addictive). This also inhibits the averse response from stress. κ-opioid receptor antagonism has been shown to ameliorate anhedonic behavior in rats.

“Nor-BNI has quickly made its way to my number 1 favorite. It is more anxiolytic than bromantane; very chill and slightly stimulating. I can definitely feel quality dopaminergic and testosterone effects, both mentally in terms of solid motivation, drive, curiosity, dominance, less bothered by things, better mood etc, and in libido, especially erections. Basically, nor-BNI just feels cleaner than bromantane, and I don't mean to say anything bad about bromantane at all, because it has been my favorite for the past 2 years and I loved it..... But nor-BNI seems to provide a clearer headspace, amplifies passion and enjoyment, and enhances resistance to stressors. On the other hand, bromantane has helped me tremendously in pushing through stressful times but it just lacks the same level of enjoyment, passion, and curiosity that nor-BNI offers. 400 mcg/week has actually allowed me to drop bromantane from my stack. It did take a couple weeks for the effects to build and they just keep getting better. I might still use bromantane occasionally, but I just feel a minimal need for it now.” - quote from ‘brenden.henry’, a Discord acquaintance and a notable member of the biohacking community.

κ-opioid receptor activation promotes mitochondrial fusion and enhances myocardial resistance to ischemia and reperfusion injury via STAT3-OPA1 pathway

Kappa opioid receptor activation is cardioprotective, due to its differences from standard κ-opioid receptor antagonists one might hope nor-BNI would side step this, but thankfully due to its use to research selective KOR antagonists we can better ascertain that this is likely not true, nor will intranasal necessarily evade this, but the evidence for this claim is more speculative. There is also some evidence of amplification of microglial mediated inflammation which is likely easier to mitigate.

I’ll try to lay out some ways I think you may be able to mitigate this downside, but the compounds that affect this pathway far exceed what I can cover.

Here we see it knocking out the cardioprotective effect against ischemia & reperfusion from acute, moderate, and high intensity exercise - albeit high intensity still had some benefit. We also learn that this effect is mediated at least in part by KOR’s positive impact on the AMPK-Akt-eNOS signaling pathway. Perhaps we can somewhat alleviate this by enhancing these downstream pathways. (0.322 mg/kg human dose - 22 mg)

Here we find that KOR modulates inflammatory pathways in the heart as well and that again, nor-BNI is disrupting cardioprotective effects, albeit this time from a straight up KOR agonist. However, we get another clue to mitigating this detriment to an extent, we see that stimulation of KOR seems to attenuate the expressions of TLR4 and NF-κB in the heart. (0.322 mg/kg human dose - 22 mg)

Here we see from another KOR antagonist that it amplifies microglia-mediated inflammatory responses, once again TLR4/NF-κB tie in since KOR activation can cause microglial to shift to an anti-inflammatory phenotype via this exact pathway

Mitochondrial Dysfunction and Apoptosis Are Attenuated on κ-Opioid Receptor Activation Through AMPK/GSK-3β Pathway After Myocardial Ischemia and Reperfusion

KOR activation also seems good mitochondria wise, can't see the dose, but safe to say kor activation has it's uses, just gotta find out what pathways are at the tippy top of the funnel so we can get a relatively free lunch. AMPK activation + TLR4/NF-κB antagonism seem most important so far.

No data on intranasal nor-BNI exists. Intranasal naltrexone (of which nor-BNI is basically just two of them stuck together) does seem to give potential clues, here we see even as low as 1 μg in mice is already having systemic and cognitive effects, specifically reducing cognitive detriment and reducing gastrointestinal side effects of opioids without affecting analgesia. This also may mean doses far lower than 100 μg a week may still be effective.

While I doubt that nor-BNI is blocking the full on cardioprotective effects of exercise at mcg doses (not sure how delta ties in, but it does - it’s how epicatechin is cardioprotective as well), nor-BNI’s trapping of KOR in a desensitized state for long periods of time is somewhat concerning and steps to mitigate its downsides should likely be taken. I haven't seen proof it causes damage by itself though, only amplifying or allowing, I can't imagine it's not involved in adaptation to exercise though.

Some additional things that might be worth adding on the benefits side somewhere.

Social status and demographic effects of the kappa opioid receptor: a PET imaging study with a novel agonist radiotracer in healthy volunteers.

There was an inverse correlation between social status and KOR levels that was largely specific to the reward/aversion (e.g., saliency) areas of the brain. This finding suggests the KOR system may act as a mediator for the negative effects of social behaviors in humans.

Common drugs of abuse when abused frequently lead to upregulation of KOR, either due to direct opioidergic effects or possibly through dopamine-MOR heteromer. Possibility as a general anti-addiction drug:

KOR Control over Addiction Processing: An Exploration of the Mesolimbic Dopamine Pathway.

TLDR: AMPK activation + TLR4/NF-κB inhibition as possible protection. Some of the downstream pathways might be good as well.

Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4/NF-κB pathway

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Also possible theoretical cardiotoxicity risk (NSVT and is asymptomatic), but otherwise no reports of any notable symptoms from the community

Credit to neochine, brenden.henry and XYZ for the information on nor-BNI

Lion’s Mane (Erinacines and Hericinones)

Daily intake of erinacineE should downregulate κ-opioid receptors because chronic κ-opioid receptor activation disinhibits dopamine release. κ-opioid activation is NOT recommended for DPDR however as it can exacerbate dissociation. Theoretically, mirtazapine/mianserin, a κ-opioid receptor partial agonist, should also work but is not ideal for various reasons. Erinacines also upregulate NGF and BDNF, which make it a potent neurogenic. Erinacines are both trkA and trkB agonists.

Erinacines

Erinacine A

Action: Potent inducer of nerve-growth-factor (NGF) synthesis in astrocytes/PC12 cells via ERK1/2→CREB signaling; also raises central catecholamine levels in rats. sciencedirect.comen.wikipedia.org

Erinacines B & C

Action: Strong stimulators of NGF production in cultured H. erinaceus mycelial extracts (in vitro), with potency A > B ≈ C; mechanism presumed similar to A but not fully dissected. en.wikipedia.orgsciencedirect.com

Erinacine E

Action: Direct agonist at κ-opioid receptors (in vitro), tying into potential neuromodulatory and analgesic effects. en.wikipedia.org

Erinacine S

Action: Not a direct target effector but notable for crossing the blood–brain barrier in vivo, confirming CNS bioavailability. en.wikipedia.orgfrontiersin.org

Erinacines D, F, G, H, I, Q, U, etc.

Action: Isolated chemically but mechanisms of action have not yet been reported in the literature.

Hericenones

Hericenones C–E & H

Action: Stimulate NGF synthesis and upregulate NGF gene expression in astroglial models via activation of the protein-kinase-A (PKA) pathway; potency varies with fatty-acid chain unsaturation (E > D > C). pmc.ncbi.nlm.nih.gov

Hericenone B

Action: Inhibits collagen-induced platelet aggregation by blocking upstream arachidonic-acid release—an anti-platelet mechanism distinct from neurotrophic effects. floydfungi.ch

Hericenones A, F, G, etc.

Action: Detected in fruiting bodies but no specific MOA has been elucidated beyond general NGF-stimulation attributed to the terpenoid class.

There is some preliminary evidence that erinacenes act as indirect CB1 PAMs by increasing Lipoxin A4 which is a CB1 PAM itself.

Erinacine S from Hericium erinaceus mycelium promotes neuronal regeneration by inducing neurosteroids accumulation

Be careful with lion’s mane however as it is hypothesised to be a moderately potent 5α-reductase inhibitor (NOT recommended for PFS or PSSD).

Modafinil and Methylphenidate

Both are decent NDRIs, but there are some concerns surrounding neurotoxicity in rats/mice with methylphenidate (although safer than every other stimulant by far). Bone loss is unfortunately a possibility with modafinil, its analogs and NRIs in general. 25-100 mg modafinil/analogs like 4-Cl-modafinil (NDRI RC) is useful for disinhibiting dopamine release downstream. The analogs are more effective than regular modafinil, but the differences are minor. Armodafinil is the alternative analog that stands out for also being a D2 partial agonist in vivo. This family of chemicals unfortunately builds tolerance for most people. Modafinil may upregulate VMAT2 significantly.

The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.

There are studies demonstrating that methylphenidate and other DRIs like modafinil are neuroprotective in models of amphetamine neurotoxicity because they limit uptake of amphetamine in to the presynaptic neuron, which limits the effect of amphetamine in the first place. Methylphenidate exerts neuroprotective effects through the AMPK signaling pathway.

In fact, there is evidence that methylphenidate exposure at doses relevant to human treatment can also induce loss of dopaminergic neurons and microglial activation in mice.

It's clear that methylphenidate is less toxic than amphetamine, but it's still not clear that methylphenidate isn't toxic to dopaminergic neurons nor is it clear that amphetamine is toxic in humans at therapeutic dosages. At abuse-level dosages, all bets are off, of course.

As for amphetamine neurotoxicity, unfortunately most of the research dollars go toward methamphetamine neurotoxicity these days. However, many of the core mechanisms for neurotoxicity are probably shared between those two.

Methylphenidate also has indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the VMAT2 protein.

This paper summarizes much of our current understanding of the various mechanisms.

Early Methylphenidate Administration to Young Rats Causes a Persistent Reduction in the Density of Striatal Dopamine Transporters

Long-Term Methylphenidate Treatment Causes Increased Superoxide Dismutase Activity and Unchanged Lipid Peroxidation in Rat Brain

Acute and sub-chronic functional neurotoxicity of methylphenidate on neural networks in vitro

Prescription Stimulant-Induced Neurotoxicity: Mechanisms, outcomes, and relevance to ADHD

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Etifoxine

Some hepatotoxicity concerns; but can be used for neurosteroid production. Another alternative would be microdosing fluoxetine/fluvoxamine for σ1 agonism and neurosteroid production. Neurosteroids like allopregnanolone can be downregulated in depression, anxiety and related disorders.

Allopregnanolone is anxiolytic and pro-dopaminergic by reinstating tyrosine hydroxylase immunoreactive neurons in Parkinson’s model mice. Allopregnanolone levels can also be increased by PPARα activators like β-caryophyllene.

Flavanones

Flavanones, a subclass of flavonoids, are natural compounds found predominantly in citrus fruits such as oranges, grapefruits, lemons, and limes. These compounds have garnered significant attention due to their potential health benefits, which stem from their antioxidant, anti-inflammatory, and antimicrobial properties. They have also been shown to maximize androgen synthesis in the testes.

Some studies suggest that flavanones may play a role in cancer prevention. Their antioxidant and anti-inflammatory properties help protect cells from DNA damage and inhibit the growth of cancer cells. Research has indicated that a diet rich in flavanones may reduce the risk of certain cancers, including breast, colon, and lung cancer.

Emerging research also indicates that flavanones may have neuroprotective benefits, helping to protect the brain from age-related cognitive decline and neurodegenerative diseases such as Alzheimer's and Parkinson's. Their antioxidant and anti-inflammatory properties are believed to contribute to these protective effects.

Inosine

Raises ATP levels along with other mechanisms. Besides raising ATP, the ingredients in Cardenosine have been studied separately over a period of several decades.

Those ingredients and have been found to possess a number of desirable properties - including anti-inflammatory, anti-serotonin, pro-dopamine, anti-glucocorticoid, anti-inflammatory, anti-endotoxin, anti-viral, anti-mutagenic, anti-microbial, anti-cancer, anxiolytic, anti-depressant, cardioprotective, anti-ischemic, neuroprotective, and generally anti-aging.

IN Insulin

Insulin can improve synaptic plasticity, which is crucial for learning and memory. This is achieved through its action on insulin receptors in the brain, particularly in the hippocampus, a region critical for memory formation, and also through mTOR activation.

Insulin has been shown to enhance LTP, a process that strengthens synapses based on recent patterns of activity, thereby supporting memory storage.

Aside from that, insulin facilitates the uptake of glucose into neurons, providing the necessary energy for proper brain function. Efficient glucose metabolism is vital for cognitive processes and helps maintain energy balance in the brain, ensuring that neurons receive adequate fuel for optimal functioning. As a result, it is considered neuroprotective and prevents cell apoptosis.

Insulin has also been shown to reduce the accumulation of amyloid-beta plaques, which are associated with Alzheimer’s disease. This potentially slows down cognitive decline in Alzheimer's patients.

It also modulates dopamine circuitry, and has many other benefits.

Melatonin

The sleep hormone has many benefits. Within the hippocampus it's been shown to normalize amphetamine-induced reductions in numerous proteins which are crucial for learning and memory (e.g. PSD-95, CaMKII, and the NMDA receptor) as well as normalizing increased expression of α‐synuclein, which is a protein associated with Parkinsonism. It also increases plasma Ca2+ and Mg2+ through VDR binding.

It up-regulates antioxidant enzymes such as superoxide dismutase, which is important since metabolism and auto-oxidation of dopamine generates reactive oxygen species

It normalizes amphetamine-induced alterations in the dopaminergic system, such as decreases in both VMAT2 expression and tyrosine hydroxylase phosphorylation, both of which will reduce the dopamine reserves.

Even at nanomolar concentrations it can normalize amphetamine-induced up-regulation of pro-inflammatory mediators (e.g. IL‐1β, IL‐6, TNF-α, and NF-κB).

Through a melatonin receptor dependent pathway, melatonin upregulates calpastatin, which is a calpain inhibitor. Calpain is a protease (i.e. it breaks down proteins) which is involved in apoptosis (i.e. programmed cell death) and it is upregulated by amphetamine (which also inhibits calpastatin). The upshot of this is that melatonin can prevent amphetamine-induced degeneration in the substantia nigra (a brain region harboring dopaminergic neurons which dies in Parkinsonism).

Caffeine

5α-reductase booster, adenosine antagonist and upregulates dopamine receptors downstream. Or 15 mg istradefylline IN (A2A adenosine receptor antagonist that is overall superior to caffeine and upregulates D2-D3 downstream).

Cordycepin is also similar and functions as a good alternative in some cases. In the human body, about 84% of ingested caffeine is broken down in the liver, with paraxanthine being the primary metabolite. Coffee is superior to caffeine due to the presence of beneficial alkaloids (ie. beta carbolines) missing in caffeine supplements. Caffeine also synergizes with various other drugs.

L-carnitine L-tartrate

Fat oxidation, boosts testosterone and other benefits. Some reports of it helping with PSSD symptoms.

L-carnosine

Antioxidant that helps with glutamatergic transmission, and inhibits dopamine-beta-hydroxylase. Especially useful for OCD.

Acetyl L-carnitine

Upregulates D2 and D3, increases acetylcholine downstream, and many other benefits. ALCAR is neuroprotective via ILK-related MMP-9 activity.

“In relation to ΔFosB, ALCAR donates acetyl groups to deacetylated proteins which acts similar to a HDAC inhibitor (HDACi). ALCAR increases BDNF and therefore ERK1/2 (a slow transcription factor) and through that may enhance the sensitivity of D1. Strange this source and this source display a D1 upregulation beyond baseline, with no changes to D2 receptor density. This may be due to NMDA activation as explained here and ALCAR has been shown to change glutamate activity long term. This upregulation of D1 activity leads to a continuation of PKA --≥ CREB activation and thus a positive feedback loop with DARPP-32, phosphorylating it at Thr34 over Thr75, when Thr75 phosphorylation inhibits PKA as evidenced here resulting in a tyrosine hydroxylase upregulation and upregulated dopamine output long-term with no tolerance as ALCAR doesn't activate ΔFosB or CDK5, and therefore upregulates D1 differently than cocaine.

Now I'd like to dispel some rumors about ALCAR. It is safe. There isn't anything proving it upregulates TMAO, which isn't healthy, however it may be hydrolyzed to L-carnitine and SCFA by the esterase HocS (hydrolase of O-acylcarnitine, short-chains) and there's some evidence that L-carnitine increases TMAO such as this and this. But if you're a hypochondriac, and let's be honest we all are at times, fish oil and riboflavin may prevent this and you should probably be taking that anyways for the health benefits. And ALCAR was well tolerated in a trial consisting of 358 Alzheimer's patients. Also some sources show it's protective of the heart, such as this.

If you want more advice on ALCAR, it appears to have dose-dependent effects on anxiety and saturates the mitochondria at just 1500 mg, and I discuss that more in the oral bioavailability post. I believe there was another post on ALCAR and anxiety saying 500 mg or 1000 mg either decreased or increased anxiety.” - u/sirsadalot

ALCAR has also been shown to upregulate mGluR2 through an HDAC2 pathway. Direct HDAC inhibitors do as well.

Effects of Long-term Acetyl-L-carnitine Administration in Rats: I. Increased Dopamine Output in Mesocorticolimbic Areas and Protection toward Acute Stress Exposure

The complete guide to dopamine and psychostimulants : u/sirsadalot

Acetyl-l-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis

Effects of Long-term Acetyl-L-carnitine Administration in Rats: I. Increased Dopamine Output in Mesocorticolimbic Areas and Protection toward Acute Stress Exposure

Huperzine A

Huperzine A is a potent, reversible inhibitor of acetylcholinesterase, an enzyme responsible for breaking down acetylcholine (ACh) in the synaptic cleft. By inhibiting AChE, Huperzine A increases the levels of acetylcholine in the brain, enhancing cholinergic transmission. This is particularly beneficial for memory and learning, as acetylcholine is a crucial neurotransmitter involved in these cognitive processes.

Huperzine A also weakly blocks NMDA (N-methyl-D-aspartate) receptors, which are involved in synaptic plasticity and memory formation. It can help balance excitatory neurotransmission by reducing excessive activation of these receptors, which can be neurotoxic.

Some studies suggest that Huperzine A may promote neurogenesis, the process of generating new neurons, particularly in the hippocampus. This can contribute to improved cognitive function and memory.

Huperzine A has been shown to reduce the accumulation of beta-amyloid plaques, which are associated with Alzheimer's disease. This action may help in slowing the progression of neurodegenerative conditions.

It also supports mitochondrial function, enhancing the production of ATP (adenosine triphosphate), which provides energy for cellular processes. Improved mitochondrial function helps maintain neuronal health and function.

Finally, it has been shown to have anti-inflammatory properties that help reduce neuroinflammation, which is a common feature in many neurodegenerative diseases and cognitive disorders.

Rosemary and Carnosic Acid

Increases the expression of VDR (vitamin D receptor), via carnosic acid, which in turn makes more dopamine. Carnosic acid also happens to be a potent antioxidant. Lemon balm which contains rosmarinic acid is a potent GABAT inhibitor which is potently anxiolytic.

There seems to be a correlation between dysfunctional VDR and PSSD incidence when taking SRIs, so if you have a VDR mutation avoid taking any SSRI.

Underexpressed VDR leads to hyperexpression of ERα relative to ERβ which increases mood swings and emotional behavior. This is because ERα mediates a lot of the stereotypes of the “high estrogen” phenotype. ERα directly upregulates mGluR5 which is the receptor involved in OCD. ERα also upregulates the mesolimbic dopamine pathways so potently, making people overall way more hedonistic and hypersexual / hyper-emotional. As for why ERα signaling was too high before PSSD, it's likely due to either vitamin D3 deficiency or an abnormal VDR allele as mentioned earlier. This could also be why people often crash miserably from vitamin D3 supplementation, since it reduces ERα signaling even further.

Sulbutiamine and Other Vitamin B1 Derivatives

Upregulates D2 and more:

Myricetin

At human equivalent doses of 200-600 mg, myricetin has a potent endurance enhancing effect, doubling endurance in 3 weeks for rodents in one study, via multiple mechanisms (PGC1α, PGC1b, SIRT1, ERRa, Myoglobin, Troponin1, etc). It is one of the only known polyphenols with such a potent physically enhancing effect.

In addition, myricetin is a nootropic by modulating CAMKII, BDNF, NGF, TrkB and COMT (inhibitor), and it also has been shown in studies to be anxiolytic, antidepressant, and anti-stress.

URB597

FAAH-inhibition decreases breakdown of anandamide. Anandamide, an endocannabinoid, has been shown to influence the release of dopamine in the brain. However, URB597 has been shown to lower tyrosine hydroxylase ironically, which leads to a net reduction in dopamine. Anandamide is anti-anhedonic by itself however, and is also great for pain.

Dose range seems to be around 1-6 mg. Keep in mind it can cause insulin resistance unfortunately.

SkQ1

Mitochondrial antioxidant related to coenzyme Q10 but more bioavailable. Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10.

Dose is around 50-200 mcg intranasally.

Peptides

Introducing Peptide Mastery, decoded from over 200 scientific research papers, giving you the most in-depth and accurate knowledge of peptides ever made available to the public

A cycle of MOTS-c might prove useful for ME/CFS, PSSD and possibly anhedonia:

ARA-290 might be interesting as well. Small Fiber Neuropathy and ARA-290 Results

VIP is a peptide that has anti-inflammatory and immunomodulatory effects. It is used to treat CIRS, a chronic inflammatory condition, according to the Shoemaker protocol. It may also have other benefits, such as blocking COVID19, repairing the gut, regulating prolactin, and balancing the circadian rhythm. It is produced in the gut, pancreas, and brain, and acts on class II G protein-coupled receptors.

30 day cycle of IM BPC-157 at 100-1000 mcg - some reports of it curing anhedonia but oral arginine salt has been reported to cause anhedonia (and sometimes acetate), therefore this is high-risk. Can also help tinnitus.

The 13+ Benefits Of BPC-157 (Body Protective Compound) and sources

IM Cerebrolysin cycle (or intranasally too at 0.10-0.50ml daily) –

Effective treatment for Neurocognitive Disorders with Cerebrolysin®

Misc. Notes from One Year of Cerebrolysin: One of the Strongest Nootropics

A 15-30 day cycle of IN PE-22-28 at 200-800 mcg (TREK-1 blocker) would be highly recommended for depression, but may build tolerance unfortunately.

PE-22-28 with phenelzine

PE-22-28 Anecdotes

Kisspeptin is also interesting. It improved memory and sexual function in this study. Worth a try for PSSD.

Early research on DNSP-11 peptide shows pro-dopaminergic action through GDNF upregulation. Ibogaine upregulates GDNF expression through Ret phosphorylation, while DNSP-11 mimics GDNF by directly activating its pathways. Though both act on GDNF signaling, they do so in distinct ways: ibogaine induces GDNF production, while DNSP-11 bypasses receptors and activates the pathways directly.

DNSP-11 is the torque wrench: it’s literally a fragment of pro-GDNF that, once inside dopaminergic neurons, phosphorylates ERK1/2 to drive survival and growth - even in cells lacking the usual GFRα1/RET receptor complex.

Ibogaine, however, doesn’t bind GDNF receptors directly. Instead, it upregulates endogenous GDNF expression in the ventral tegmental area, which then engages the canonical GFRα1/RET pathway to produce anti-addictive and neuroprotective effects.

Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data - PMC

Peptides for Mood Improvement

1. α-casozepine (Sold through the patent: Lactium®) is a bioactive peptide originating from a S1 casein, α protein in cow’s milk, which has an affinity for GABA receptors in the brain.

2. Astressin BL reduces the synthesis of ACTH and cortisol.

3. BPC-157 may influence essential functions and counteract the dysfunction underlying schizophrenia-like symptoms. It counteracts the symptoms of Porsolt’s depression model and the chronic unpredictable stress depression model; it also fully counteracts all manifestations of serotonin syndrome and induces acute and chronic serotonin release in specific brain nigrostriatal regions.

4. CBD3 has been shown to reduce pain behavior in inflammatory and neuropathic pain models.

5. Cerebrolysin. Treatments with Cerebrolysin also led to medium anxiolytic outcome, but, in contrast to Cortexin, it was less noticeable. After 2 weeks of, symptoms of Treatment-resistant depression were more improved in group B (those who did Cerebrolysin treatments) compare with group A (who were given antidepressants). After treatment with cerebrolysin, 62.8% of subjects with autism showed signs of improvement.

6. Dilept is able to eliminate the PSI deficiency in the acoustic startle reflex test on the model of glutamate-negative psychosis in rats can be considered as a prognostic sign for the drug efficiency with respect to the negative and cognitive symptoms of schizophrenia and autism manifestations.

7. DSIP is mainly prescribed for the treatment of pain conditions, alcohol and opioid withdrawal, CRH and stress-related symptoms, low testosterone (via stimulation of LH), and even sometimes as an antioxidant and antioncogenic protein. It modulates on central regulatory processes, the modulating influence on the activity of GABAergic, glutamatergic, and other neuronal systems.

8. Glutathione prevented depression under stress. It improved symptoms of schizophrenia in clinical studies. Oral and transdermal glutathione are being developed to restore levels in autistic children.

9. GLYX-13 behaves as a weak NMDA agonist. Neuroprotective to cortical neurons against oxygen/glucose deprivation.

10. GSB-106 is classed as a psychostimulant, anti-opioid, synaptogenic, neurogenic, neuroprotective antidepressant, weakly antidiabetic neuroplasticity enhancer.

11. Humanin/Humanin G exerted an anxiolytic-like activity as a FPR2 agonist.

12. Met-enkephalin is a δ & μ opioid agonist. Inhibits enkephalin degradation (but it is predominately used as a anticancer treatment).

13. MIF-1 increased the brain regions that are critically involved in the regulation of mood, anxiety, depression, and memory.

14. Kisspeptin enhanced activation of the amygdala in response to bonding images correlated with improvements in positive mood. The data demonstrates that kisspeptin enhanced activity in key “romance and bonding” structures in response to viewing couple-bonding images and that this correlated with improved positive mood.

15. Noopept It improved anxiety, irritability, mood, energy, apathy, sleep disturbances, daytime drowsiness, and headache, some of it within the first week, but not after 56 days.

16. Nonapeptide-1 is a dopamine uptake inhibitor.

17. Oxytocin/(Carbetocin) positively (albeit mildly) modifies hypervigilance toward threats, extreme mistrust, and altered non-verbal social behavior. Might offset some learning deficits caused by stress. Intranasally administered oxytocin was found to strengthen avoidance behavior to social threat cues and, thus, to normalize fast action tendencies in borderline personality disorder (BPD) patients. Oxytocin has become a rising topic in BPD research and is currently tested as an adjuvant in the treatment of BPD.

18. PE-22-28 (Spadin) This peptide that mimics the natural human peptide spadin, that connects with TREK-1 which is located in the brain and responsible for learning, mood, and memory. PE-22-28 is being researched as a treatment to help depression, leaning, recovery from stroke, and diseases such as Alzheimer’s.

19. Pinealon positively changes the epigenetic expression 5-tryptophan hydroxylase (5-TH).

20. Rubiscolin-6 has anxiolytic effects by activating sigma1 and dopamine D1 receptors.

21. Selank moderates the GABAergic system to the genetic levels. Lower stress levels. positively influences memory and learning. An enkephalinase inhibitor.

22. Neuropeptide S was shown to produce anxiolytic-like effects in the brains exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety.

23. Tesamorelin raises GABA levels. (GHRH analogues in general are effective in suppressing seizures by activating GABA receptors).

24. Thymosin alpha-1 may offer improved pain relief. It acts directly at the sight of inflammation to reduce the production of cytokines and other molecules (e.g. TNF-alpha, IL-1beta, etc.) that trigger pain in the first place.

25. Thyrotropin TRH could become a mainstay of the fight against opioid overdose because it provides the same benefits of naloxone with fewer side effects. Doctors who administered TRH directly into the spines of patients suffering from severe depression. Five of the eight patients tested responded favorably, showing a 50% or greater reduction in the symptoms of depression as well as a significant reduction in thoughts of suicide. It appears to be more effective in women with a specific kind of depression that had no symptoms of anxiety. Research in bipolar patients has shown that TRH has more profound effects on depression when given at night.

NSI-189

At 40 mg sublingually, it is a neurogenic and mitochondrial enhancer. Some reports of it curing anhedonia. But also few reports of it causing side effects like paresthesia that CAN be permanent in rare cases. It is also hypothesized by some to increase aldosterone levels which reduces tolerance to racetams. Here is a compilation of all the anecdotes on it.

Mechanism of action (predicted according to leaked investor presentation)

-Increases BDNF

-Increases Cullin

-Increases F-box

-Increases GDNF

-Increases Skp

-Increases VEGF

Advanced

-NSI-189 is a benzylpiperizine-aminiopyridine.

-It may pass the blood-brain barrier.

-In humans in vitro as well as rodents in vivo, NSI-189 stimulates neurogenesis in hippocampal slices (specifically profound in the dentate gyrus).

-In vivo, NSI-189 improves the left side of the hippocampus.

-It reportedly has no effects on monoamine transporters/receptors or amino acid targets.

-After stroke, NSI-189 may increase Ki67 and MAP2.

-Paradoxically reduced central and peripheral neuropathy in animal models which would result in lower paresthesias.

-As well as increasing BDNF, GDNF and VEGF, NSI-189 works on the Skp, Cullin, F-box containing complex (or SCF complex).

Possible Other Mechanisms of Action (Speculation)

-Increase hippocampal size (by 20%)

-Improves glucocorticoid resistance (possibly modulating aldosterone receptors)

-TRPV1 antagonist

Some of this came from the leaked investor presentation but other is speculation based on target predictions:

Black Seed Oil (Nigella Sativa)

Thymoquinone in nigella sativa is an HDAC inhibitor and a powerful antioxidant. The higher the thymoquinone % the better the extract usually. Triquetra has the most potent extract on the market. Oil should preferably be cold-pressed. It is a weak MAOI as well, so not a good idea to combine with SRIs in high doses, but low doses are fine.

Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety

β-caryophyllene

It is a CB2 agonist which upregulates 5-HT2A (helps with reducing tolerance to psychedelics and antidepressants in the short-term), enhances dopaminergic transmission downstream, and provides anti-inflammatory and analgesic effects. Also a PPARα activator (other PPARa activators are pinealon, PQQ, DHA, Na-R-ALA, R-ALA, DHEA, L-carnitine, fasting, PEA, β-caryophyllene and exercise).

Ideal cannabis strain profile is CBD + CBG + β-caryophyllene + limonene + linalool (+ myrcene + pinene) without THC as it is neurotoxic and damages the hippocampus in the long-term.

Palmitoylethanolamide (PEA)

PEA is endocannabinoid-like and anti-inflammatory. Good for pain too, and increases allopregnanolone levels downstream. Its bioavailability is enhanced greatly when taken alongside vitamin D3 and Alpha Lipoic Acid (R-ALA), so it is ideal to take all three together if you plan on trying it out. Good for reversing stimulant/amphetamine tolerance.

Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity

Palmitoylethanolamide counteracts brain fog improving depressive‐like behavior in obese mice: Possible role of synaptic plasticity and neurogenesis

Palmitoylethanolamide Modulates GPR55 Receptor Signaling in the Ventral Hippocampus to Regulate Mesolimbic Dopamine Activity, Social Interaction, and Memory Processing

NAC/NACET

NAC is a very important antioxidant that has antidepressant effects, is a hepatoprotectant and is the precursor to glutathione (main antioxidant in the liver and body in general). It modulates AMPA along with many other targets in the brain that benefit all psychiatric illnesses. Happens to be a mGluR modulator as well (not entirely understood). It also chelates heavy metals so can help with treating heavy metal toxicity, but this also deplete zinc, copper and other important trace metals.

If you take NAC for too long and end up chelating most of your copper, you can develop a DAO deficiency which will lead to histamine intolerance. NAC is also processed by the SUOX pathway so proper molybdenum (depleted by NAC itself) status is also important. NAC can also protect already existing cancers in the body, this is an issue with all potent antioxidants. NAC also messes with the HPA axis long-term by upregulating ACTH receptors and downregulating glucocorticoid receptors in the pituitary. In summary, it’s best used acutely like during or after a respiratory illness especially or any illness in general. Reduced/liposomal glutathione is safer to use long-term. Ideal dose is between 500 and 3000 mg daily for 1-3 month cycles.

Sarcosine + NAC/NACET

This combo has been proven to be effective in treating many cases of anhedonia and schizophrenia symptoms. You can also replace sarcosine with TMG or DMG, or perhaps neboglamine theoretically (since it’s a NMDA glycine site PAM).

Opioidergic system dysfunction is implicated in depersonalization/derealization disorder (DPDR). NMDA modulators like NAC/NACET, glycine, piracetam, sarcosine, neboglamine and maybe fasoracetam too are likely helpful for DPDR. Avoid NMDA antagonists if you have DPDR.

Effect of naloxone therapy on depersonalization

Sarcosine Therapy - A New Complementary Direction for Schizophrenia Treatment?

Recovery after 3 years: What helped

Glycine/Sarcosine/NAC trial

D-Serine: The holy grail of cognitive enhancers?

Neboglamine and the concept of glutamate fine tuning

Trimethylglycine + L-tryptophan

Taken together at the same time orally produces a mild psychedelic effect about 30 minutes later.

Tropisetron

5-HT3 antagonist and α7 nicotinic receptor agonist. It is a very broadly applicable drug, showing promise for OCD, and fibromyalgia. Also anxiety, but only mildly. It reports strong antidepressant effects in rodent models, which correlates with other 5-HT3 antagonists. 5-HT3 antagonism is a desirable target, as it isn't associated with side effects or tolerance and appears neuroprotective and pro-cognitive potentially due to enhancing acetylcholine release. An atypical SSRI and 5-HT3 antagonist, vortioxetine was also shown to improve cognition in the majorly depressed, an unexpected outcome for most antidepressants. It has been reported to help with HPPD.

Piracetam

One of the most well known nootropics of all time. It is an AMPA agonist mainly, and does other stuff. It works for HPPD according to some reports; possibly due to increases in dlPFC delay cell firing modulating visual inputs.

Piracetam enhances cholinergic neurotransmission by increasing the density of muscarinic acetylcholine receptors, particularly in the hippocampus. This is important for learning and memory processes.

It also improves the fluidity of neuronal cell membranes. This can enhance the function of membrane-bound proteins, such as receptors and ion channels, leading to better signal transduction and overall neuronal function. Piracetam improves microcirculation in the brain by increasing red blood cell deformability and reducing blood viscosity, which leads to better blood flow and oxygen delivery to brain tissues. This enhances the brain's use of oxygen and glucose, which can improve energy production and support cognitive functions, especially under conditions of hypoxia (low oxygen levels).

Piracetam has neuroprotective properties that help protect neurons from damage caused by hypoxia, toxins, and other harmful conditions. This may be due to its ability to stabilize cell membranes and reduce oxidative stress.

Noopept

WIP

Stay away from Noopept (omberacetam) if you have HPPD.

Phenylpiracetam

Increases dopamine receptor density immediately by 16%, 29%, and 62% for D1, D2, and D3 respectively. Also upregulates GABAA receptors by 25%. Aside from that, it has pro-cognitive effects and is mildly stimulating due to DRI action. Racemic phenylpiracetam binds to nAChRs (IC50 = 5.86 uM) and increases binding/upregulates (as measured by Bmax) nAChRs and NMDA receptors.

Kavalactones

The major kavalactones (except for desmethoxyyangonin) have been shown to potentiate the activity of GABAA receptors, which may underlie the anxiolytic and sedative properties of kava. Further, inhibition of the reuptake of norepinephrine and dopamine, binding to the CB1 receptor, inhibition of voltage-gated sodium and calcium channels, and MAOB reversible inhibition are additional pharmacological actions that have been reported for kavalactones. Kavalactone type compounds may help protect against high glucose induced cell damage.

Methylene Blue

Methylene blue is an electron acceptor, the only one of its kind. It works through improving mitochondrial function, and inhibiting MAOA at 1 mg/kg +. Methylene blue is especially useful for bipolar disorders. Daily consumption of methylene blue reduces attentional deficits and dopamine reduction in a 6-OHDA model of Parkinson's disease, and happens to exert neuroprotective effects against traumatic brain injuries (should therefore be synergistic with something like 9-methyl-β-carboline or Cerebrolysin). It also happens to be a good antimicrobial, making it useful for treating SIBO and SIFO. This book is a good guide to using it therapeutically. There are, however, some concerns with using it in the long term like inhibiting nitric oxide synthase and increasing hydrogen peroxide. 1-15 mg is the recommended dose. Since it is a MAOI, do not stack with SRIs.

ACD-856

ACD-856 is a neurogenesis promoter, which means it activates the pathways that create new neurons in the brain. It is in clinical phase 3 trials (which means it has passed safety trials on humans and the FDA is evaluating how the new drug works in comparison to existing medications) for Alzheimer’s. The majority of users say they feel like they're looking at the world through the eyes of a child in terms of wonder and the ability to think clearly. Any previously existing brain fog is decimated and the verbal flow is incredible. Words come to the mind much easier, and vision is sharp(er). Some report odd psychedelic-like visual disturbances, and this probably has to do with 5-HT2A upregulation and glutamatergic pathways, and it seems to be basically mimicking psychedelic drugs without the distinct hallucinations or the messy thought patterns that can often be nonsensical.

Neuroplasticity is the ability of the brain to form new connections responsible for actions and thoughts. Someone with poor neuroplasticity will tend to be depressed and/or obsessive, unable to think and it also affects how you react to drugs in general (makes them weaker because TrkB controls serotonin and dopamine downstream, which means it acts above them as a master regulator). Neuroplasticity is also the most important concept for learning and cognition; but unfortunately a lot consider dopamine to be the only useful target. Focus, mood and cognition are all controlled by multiple factors ranging from serotonin to even the opioid system. Most cognitively enhancing drugs and all antidepressants actually do induce neurogenesis. But the difference in neurogenesis induced from TrkB activation between SSRIs and a psychedelic like psilocin at an equivalent dose, is around a factor of 1000. Notably, studies have also demonstrated that ACD-856 facilitates long-term potentiation (LTP) in hippocampal slices and increases brain acetylcholine levels in awake rats.

ACD-856 acts quite a bit differently than psychedelics, with a half life of 24 hours which is really long for one, and two it does allosterically modulate the Trk receptors vastly differently. It increases nerve growth factor through trkA positive allosteric modulation, which is the protein that regrows target neurons. Hearing loss and tinnitus are improved with NGF. When neuroplasticity is induced, ingrained depressive/obsessive thought patterns and habits are easier to break. Anecdotally, users report that they are more introspective in a positive way, and more in the moment when they need to be. Negative irrational thoughts are essentially ignored easily on ACD-856 and replaced with more positive thought patterns with practice/CBT. It’s been considered life changing according to countless anecdotes.

Minerals, Hormones & Supplements

Minerals

Magnesium

Magnesium N-Acetyl Taurinate has shown superior brain tissue absorption compared to most other forms (in rodents), including Magnesium L-threonate. There are two patented formulations called ‘ATA Mag’ and ‘TauroMag’. The taurinate compound has also shown positive benefits to synaptic neuroplasticity in rodents. For systemic absorption, magnesium oxide reigns supreme.

Butyrate reduces cellular magnesium absorption independently of metabolic regulation in Caco-2 human colon cells

Magnesium can influence the dopaminergic system in several ways:

Magnesium can block NMDA receptors, a type of glutamate receptor. Overactivation of NMDA receptors can lead to excitotoxicity and neuronal damage, which can in turn affect dopamine neurons.
Magnesium is a cofactor for tyrosine hydroxylase, the enzyme responsible for the conversion of tyrosine to L-DOPA, a precursor to dopamine. Thus, adequate magnesium levels are needed for the synthesis of dopamine.
By blocking NMDA receptors, magnesium may provide neuroprotective effects for dopamine neurons, potentially reducing the risk of neurodegenerative disorders like Parkinson's disease, which is characterized by the loss of dopamine neurons.

Magnesium is also a vital mineral that plays numerous essential roles in the human body aside from the CNS and the brain. Its functions are diverse and impact many physiological processes:

Magnesium is a critical component of the bone matrix and is essential for bone health. It works in concert with calcium and vitamin D to maintain strong bones and prevent conditions like osteoporosis.
Adequate magnesium levels are necessary for proper bone mineral density.
Magnesium acts as a natural calcium blocker to help muscles relax. In muscles, calcium binds to proteins such as troponin C and myosin. This process changes the shape of these proteins, leading to muscle contraction. Magnesium competes with calcium for these same binding spots to help relax the muscles.
By aiding in muscle relaxation, magnesium can help prevent or alleviate muscle cramps.
Magnesium plays a critical role in neurotransmitter release, which affects nerve function throughout the body.
It helps maintain normal nerve function and keeps the nervous system sending messages smoothly.
Magnesium is required for the activation of adenosine triphosphate (ATP), the energy currency of the cell. This makes it vital for energy production at the cellular level.
Magnesium contributes to maintaining a normal heart rhythm and is used to treat certain heart conditions.
It helps to dilate blood vessels, which can lower blood pressure and reduce the risk of hypertension.
Magnesium plays a role in carbohydrate metabolism and influences the release and activity of insulin, the hormone that controls blood sugar levels.
Adequate magnesium intake is linked to a lower risk of type 2 diabetes.
It is involved in protein production and the synthesis of nucleic acids like DNA and RNA.
Magnesium may have a calming effect on the nervous system and is sometimes used to promote relaxation and improve sleep quality.
Magnesium acts as a cofactor in over 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation.
Magnesium aids in the digestion of food and the absorption of nutrients such as calcium, potassium, phosphorus, and sodium.
Magnesium is a key electrolyte involved in maintaining the body's fluid balance.
Magnesium dose-dependently decreases blood pressure in hypertensives, with a less clear relationship for normotensives. Which may be attributed to its effect as a calcium channel blocker.

Lithium

Lithium orotate or equivalent for lithium carbonate - around 18.8% of the carbonate molecule is lithium, while around 3.7% of the orotate molecule is lithium (therefore there is 5 mg of lithium in 135 mg of orotate salt). Despite the orotate salt having lower elemental lithium per weight, it has 3x higher brain availability. Hence, orotate might produce less peripheral side effects but should potentiate psychedelics more as compared to equivalent elemental dose of carbonate, even slightly lower elemental dose of orotate might be more serotonergic than carbonate. Ideal dose is ≤30 mg of elemental lithium for unipolar patients. Benefits include longevity, positive effects on serotonin and dopamine system and multiple other mechanisms listed below:

Lithium inhibits the enzyme inositol monophosphatase, leading to a decrease in the availability of inositol, a substance required for the production of certain secondary messengers involved in the transmission of signals in the brain. Supplement with 1-20 g of inositol to make up for the depletion as inositol in high doses is helpful for OCD and depression in some cases, but can make bipolar mood swings worse theoretically.
Lithium inhibits glycogen synthase kinase-3 (GSK3), an enzyme involved in various cellular functions, including cell division and survival. This inhibition may contribute to the mood-stabilizing effects of lithium, but can also be pro-anhedonia for some people.
Lithium has been found to increase the expression of Bcl2, a protein that protects neurons from death. It may also enhance neurogenesis (the growth of new neurons) and increase the levels of brain-derived neurotrophic factor (BDNF), which supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses.
Lithium can influence the function and release of several neurotransmitters, including dopamine, glutamate, and serotonin. For some this is positive and for others it’s negative. See if it works well for your genetic makeup (usually COMT val/val respond well).
- Lithium may help to regulate circadian rhythms.
Lithium increases PGC-1a expression and mitochondrial biogenesis in primary bovine aortic endothelial cells
Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue
Orotate salt is more bioavailable in the brain compared to the carbonate salt
Supports the enzyme that converts some DHT into the beneficial -adiols
Improves bone and tooth strength
Attenuates glutamate (NMDA) excitotoxicity
Reduces cellular senescence
Influences circadian entrainment in at least some people, possibly by influencing both temperature and light sensitivity.
Protects the brain from general insults, and possibly extends lifespan
Reduces suicidality and violence
Lithium enhances metabolism of vitamins B9 and B12
Effective augmentation for treatment-resistant depression and OCD (especially effective with TCAs)
Potentially useful for Parkinson’s (protects dopaminergic neurons from MPTP toxicity)
AMPA agonist which is pro-cognition and mood
Lowers inflammatory cytokines IL-1B, TNFa, and increases anti inflammatory cytokines IL-2, IL-10
Lowers prostaglandins and COX2 expression. Prostaglandins are pro inflammatory mediators, and also negatively regulate dopamine
Lowers gut inflammation, and positively regulates the microbiome via GPR43
Lithium inhibits GSK3b which increases Wnt/B-Catenin signaling, which increases neurogenesis, and attenuates oxidative stress, and inflammation.
Wnt/B-Catenin is synergistic with BDNF, and SHH for neurogenesis and upregulating dopamine transcription factors and genes. Lithium would be synergistic with cerebrolysin, NSI-189, ketamine, NA-semax-amidate, etc.
Lithium can possibly improve sex hormone signaling (in the brain) by lowering NF-kB, and FoxO, and through activating PI3K/AKT. NF-kB is a negative regulator of ER, and FoxO negatively regulates ER/AR and TH (dopamine synthesis).
Lithium leads to GR-MR complex downregulation via upregulation of BAG1 which inhibits HSP-70

Do not take lithium on the same day as psychedelics. This can cause seizures due to AMPA agonism causing excitotoxicity. Ideally wait a whole week between taking lithium and the psychedelic of choice (elimination half life of lithium is around 24-48 hours depending on the study and person). Multiply by 5 for complete elimination as rule of thumb for drugs.

Zinc

Being one of the cofactors for tyrosine hydroxylase, zinc intake is beneficial for dopaminergic neurotransmission. The picolinate salt is the best type for most people, although L-methionine salt could be superior if you are an under-methylator. If you are an over-methylator on the other hand, stick to picolinate as it inhibits dopamine beta-hydroxylase which is good. Ideal dose is between 15 and 30 mg, unless you are deficient then you can go up to 50 mg.

Zinc in low doses upregulates 5α-reductase but inhibits 5α-reductase in high doses. It potentiates antidepressants due to multiple mechanisms including 5-HT1A agonism at low dose (opposite at high levels), and nAChR positive allosteric modulation (PAM).

It also modulates AR expression and function, which is useful for treating disorders such as CRPC, PFS and PSSD. Zinc is what holds your androgen receptor’s DNA-binding domain together. The AR DBD contains two Cys2–Cys2 “zinc fingers,” each chelating a Zn²⁺ ion to fold properly and grab onto androgen response elements.

Structure: remove the Zn²⁺ and the DBD unfolds—AR can’t bind DNA or drive transcription.

Regulation: low cellular zinc → reduced AR stability and activity; normal zinc levels → proper AR expression and target‐gene activation.

Overload: very high Zn²⁺ (e.g. in prostate cancer cells) can actually block AR–HSP90 interactions or nuclear translocation, dampening its activity.

In short: zinc is essential scaffolding for AR, and your zinc status dial-sets AR’s level and transcriptional power.

A role of zinc in the regulation of gene expression

Make sure to supplement with 500-2000 mcg of copper a few hours away from taking zinc if your copper levels are low (zinc depletes copper in the long-term, which is only beneficial if you have lots of copper in the blood serum).

Copper

Copper is a trace mineral that is vital for the human body, playing a role in various physiological processes. It is not recommended to supplement copper unless you are sure you are deficient in it. Copper deficiency is hard to come across and is pretty rare, unlike zinc deficiency, so supplementation is not advised unless you are confirmed deficient.

Here's an overview of its key roles:

Copper acts as a cofactor for several enzymes, known as cuproenzymes. These enzymes facilitate various biochemical reactions in different parts of the body.
Many of the enzymes that require copper are involved in oxidation-reduction (redox) reactions, essential for cellular energy production and antioxidant defenses.
Copper is involved in the absorption and transport of iron from the intestinal tract and its release from storage sites like the liver. It helps in the conversion of iron into a form that can be incorporated into hemoglobin.
Copper plays a key role in the synthesis of collagen and elastin, vital components of connective tissues. This is crucial for the health and integrity of the skin, blood vessels, and bones.
Copper is important for brain development and normal nervous system function. It is involved in myelination, the process of forming a protective sheath around nerves.
The role of copper in collagen and elastin formation is also important for maintaining the strength and flexibility of heart and blood vessels.
Copper has a role in the functioning of the immune system, although the exact mechanisms are still being studied.
Copper is a component of the antioxidant enzyme superoxide dismutase (SOD), which protects cells from damage by reactive oxygen species (ROS).
Copper is involved in the production of melanin, the pigment that gives color to the skin, hair, and eyes.
Copper enzymes are involved in cellular respiration and the production of adenosine triphosphate (ATP), the energy currency of the cell.
Copper plays a role in the metabolism of thyroid hormones, although its exact role in thyroid function is complex and involves interactions with other minerals like zinc.
Copper inhibits type 1 5α-reductase as potently as zinc and also type 2 5α-reductase unlike zinc. However, type 2 inhibition requires high dosage.

Iodine

Iodine from kelp helps maintain thyroid function, which is the gland responsible for many body functions. Make sure you take cofactors like selenium, L-tyrosine/N-acetyl-L-tyrosine, vitamin C + E and zinc. Copper is actually important too but it’s rarely advisable to supplement it so it is not advisable to supplement with unless you know you are deficient, or take copious amounts of zinc (depletes copper acutely so not recommended to take more than 30 mg zinc daily). Get thyroid and blood panels done and ideally test for all vitamins, minerals and hormones.

If you can’t get your doctor to refer you for those tests, then get lab tests done yourself at a Spectracell lab or order an Idealabs kit.

Iron

Iron metabolism dysfunction is implicated in RLS, ADHD and anhedonia. Improve ferritin levels by supplementing with Feramax or ferrous fumarate if ferritin is in the low range because iron increases oxidative stress when levels get high. Iron chelators (ie. IN deferoxamine, M30 or roxadustat) are possibly useful due to hypoxia mimetic property which increases GDNF and BDNF downstream (potentially risky long term causing anemia and hearing problems).

Iron ions are required for dopamine autoxidation, so by chelating iron you induce benefits similar to that of VMAT2 upregulation; one prevents oxidation and packaging into vesicles, while the other prevents spontaneous autoxidation. VMAT2 upregulation or iron chelation is superior to MAO inhibition for dopaminergic enhancement.

Potassium

Potassium is an essential mineral and electrolyte that plays several critical roles in the human body. Its functions are fundamental to the maintenance of normal body functions. Here’s an overview of potassium's key roles:

Potassium is crucial for maintaining proper fluid balance in the body's cells and tissues.
It helps in maintaining the electrolyte and acid-base balance in the body.
Potassium is essential for the normal contraction of muscles, including the heart muscle.
It plays a critical role in the transmission of nerve signals that affect muscle contraction and various bodily functions.
Potassium is vital for maintaining a healthy heart rhythm. Imbalances can lead to arrhythmias.
It helps relax blood vessel walls, which can lower blood pressure and reduce the risk of hypertension.
Adequate potassium levels are essential for healthy nerve function and efficient signal transmission in the nervous system.
Potassium plays a role in the breakdown of carbohydrates and the building of muscle, essential for energy production.
It is involved in protein synthesis from amino acids in the cell.
Potassium helps maintain the integrity and function of cells, including cell membrane potential and cellular osmolarity.
It is critical in maintaining the membrane potential, vital for various cellular processes.
Potassium aids in the digestive process and helps in the metabolism of nutrients.
It is especially important in replenishing electrolytes lost through sweat during physical activity.
Some studies suggest that potassium may help improve bone density by reducing bone resorption.
The kidneys regulate the body's potassium levels, filtering excess potassium into the urine.

Vitamins

Vitamin A, C, E and D3 + K2

Good for dopamine production downstream due to being cofactors for tyrosine hydroxylase enzymes. Estroban and Tocovit are recommended. Vitamin A (retinyl acetate or retinyl palmitate ideally) should be taken once weekly (3,000 to 10,000 IU) strictly to avoid toxicity. Your vitamin D3 levels should be 50-60 ng/ml ideally. Avoid going over the limit unless you are homozygous for a VDR mutation; in that case you would need to use calcipotriol (prescription-only in the US) and aim for ~100 ng/ml as your vitamin D receptors would need more D3 to be activated in that case.

Also, calcipotriol may be protective against Alzheimer's and Parkinson's diseases because it encourages the degradation of amyloid-beta (in neuroblastoma cells or vitamin-D-deficient mouse brains) and suppresses alpha-synuclein aggregation, respectively. However, be careful with prescription-only VDR agonists (e.g., paricalcitol, alfacalcidol, dihydrotachysterol, and calcitriol) as they carry a higher risk of serious side effects, including hypercalcemia, than cholecalciferol (OTC vitamin D3). Resveratrol, carnosic acid and progesterone upregulate VDR.

Vitamin K2 MK4 vs MK7

Vitamin B1, B2, B3, B5, B7 and B12

Cofactors in dopamine synthesis. Vitamin B2 (freebase riboflavin not R5P) is very important for maintaining proper methylation status. Vitamin B1 deficiency is more common than people think, and can affect a myriad of bodily processes. Sulbutiamine is a fat soluble form of vitamin B1 which is sold under the brand name of Enerion or Arcalion for fatigue. It improved energy and fatigue more effectively than piracetam in one study. Sulbutiamine modulates the dopaminergic and glutamatergic systems along with other mechanisms.

Pantothenic Acid (Vitamin B5) and its derivatives appear to compete with Biotin (vitamin B7) and lipoic acid for uptake by the human sodium-dependent multivitamin transporter (hSMVT).

Methylfolate + MPH has no greater effect than MPH in isolation for ADHD

Vitamin B6, specifically Pyridoxal 5'-phosphate (P5P)

Prolactin inhibitor and dopamine agonist. Make sure to take with B1, B9 (methylfolate if undermethylating, otherwise use folinic acid) and B12. Few reports of pyridoxal causing toxicity somehow but risk is low. Pyridoxine HCl is the form that has a high chance of causing B6 toxicity in the long term. B6 deficiency is a symptom of ADHD. Ideal dose is between 10-50 mg daily.

Do NOT supplement with pyridoxine if you’re taking phenelzine, instead opt for P5P form

B8 Inositol

Vitamin B8 seems to play a significant role in regulating serotonin receptors, specifically the sensitivity of 5-HT1A-2C. There is at least one report of mania induced by inositol, so bipolar patients should be very careful with supplementing this vitamin specifically. It also upregulates striatal D2 receptors so should help with anhedonia especially when megadosed (10-20 g).

One of lithium’s hypothesized mechanisms of action is inhibition of the enzymatic breakdown of inositol phosphates to free inositol. Therefore it makes sense that at least in some patients, megadosing inositol could cause mania.

B9 Methylfolate

Folate is a water-soluble B vitamin (B9) that is essential for cell growth, breakdown/utilization of proteins, formation of nucleic acids, and other functions. L-methylfolate, or 6-(S)-5-methyltetrahydrofolate, is derived from folate and is the form that enters the brain and works directly as a methyl donor and monoamine synthesis modulator.

It regulates tetrahydrobiopterin (BH4), a critical enzyme cofactor for trimonoamine neurotransmitter synthesis. Methylated vitamins including B9 are methyl donors which are very important for epigenetic regulation.

B12 Adenosylcobalamin/Methylcobalamin

Depending on your MTHFR/MTRR status, undermethylators should take methylcobalamin while normal and overmethylators should take adenosylcobalamin + hydroxocobalamin. Dose is 500-1000 mcg at least once weekly. Make sure your B12 level is in the high range ideally (at least 300 pg/ml). B12 cyanocobalamin/methylcobalamin weekly injections (intramuscular injections in the latissimus dorsi muscle) are ideal but not necessary. Sublingual liquid administration does the job but is less bioavailable.

Nicotinic Acid or NMN or Nicotinamide Riboside (NR)

Nicotinic acid, also known as niacin or vitamin B3, is an essential nutrient that plays a crucial role in various bodily functions. It is commonly found in foods such as meat, fish, eggs, and green vegetables, and is also available as a dietary supplement.

It is a coenzyme for tyrosine hydroxylase and a component of coenzymes NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate), which are crucial for cellular metabolism, energy production, longevity and mitochondrial health. Nicotinic acid is the most cost effective supplement to raise NAD+ levels.

Niacin is often used to treat conditions like pellagra, which is characterized by dermatitis, diarrhea, and dementia due to niacin deficiency. Niacin has also been used to help reduce symptoms of osteoarthritis by improving joint mobility and reducing inflammation.

Adequate levels of niacin help prevent neurological disorders and may support cognitive function, particularly in aging populations. Deficiencies in B3 have been associated with depression, anxiety, and other mood disorders.

It helps regulate blood sugar levels by improving insulin sensitivity, which can be beneficial for individuals with type 2 diabetes.

Supplements

Creatine Monohydrate

Creatine is a naturally occurring compound that plays a crucial role in energy metabolism, not only in muscles but also in the brain. It is synthesized in the liver, kidneys, and pancreas from the amino acids arginine, glycine, and methionine, and can also be obtained from dietary sources such as meat and fish.

Many of its functions include 5-HT1A activation, 5α-reductase upregulation, recycling of ATP, cellular energy enhancement and increase in DHT.

Creatine exists in the brain in its phosphorylated form, phosphocreatine, which acts as a rapid reserve of high-energy phosphates. This system buffers and maintains ATP (adenosine triphosphate) levels during periods of high energy demand. During intense neuronal activity, phosphocreatine donates a phosphate group to ADP (adenosine diphosphate) to regenerate ATP , the primary energy currency of the cell. This ensures a steady supply of energy for various brain functions.

Creatine has antioxidant properties that help reduce oxidative stress in the brain. By neutralizing free radicals, it protects neurons from oxidative damage, which is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's disease. Creatine stabilizes mitochondrial membranes and prevents the release of pro-apoptotic factors, thus protecting neurons from programmed cell death.

Adequate ATP levels are crucial for the synthesis and release of neurotransmitters, which facilitate communication between neurons. By supporting ATP production, creatine enhances synaptic function and efficiency. Creatine supports LTP, a process underlying learning and memory, by ensuring sufficient energy supply for the synaptic changes associated with memory formation.

Studies have shown that creatine supplementation can improve cognitive performance, particularly in tasks requiring short-term memory, attention, and processing speed. This is especially notable in conditions where brain energy demand is high or in individuals with low creatine levels, such as vegetarians. It can help reduce mental fatigue by enhancing brain energy metabolism, thereby improving endurance during prolonged cognitive tasks.

Creatine may help in Alzheimer's disease by protecting neurons from oxidative stress and mitochondrial dysfunction, both of which are hallmarks of the disease. In Parkinson’s disease, creatine has been shown to improve mitochondrial function and reduce oxidative stress, potentially slowing disease progression.

Finally, creatine supplementation can provide neuroprotection following TBI by enhancing brain energy reserves, reducing oxidative damage, and preventing cell death. This can aid in the recovery of cognitive and motor functions.

You can also try intranasal creatine for enhanced cognition and mood. If you are taking creatine intranasally, the HCl form is preferable to the monohydrate. 5 g is the recommended dose.

L-glutamine

Contributes to the production and regulation of other neurotransmitters (like glutamate and GABA). May indirectly influence dopamine levels. 5 g is the recommended dose.

Taurine

Modulates GABA, cardioprotective, and other benefits. 1-3 g is the recommended dose.

R-ALA/NA-R-ALA

Neuroprotection + chelation of copper which is anti-dopaminergic in excess. 300 mg is the recommended dose.

DHA

Has been shown to be anti-serotonergic, anti-inflammatory and anti-depressant. Make sure the EPA:DHA ratio is around 1:3 or 1:4. DHA is superior to EPA, and it is recommended to supplement DHA with neurogenic nootropics like lithium or NSI-189 due to DHA being a building block for neurons. 500 mg is the recommended dose.

Gut Health

You may choose to get a microbiome test to judge gut microbiome health properly. Certain probiotics like BioGaia Gastrus/Osfortis or TWK10 can increase testosterone which is dopaminergic downstream, but I do not recommend probiotics in general as they can cause a crash. You should only consider probiotics if you have severe gut problems. If you suffer from overgrowth of fungus/bacteria, you can use the antimicrobials instead.

Recommended probiotics would be Innovixlabs Mood, Mood Super Strains, Linex Forte, GabaPral, Visbiome, Microbiome Labs MegaSporeBiotic or Youtheory Spore Probiotic/MegaSporeBiotic for enhanced gut health and mood benefits.

Camphosal is the most effective OTC antibiotic available. Cycle wisely if your gut is inflamed. Another alternative is Candibactin-AR for bacterial overgrowth, and the renowned SF722/undecylenic acid for candida/fungus overgrowth. Rifaximin is the safest prescription antibiotic that’s devoid of systemic side effects (completely absorbed in the gut). Dose of 550 mg 3 times daily for 14 days (with partially hydrolyzed guar gum ideally for extra efficacy) will kill lots of bad strains of bacteria. Gut dysbiosis is heavily implicated in neuropsychiatric diseases.

You should pair antibiotics with probiotics and prebiotics (ie. partially hydrolyzed guar gum, psyllium husk, apple cider vinegar) always. Another good prebiotic is GOS.

Probiotic strains with the best effect profiles for physical enhancement:

TWK-10 (Lactobacillus plantarum)
F19 (Lactobacillus paracasei)
OLP-01 (Bifidobacterium longum subsp. longum)
PS128 (Lactobacillus plantarum)
PL-02 (Lactobacillus plantarum)
SA-03 (Lactobacillus salivarius subsp. salicinius)
LY-66 (Lactococcus lactis subsp. lactis)
TYCA06 (Lactobacillus acidophilus)
K301 (Lactobacillus acidophilus)
CS-773 (Lactobacillus casei)
BLI-02 (Bifidobacterium longum subsp. infantis)
LPL28 (Lactobacillus plantarum)
K301 (Lactobacillus acidophilus)

Other good probiotics:

Clostridium Butyricum Pendulum Metabolic Daily Pro Or MIYARISAN

Biogaia Reuteri Protectis

L. Rhamnosus GG

L. Fermentum ME3

Microbiome Labs B. Subtilis HU58

Enterogermina B. Claussi

Bacillus coagulans GBI-30

Ruscio Triple Therapy

S-tier prebiotics:

Lactulose

Glucomannan

Yeast Beta-glucans
GOS
PHGG

Do not take antimicrobials if you do not have SIBO/SIFO.

Hormones

T3 for Hypothyroid (Including Subclinical)

T3 enhances dopaminergic and serotonergic signaling. Check your hormone panels (thyroid and androgens most importantly) if your depression is treatment-resistant. Sometimes that’s caused by hypothyroidism or another hormonal imbalance. Dose range is 5-50 mcg usually, although sometimes higher for severe cases. Do not take T3 unless you are confirmed hypothyroid as it can be dangerous otherwise.

TSH should be 0.2-1.2 mIU/L (not <4.5 as the standard lab reference ranges usually say), T3 should be ~5 pmol/L and T4 should be ~12 pmol/L.

DHEA + Pregnenolone

For neurosteroid synthesis (ie. allopregnanolone downstream), upregulating 5α-reductase and CB1 NAM action (good for reducing cognitive deficits from Δ-9THC, is anti-psychotic and helps with weed withdrawals). DHEA happens to modulate GABAergic action. Pregnenolone, progesterone, vitamin A and androsterone happen to be aromatase inhibitors as well.

Liquid Androsterone for Lab/R&D

6-keto P4 - Liquid 6-keto progesterone for Lab/R&D

AlloP - Liquid Allopregnanolone for Lab/R&D

Progestene - Liquid Progesterone

Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress

GABAergic neuroactive steroids: a new frontier in bipolar disorders?

HCG

NOTE: not a hormone, but influences them.

HCG is an LH mimetic peptide found in human ovaries. It possesses androgen boosting properties due to mimicking LH. Some of its functions include:

1. Increases the natural production of testosterone, and has been shown to increase 5 alpha reductase activity in vitro.

2. It has been shown to downregulate androgen receptors in a specific application in women (uterus-related). Unclear how it impacts men in other applications.

3. Boosts neurosteroid production by increasing the upstream “building blocks”, such as progesterone, which can be synthesized into allopregnanolone, an important and deficient neurosteroid in PFS patient CSF.

4. May directly impact the brain’s LH receptors, somehow improving/repairing the brain’s function after finasteride persistently disrupted and potentially damaged its processes and structures.

5. May have autoimmune modulating properties, as seen from its impact on type 1 diabetes.

DHT

Dihydrotestosterone is a metabolite of testosterone, which depends on the enzyme 5-αR for its formation in the prostate.

Testosterone

Anabolic Steroids

Hallucinogens & Psychedelics

Psychedelics, a class of psychoactive substances, have been the subject of increased research and interest in recent years, especially regarding their potential therapeutic benefits. Contrary to what some may think, psychedelics are not addictive (anti-addictive in fact), and are not for recreational use (aside from cannabinoids and dissociatives which are not recommended to be used recreationally, and should only be used responsibly in a medical context).

Here's a comprehensive list of the benefits that have been explored or observed in studies:

Psychological and Emotional Benefits

Psychedelics like psilocybin and LSD have shown promise in treating depression, anxiety, and PTSD in clinical trials.
Psychedelics like ibogaine and psilocybin may aid in treating addiction to substances such as alcohol, nicotine, and opioids.
Psychedelics can reduce anxiety and improve mood in terminally ill patients
Many users report increased creativity and problem-solving capabilities during and after psychedelic experiences.
Psychedelics can induce positive mood states and euphoria
Users often report gaining deeper personal insights and perspectives on life issues.
Psychedelic experiences can lead to increased openness and a sense of connectedness with others and the environment.
Psychedelics can promote cognitive flexibility, allowing people to break free from rigid thought patterns.

Neurological and Physiological Benefits

Psychedelics can promote neuroplasticity, encouraging the growth and development of new neurons and neural connections.
Some studies suggest psychedelics may stimulate the growth of new brain cells.
Certain psychedelics have been observed to have anti-inflammatory properties.
Psychedelics like LSD and psilocybin have been reported to help relieve chronic cluster headaches.
Psychedelics can increase connectivity in various brain regions, potentially beneficial for certain mental health conditions.

Sociocultural and Spiritual Benefits

Many users report profound spiritual or mystical experiences, which can have lasting positive effects on their life outlook and mental well-being.
Psychedelics have been used in various cultures for spiritual and healing purposes, contributing to their sociocultural richness.
Psychedelic experiences can enhance feelings of social connectedness and empathy.

Risks and Considerations

Many psychedelics are illegal in numerous countries, which affects research and therapeutic use unfortunately, despite their great benefits. Although they are slowly being legalized in many countries including Canada and the US.
Psychedelics can exacerbate certain mental health conditions and are not recommended for individuals with a history of psychosis or bipolar disorder in their family.
The benefits of psychedelics are often maximized when used in a controlled, therapeutic setting with professional guidance.

LSD: the Renowned Lysergamide

LSD is the most well known psychedelic drug by far. It is part of the lysergamide class. Unlike tryptamines like N,N-DMT and psilocin, it is a dopamine agonist which is why lysergamides are stimulating compared to tryptamines. This may be undesirable if your main goal is to selectively enhance serotonin or want cognitive enhancement.

LSD primarily exerts its effects by binding to and activating the 5-HT2A serotonin receptors like most other psychedelics. These receptors are found throughout the brain but are particularly dense in areas involved in sensory perception, cognition, and mood regulation. Activation of 5-HT2A receptors leads to increased excitability and synchronization of cortical neurons, contributing to the altered perceptions and heightened sensory experiences associated with LSD use. LSD also acts as a partial agonist at 5-HT1A receptors, which influences mood, anxiety, and other emotional states.

Unlike other classical psychedelics, it has been found to have potent agonist activity at dopamine D2 receptors, which contributes to its stimulating and rewarding effects.

The thalamus acts as a sensory relay center, filtering and forwarding sensory information to the cortex. LSD alters thalamic function, leading to changes in the way sensory information is processed and perceived, contributing to hallucinations and altered sensory experiences. LSD-induced changes in thalamocortical connectivity can lead to a breakdown of the usual filtering mechanisms, resulting in the flooding of the cortex with sensory information and the characteristic perceptual distortions of an LSD experience.

Like psilocin, LSD has been shown to increase the connectivity between different regions of the brain, leading to a more integrated and less constrained network. This can result in novel associations and heightened creativity, as well as the blending of sensory modalities (synesthesia). LSD disrupts the activity of the DMN, a network involved in self-referential thought and the sense of self. This disruption can lead to a loss of ego boundaries and the experience of ego dissolution, where users feel a sense of unity with their surroundings.

Co-use of MDMA with psilocybin/LSD/DMT may buffer against challenging experiences and enhance positive experiences

Psilocybin: the Beginner’s Psychedelic

Psilocybin mushrooms (also known as magic mushrooms and shrooms colloquially) are a family of psychoactive fungi that contain psilocybin, a psychedelic substance of the tryptamine class. Psilocybin (and its metabolite psilocin) act as 5-HT2A agonists, which is responsible for its hallucinogenic effects.

Magic mushrooms are known to be among the easier psychedelics to get into. The duration of effects is only around 6 hours compared to 12+ hours for LSD and 36 hours for ibogaine. The intensity is also notably lower than N,N-DMT and ibogaine.

Ibogaine: the Cure for Maladaptive Neuroplasticity

Out of all psychedelics, ibogaine is by far the most promising for permanently rewiring the brain positively. It has been proven to cure addictions, ie. opioids and pornography, by reversing the maladaptive neuroplasticity involved in addiction, which is very severe. Here is a paper summarizing all research on this fascinating compound. Ibogaine reverses the long-term depression (LTD) that's semi-permanent. Unlike psilocybin, ibogaine upregulates not only BDNF but also GDNF. Not only that, it has also been proven to have anti-diabetic effects in this study. It is also hypothesized to help with tinnitus too through glutamatergic modulation, and even fight off candida infections.

Ibogaine: Effects, Dosage, How To Take It & More - TrippyWiki

Ibogaine 101: Your FAQs Answered

Structure-based discovery of conformationally selective inhibitors of the serotonin transporter

Microdosing of ibogaine is able to repair neurology and flood doses are not needed (although preferable because flood doses trigger a more complete rewiring of the brain). It’s also been shown to be highly effective at resolving anhedonia.

Flood doses induce a potent adaptation due to the greater number of neurons & signaling pathways that are activated, resulting in a more significant adaptation by the brain. However microdosing over a long period of time (20-90 days) can be just as effective for some people.

Stack it with 1000-2000 mg of magnesium glycinate (or taurate form because it is cardioprotective) to protect against the QT prolongation induced by ibogaine. It is somewhat recommended to use an ECG monitor while tripping to monitor your heart status, although it is not necessary if you are just microdosing as the QT prolongation is not supposed to be significant. If you are doing flood doses however, you should be under supervision or at the very least monitoring your heart. According to an ibogaine clinic, TA extract seems to have a way lower risk of QT prolongation than ibogaine HCl. Testosterone has been proven to shorten QT interval, so it is likely that injecting testosterone a few weeks before the trip could lower the risk of Torsades de pointes. A lot of caution should be taken with dosing as the risk of cardiac arrest due to QT prolongation skyrockets above 900 mg like in this case.

Fast CYP2D6 metabolizers should have less cardiac side effects than normal or poor metabolizers as ibogaine is more cardiotoxic than noribogaine, the CYP2D6 metabolite. A QTc of >440 ms for men and >460 ms for women could be worrying.

Ibogaine also has the highest duration of social reward learning opening out of all psychedelics.

“For mice given ketamine, the critical period of social reward learning stayed open in the mice for 48 hours. With psilocybin, the open state lasted two weeks. For mice given MDMA, LSD and ibogaine, the critical period remained open for two, three and four weeks, respectively.”

Sex Differences in Ibogaine Antagonism of Morphine-induced Locomotor Activity and in Ibogaine Brain Levels and Metabolism

Iboga alkaloids also happen to have synergy with ibogaine. Among iboga alkaloids, ibogamine, coronaridine and tabernanthine mainly produce persistent/long lasting anti addictive effects. Ibogamine shares a common mechanism with ibogaine (nAChR blockade, KOR affinity, sigma1 affinity, NMDA antagonism, serotonin occupancy and AChEi). Coronaridine also shares some mechanisms like nAChR blockade (α3β4, α9α10), opioid affinity, and NMDA antagonism; while tabernanthine is primarily NMDA antagonist, KOR agonist with weak affinity to sigma receptors.

Ibogalogs such as DM506 and IBG have been shown to decrease neuropathic and visceral pain in mice. Ibogalogs also activate both 5-HT2A and 5-HT6 receptor subtypes. DM506 and IBG, but not TBG, act as inverse agonists of the 5-HT7 receptor. Pain-relieving effects of ibogalogs are mainly mediated by 5-HT2A receptor activation. Pain-relieving effects of ibogalogs are blocked by the 5-HT2 receptor antagonist ketanserin.

Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation

The Case for Ibogaine by Thomas Kingsley Brown | TEDxVeniceBeach

64 Days of Microdosing a Little-known Hallucinogenic and How it Changed my Life | by Tyler Clemmer

A review of the mechanisms involved in the neuroprotection and neurotoxicity of Iboga alkaloids

Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

5-MeO-DMT: the God Molecule

5-MeO-DMT (5-Methoxy-N,N-Dimethyltryptamine) is a potent psychoactive compound that is gaining interest for its potential therapeutic effects. It's one of the most powerful psychedelic substances known along with salvia and ibogaine, and is naturally found in some plant species and in the venom of the Bufo alvarius toad.

5-MeO-DMT is known for its rapid onset and intense psychoactive effects. The experience is often described as life-changing, encompassing profound alterations in consciousness, sense of self, and perception of reality. Unlike other psychedelics, it is primarily a 5-HT1A agonist (not 5-HT2A) which is why it is said to have markedly different effects from its relatives N,N-DMT and psilocybin/psilocin that are potent 5-HT2A agonists primarily.

5-MeO-DMT's psychedelic effects are best compared to N,N-DMT in terms of intensity (extreme) and duration (very short). However, it generally lacks a visual geometry component and tends to produce more physical euphoria as well as even stronger transpersonal or mystical-like effects (e.g. ego loss) than N,N-DMT. It is therefore called the ‘God molecule’.

5-MeO-DMT's binding affinity to σ1 receptors is >10,000 nM, although one study indicated that 5-MeO-DMT can impact immune responses in human monocyte-derived dendritic cells via σ1 (Szabo et al., 2014).

A narrative synthesis of research with 5-MeO-DMT

N,N-DMT: the Spirit Molecule

Ayahuasca containing N,N-DMT can be great for anhedonia and treating PTSD/traumatic disorders. Banisteriopsis caapi extract in ayahuasca contains harmala alkaloids (harmine, harmaline, THH, norharman, beta carbolines like 9-me-BC and others) that are reversible MAOIs with interesting properties as explained before. You can either DIY ayahuasca or get a pre-made tincture. DIY method uses full-spectrum extract of harmine and harmaline then vaping DMT cart or taking freebase DMT powder orally/sublingually/intranasally.

Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process

Ïn terms of its pharmacology, N,N-DMT is a potent agonist at all serotonin receptors along with other pathways like σ1, TAAR1 and VMAT2.

Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT

Drugs and nootropics such as benzodiazepines and phenibut/baclofen can cause a very noticeable increase in productivity/motivation by reducing perceived stress or anxiety of a task with their GABAergic mechanism.

But of course, the mechanisms of stronger dopaminergic and GABAergic drugs for motivation or productivity are known to be extremely unsustainable in the long term.

Since 5-HT2A receptors are expressed on GABAergic interneurons [x], they facilitate GABAergic activity in DMN regions to selectively suppress the DMN unlike GABAergic drugs that are also inhibitory to the frontal cortex impairing cognitive function [x] [x] [x].

DMT is also the only sigma-1 agonist out of the three classical psychedelics which has its own synergistic benefits like anti-inflammation and neurogenesis, contributing to mental clarity and cognitive enhancement unique to DMT.

All these factors lead to very noticeable effects such as cognitive enhancement, productivity, mental clarity/removal of brain fog, and a significant reduction in anxiety unique to DMT found in the Google Sheet and our own personal experiences by selectively suppressing the DMN, while potentiating the activity of the PFC by binding to 5-HT2A - mGluR2 heterodimer superagonist site increasing 5-HT2A excitatory signaling while inhibiting mGluR2, a receptor that inhibits the release of glutamate resulting in selective enhancement of PFC neurotransmission.

[THESIS]: A sub-visual dose of Pharmahuasca is the strongest anxiolytic and cognitive enhancer that exists

Salvia: the Mysterious Hallucinogenic Terpenoid

Salvia, also known as Salvia divinorum, is a plant native to the Sierra Mazateca region of Oaxaca, Mexico. It is a member of the sage family and is known for its psychoactive properties. The primary active compound in Salvia divinorum is salvinorinA, which is responsible for its hallucinogenic effects. Here are some key aspects of Salvia:

Psychoactive Effects

Salvia divinorum is a potent hallucinogen. It can induce intense, albeit short-lived, alterations in perception, mood, and consciousness.
It is typically consumed by quidding fresh leaves or smoking extracts/leaves. Quidding causes a slower onset and is described as less scary than smoking it. The latter method gets you dissociated way quicker which is scary.
Users often report drastic changes in visual perception, sensations of traveling through time or space, encounters with entities, or revisiting past memories. The experience can be disorienting and intensely vivid.

Mechanism of Action

Unlike many other hallucinogens like LSD or psilocybin, which act on serotonin receptors, salvinorinA primarily acts on the kappa opioid receptor (KOR) system in the brain. This is unique among naturally occurring hallucinogens.
The activation of kappa opioid receptors can lead to dysphoria and hallucinations, which is markedly different from the effects produced by classical psychedelics.

Cultural and Traditional Use

Indigenous communities in Mexico, such as the Mazatec people, have traditionally used Salvia divinorum in religious rituals and healing ceremonies. It is often used for divination, to induce visionary states in shamans.
Its use is deeply embedded in the spiritual and medicinal practices of these communities.
The legal status of Salvia divinorum varies significantly by country and, in countries like the United States, by state. In some places, it is entirely legal, while in others, it is classified and regulated similarly to more well-known psychedelics or controlled substances.
While salvia is not considered addictive and does not appear to have any toxicity, its powerful psychoactive effects can be disorienting and potentially psychologically harmful in unsupervised settings.

MDMA: Ecstasy in a Pill

Unlike other psychedelics, MDMA is an empathogen which means it heightens empathy much more than classical psychedelics. It is a serotonin, dopamine and norepinephrine releaser which causes a state of ecstasy that lasts 4-6 hours, but is neurotoxic and increases oxidative stress especially to serotonergic neurons.

MDMA causes a significant release of serotonin from presynaptic neurons. It does this by entering the neuron through the serotonin transporter (SERT) and then promoting the release of serotonin into the synaptic cleft. MDMA also increases the release of dopamine and norepinephrine, although to a lesser extent than serotonin. This contributes to its stimulating and rewarding effects.

Similar to other psychedelics, it activates 5-HT2A downstream from the increase in serotonin which leads to visual hallucinations although they tend to be less intense than LSD and psilocybin.

MDMA also stimulates the release of oxytocin, a hormone associated with social bonding, empathy, and trust. This effect is thought to underlie the increased sociability and emotional openness often reported by MDMA users.

Another lesser known effect of MDMA is increase in the release of vasopressin, an antidiuretic hormone. This can lead to water retention and, in extreme cases, hyponatremia (low sodium levels in the blood) if excessive water is consumed.

MDMA-assisted psychotherapy has shown promise in treating post-traumatic stress disorder (PTSD). It is believed that MDMA's effects on serotonin and oxytocin release, combined with its ability to reduce fear and anxiety, help patients process traumatic memories more effectively.

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

Mescaline: the Cactus-derived Phenethylamine

WIP

2C-B: Shulgin’s Personal Favorite

WIP

DOM: the Psychedelic Amphetamine

WIP

Microdosing

Microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (LSD) or psilocybin-containing mushrooms. According to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. There has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized. However, even with repeated microdosing there is a possibility that 5-HT2B receptors might be stimulated enough to lead to tissue overgrowth.

Microdosing salvia may work theoretically for fear extinction due to downregulation of κ-opioid receptors. Ibogaine is a κ-opioid receptor agonist so it should work too, but is less potent than salvinorinA. Matrine is a κ-opioid agonist as well.

Microdosing ibogaine is able to repair neurology and flood doses are NOT needed. It’s also been shown to be highly effective at resolving anhedonia. Stack it with 100-200 mg elemental magnesium to protect against the QT prolongation induced by ibogaine.

For PTSD and trauma, something like 5-MeO-DMT/ibogaine + vorinostat + cerebrolysin/NSI-189 + TAK-653 + NA-semax-amidate + nor-BNI could very well treat trauma in theory.

Hallucinogenic Psychedelic Classes

Tryptamines

aMT
αET
DET
DiPT
N,N-DMT
DPT
EiPT
EPT
MALT
MBT
MCPT
MET
MiPT
MPT
NMT
PiPT

Substituted Tryptamines

2-Me-DET
2-Me-DMT
4-AcO-DET (Ethacetin)
4-AcO-DiPT (Ipracetin)
4-AcO-DMT (Psilacetin)
4-AcO-DPT (Pracetin)
4-AcO-EPT (Epracetin)
4-AcO-MET (Metacetin)
4-AcO-MiPT (Mipracetin)
4-AcO-MPT (Mepracetin)
4-HO-αMT
4-HO-DET (Ethocin)
4-HO-DiPT (Iprocin)
4-HO-DMT (Psilocin)
4-HO-DPT (Procin)
4-HO-EPT (Eprocin)
4-HO-MCPT
4-HO-MET (Metocin)
4-HO-MiPT (Miprocin)
4-HO-MPT (Meprocin)
4-HO-PiPT
4-Me-αMT
4-Me-αET
4-MeO-DMT
4-MeO-MiPT
5-Pro-DMT
5-Br-DMT
5-Chloro-DMT
5-Chloro-αMT
5-Eto-DMT
5-Fluoro-αMT
5-Fluoro-DMT
5-HO-DMT (Bufotenin)
5,6-MeO-MiPT
5-MeO-7-TMT
5-MeO-AET
5-MeO-aMT
5-MeO-BFE (Dimemebfe)
5-MeO-DALT (Foxtrot)
5-MeO-DiBF
5-MeO-DiPT (Foxy)
5-MeO-DPT
5-MeO-DMT (Toad Venom)
5-MeO-MALT
5-MeO-MET
5-MeO-MiPT (Moxy)
5-MeO-NMT
5-MeO-PiPT
5-MeO-pyr-T
5-MeO-Tryptamine
5-MeS-DMT
5-MeO-TMT
6-MeO-THH
7-Me-αET
7-Me-DMT
Alpha,N-DMT
Ibogaine
Melatonin

Lysergamides

LSA
LSD-25
1cP-LSD
1B-LSD
1P-ETH-LAD
1P-LSD
AL-LAD
ALD-52
ETH-LAD
LSM-775
LSZ
MIPLA
PARGY-LAD
PRO-LAD

Phenethylamines

2C-x Series

2C-B (Shulgin’s favorite)
2C-C
2C-D
2C-E
2C-G
2C-H
2C-I
2C-iP
2C-P
2C-T
2C-TFM

2C-T-x Series

DOx Series

Aleph-2
Aleph-4
Aleph-6
Aleph-7
DO3MeOBZ
DOAM
DOB
DOBZ
DOBU
DOC
DOCN
DODFM
DOET
DOF
DOEF
DOI
DOiP
DOM
DOMOM
DOMOE
DON
DOPR
DOT (Aleph-1)
DOTHFM
DOTFM
DOYN
MEM

25x-NBOMe Series

25B-NBOMe
25C-NBOMe
25D-NBOMe
25E-NBOMe
25G-NBOMe
25H-NBOMe
25I-NBOMe
25iP-NBOMe
25N-NBOMe
25P-NBOMe
25T-2-NBOMe
25T-4-NBOMe
2C-B-FLY-NBOMe

25x-NBOH series

25B-NBOH
25C-NBOH
25E-NBOH
25I-NBOH

Others

3C-E
3C-P
3-methyl-DOM
4C-B
4C-C
4C-D (Ariadne)
4C-E
4C-I
4C-I
4C-P
4C-T-2
5-APB
5-IT
6-IT
6-APB
Efavirenz
DODC
DOB-FLY
DMMDA
G-3
G-4
G-5
G-O
IDNNA
N-methyl-DOB
N-methyl-DOM
TMA
TMA-2
TMA-6

Non-psychedelic Hallucinogens

Cannabinoids

Dissociatives

Terpenoids

SalvinorinA (the only hallucinogenic terpenoid)

Non-hallucinogenic Analogs

Ketamine: the Dissociative Anaesthetic

If you do not respond to either antidepressants or psychedelics, you can try ketamine (either DIY or in a clinic). Ideally you should IM it, but you can take it intranasally (half the bioavailability thus double the dose).

Positive effects are long-term (and sometimes permanent). Intranasal dose is 20-160 mg and IV dose is around 10-80 mg. Do not abuse it as it will damage your bladder.

You do NOT want to develop “ketamine-induced cystitis”. You will be in agony for a long time and can be irreversible if the damage gets bad enough. Space out your infusions/trips by a week or two apart to keep tolerance low. Ketamine has no notable interactions, but it gets dulled by lamotrigine.

It can be potentiated by AMPA PAMs like TAK-653, or agonists like piracetam/noopept and lithium. NMDA antagonists like magnesium (threonate for maximum BBB penetration), memantine and agmatine have been reported to potentiate dissociatives.

Its rapid, long-lasting antidepressant effect depends on two mechanisms. Both have to be simultaneously present:

1. Postsynaptic AMPA upregulation AND activation. NMDA receptors are present on GABA interneurons to AMPA, so Ketamine disinhibits AMPA firing while keeping those receptors upregulated through a separate mechanism.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

SSRIs and Imipramine share this AMPA upregulation after chronic intake:

The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity?

2- Inhibition of the phosphorylation of eukaryotic elongation factor 2 (eEF2) which results in a boost of BDNF and synaptogenesis.

The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine

Antidepressants also upregulate BDNF signaling, in part through blunting the HPA axis response:

BDNF — a key transducer of antidepressant effects

ANTIDEPRESSANTS REVERSE CORTICOSTERONE-MEDIATED DECREASE IN BDNF EXPRESSION: DIFFERENTIAL REGULATION OF SPECIFIC EXONS BY ANTIDEPRESSANTS AND CORTICOSTERONE

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters

Ketamine's antidepressant effect is abolished if either of these mechanisms is blocked. It seems that ketamine targets the same pathways ADs target but in a much more direct (less dependent on downstream cascade) and rapid manner. Effects are more long-lasting with fewer sessions needed compared to the daily AD dosing needed to achieve the same effect.

Since ketamine doesn't target the serotonergic pathway directly, it's devoid of sexual side effects. Furthermore, its own side effect profile is relatively mild due to the fewer sessions needed far in between. (i.e. ketamine cystitis).

Credit to Meso for a lot of the research

Memantine: the Little-Known Dissociative Adamantane

Memantine is a dissociative substance of the adamantane class that produces long-lived dissociative effects when administered. It is a derivative of amantadine and is pharmacologically related to compounds like PCP, ketamine, and DXM, although its recreational use is comparatively rare.

It is prescribed for Alzheimer’s mainly, and sometimes off-label for anxiety/depressive disorders like OCD or chronic pain. As an NMDA antagonist it possesses neuroprotective qualities which make it useful for treating anxiety and depression.

Dextromethorphan: the Dissociative Cough Syrup

Dextromethorphan (also known as robo, dex, DM, and DXM) is a dissociative substance of the morphinan class. It is the primary active ingredient in many common over-the-counter (OTC) cold and cough medicines. When exceeding approved doses, DXM produces dissociative effects similar to those of ketamine and phencyclidine (PCP). It acts as a noncompetitive NMDA receptor antagonist similar to memantine. Recreational use is (unfortunately) relatively common among teenagers in North America.

It does have medicinal value however. It was approved by the FDA in 2023 for depression under the brand name of Auvelity in combination with the CYP2D6 inhibitor bupropion (which extends its half-life). As another NMDA antagonist, it possesses neuroprotective qualities which make it useful for treating anxiety and depression (like memantine and ketamine) when used responsibly.

While somewhat impractical to dose ultra-low doses of DXM, it may even retain a neuroprotective effect, here we see subcutaneous DXM in rats exerts an anti-epileptic and neuroprotective effect administered at 10ng/kg that outlasted the DXM treatment itself. This effect is attributed to its inhibition of microglial NADPH oxidase 2. A protective effect on DA neurons also likely occurs as well, at least in isolated neurons. While only concentrations are listed, it also showed protection against “endotoxin-induced sepsis-like hepatotoxicity” at ultra-low concentrations here.

DXM’s metabolite 3-hydroxymorphinan acetylates H3 histone and raises neurotrophins through that mechanism; acetylation of H3 can either be increasing HAT directly or HDAC inhibition leading to indirect increase.

Cannabigerol (CBG)

Occasional use might help with PSSD as it is a 5-HT1A antagonist and α2 adrenergic receptor agonist. Vaped dry CBG herb is superior to oil isolate due to the entourage effect of cannabinoids present in dry herb. Terpenes like limonene and β-caryophyllene are anti-depressant.

Cannabidiol (CBD)

CBD has low affinity for the cannabinoid CB1 and CB2 receptors, although it acts as an antagonist in presence of CB1/CB2 agonists like Δ-9THC, despite this low affinity. It’s technically a CB1 negative allosteric modulator (NAM). The core effect of antagonism of CB1 receptors is reduced binding affinity of Δ-9THC and any of its related isomers. Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It also may act as an inverse agonist of GPR3, GPR6, and GPR12.

CBD has been shown to act as a 5-HT1A receptor partial agonist. At higher concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. It is a positive allosteric modulator of the μ-opioid and δ-opioid receptors as well (PAM). The pharmacological effects of CBD may involve PPARγ agonism, inhibition of voltage-gated cation channels, and intracellular calcium release. It has been shown to be anti-psychotic as well. Smoked CBD heated to 250-300 C will partially be converted to Δ-9THC, so ideally you should vape CBD dry herb at ≤ 220 C to vaporize all terpenes and cannabinoids in the CBD hemp without converting any to Δ-9THC.

CBD is also a TRPM8 antagonist, which helps upregulate the receptor in the long term and that should enhance genital sensitivity. TRPM8 is involved in pain signals as it is expressed in sensory neurons.

---------------------------------------

Diet & Fitness

Diet

WIP

Generally speaking, stay away from fad diets (including keto diet except in very rare cases) and stick to a low FODMAP balanced diet. Keep sugar to a minimum but do not cut it off completely as glucose is necessary for many metabolic processes in the body.

Fitness

WIP

Avoid training until failure for the most part to minimize recovery time.

Genes & SNPs

Genes

There are many SNPs and polygenic traits that have been discovered to affect brain function, such as neurotransmitter receptor density in different parts of the brain, rate of reuptake for neurotransmitters, and the density variation of each type of neurotransmitter.

Dopamine Receptor SNPs

Rs1800497 - The Taq1 D2 dopamine receptor allele, with a

Pathways & Ligands

Transporters

SERT

Chronic pharmaceutical SRI treatment can permanently downregulate SERT expression which leads to PSSD so they should be avoided as much as possible.

Antidepressant-induced internalization of the serotonin transporter in serotonergic neurons

“Regulation of neurotransmitter transporter cell surface expression is known to be regulated by various therapeutic drugs and drugs of abuse, as well as by multiple protein kinase interactions (41⇓ , 42)⇓ . In this respect, it has been shown that activation of the mitogen-activated protein kinase (MAPK) p38 MAPK leads to enhanced SERT surface expression, whereas activation of protein kinase C down-regulates SERT surface expression (22⇓ , 43)⇓ . Substrates of SERT, such as 5HT and amphetamines, protect SERT from PKC-dependent internalization, whereas SERT antagonists, such as antidepressants and cocaine, block this substrate-mediated protection (44)⇓ . Interestingly, cocaine alone up-regulates the cell surface expression of SERT (45)⇓ . Comparably, it has been shown that the dopamine transporter (DAT) also is down-regulated by PKC activation and up-regulated by exposure to cocaine”

Reuptake should be increased ideally (ie. tianeptine temporarily, but not for PSSD as it desensitises MOR) unless you have OCD. OCD patients have generally low serotonin levels and benefit from reduced serotonin reuptake, so SRIs like mesembrine and hyperforin can be good (do not combine with MAOIs). MAOIs are also very helpful for OCD and can be preferable over SRIs due to lack of PSSD risk, but are not as effective as ultra-potent SRIs (ie. high dose fluvoxamine or clomipramine) at combating OCD symptoms.

Functional consequences of 5-HT transporter gene disruption on 5-HT1A receptor-mediated regulation of dorsal raphe and hippocampal cell activity

“Extracellular recordings showed that application of selective 5-HT reuptake inhibitors such as paroxetine and citalopram onto brainstem slices resulted in a concentration-dependent inhibition of 5-HT neuron firing in the dorsal raphe nucleus of wild-type 5-HTT+/+ mice, but not 5-HTT-/- mutants. By contrast, the 5-HT(1A) receptor agonists ipsapirone and 5-carboxamidotryptamine inhibited the discharge in both groups. However, the potency of these agonists was markedly decreased (by approximately 55- and approximately 6-fold, respectively) in 5-HTT-/- compared with 5-HTT+/+ animals. Similarly, intracellular recordings showed that the potency of 5-carboxamidotryptamine to hyperpolarize 5-HT neurons in the dorsal raphe nucleus was significantly lower in 5-HTT-/- than in 5-HTT+/+ animals.”

“These data showed that 5-HTT gene knock-out induced a marked desensitization of 5-HT1A autoreceptors in the dorsal raphe nucleus without altering postsynaptic 5-HT1A receptors functioning in the hippocampus.”

Modifications of the Serotonergic System in Mice Lacking Serotonin Transporters: An in Vivo Electrophysiological Study

Famotidine and thiamine inhibit serotonin synthesis which helps with symptoms induced by low SERT expression (PSSD). The only pharmaceuticals that work for stopping serotonin syndrome are cyproheptadine and famotidine. Bacopa monnieri helps upregulate SERT expression. Berberine and evodiamine seem to do the same as well. High dose testosterone increases serotonin transporter binding. Estradiol also upregulates tryptophan hydroxylase enzymes as well as SERT expression. KOR antagonists also upregulate SERT. Zinc, too, increased 5-HT uptake in a concentration-dependent manner. Finally, exercise helps upregulate SERT so it’s recommended for PSSD patients to ensure they are physically active.

The impact of estradiol on serotonin, glutamate, and dopamine systems

“OVX rats treated with estradiol benzoate, an E2-based estrogen medication, exhibit significantly increased SERT mRNA expression in the DRN and heightened SERT-binding site density in various brain areas, including the ventromedial hypothalamic nucleus”

Protein Kinase C Activation Regulates Human Serotonin Transporters in HEK-293 Cells via Altered Cell Surface Expression

Monoamine depletion by reuptake inhibitors

Inhibitors can function on 3 different profiles of this transporter, which makes SRIs different from each other. For example ibogaine is vastly different from clomipramine as explained in this study.

“In addition to Na+, cocaine and antidepressants stabilize SERT in an outward-open conformation, whereas ibogaine and noribogaine stabilize an inward-open conformation. The opposing influence of these ligands on conformation mimics two functional states of SERT.”

DAT

Methylphenidate, modafinil, phenylpiracetam, amantadine and armesocarb are notable DRIs. Inhibition of this transporter leads to an increase in synaptic dopamine, which leads to stimulation (and sometimes euphoria) without neurotoxicity in most cases. Similar to SERT, DAT can be inhibited in different conformational states thus giving cocaine a vastly different profile than inhibitors like methylphenidate.

Generally speaking, inhibiting this transporter produces less side effects than activating TAAR1 (mechanism of dopamine releasers like dextroamphetamine). It should also be less neurotoxic like in the case of methylphenidate vs. amphetamine.

NET

Norepinephrine upregulates the expression of tyrosine hydroxylase and protects dopaminergic neurons against 6-hydroxydopamine toxicity, so NET should be Inhibited ideally if it’s not anxiogenic. Methylphenidate is the best NDRI overall followed by modafinil, and maybe reboxetine if you can handle the side effects. Stay away from bupropion as it is ototoxic and a melanocortin-4 agonist (can induce anhedonia). NSI-189 is supposedly an NRI according to a leaked investor presentation by Neuralstem.

Norepinephrine activates α1 receptors which leads to serotonin release downstream; hence why SNRIs tend to be better for OCD than SSRIs. Adding a norepinephrine reuptake inhibitor like reboxetine to a MAOI completely prevents the tyramine reaction.

EAAT2

Addiction to certain drugs (e.g. cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus accumbens (NAcc); the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior. In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.

Drugs which help to normalize the expression of EAAT2 in this region, such as NAC have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs. Riluzole increases its activity, reducing glutamate.

VMAT2

Upregulate with kanna. Tricylic and tetracyclic antidepressants like mirtazapine seem to upregulate VMAT2 in the long term too. Modafinil may upregulate VMAT2 significantly. Cyclazodone, N-methyl-cyclazodone and pemoline work on this transporter with an unknown mechanism of action. Lithium has also been shown to upregulate VMAT2 by 197%. HDAC inhibition has also been shown to upregulate DAT, VMAT2 and c-Fos. Amphetamines downregulate VMAT2 in the long term. Reminder to not take kanna with MAOIs, phenethylamines (ie. MDMA or 2C-B) or SRIs. Can also be risky for PSSD patients due to SRI action.

Methylphenidate has indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the VMAT2 protein.

Ca2+ dependent activator proteins of secretion promote vesicular monoamine uptake

Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase and vesicular monoamine transporter 2-positive neurons in the substantia nigra." "In conclusion, our results show that exendin-4 is able to promote adult neurogenesis in vitro and in vivo, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson's disease.

We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum.

NBP and edaravone both upregulated VMAT2 gene activity, again suggesting that high VMAT2 activity protects dopaminergic neurons, and implying a therapeutic approach for PD
"Moreover, immunostaining of VMAT2 showed that VMAT2 protein expression in the dopaminergic neurons of the puerarin-treated rats was upregulated by 1.72-fold compared with the vehicle-treated rats (Fig. 4B–H). Together, puerarin upregulated both VMAT2 mRNA and protein levels”. "In this study, neuroprotective puerarin can upregulate VMAT2 in vivo. Most interestingly, upregulation was cell line haplotype-dependent (Fig. 3)."

Dl-3-n-butylphthalide (NBP) upregulates VMAT2. Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson’s disease.

Edaravone upregulated VMAT2 expression without affecting SNCA expression.

Puerarin upregulated TH and VMAT2 expression and dopamine levels in dopaminergic cells

HDC, VMAT2 and CgA mRNAs are upregulated by "chronic, but not acute stimulation of the ECL cell upregulates vesicular monoamine transporters.

"We demonstrate that treatment of SH-SY5Y cells with U18666A, a SREBP activator, increases the translocation of SREBPs into the nucleus, increases expression of SREBP-1, SREBP-2 and of the presynaptic dopaminergic markers such as vesicular monoamine transporter 2, synaptic vesicle glycoprotein 2A and 2C, synaptogyrin-3 and tyrosine hydroxylase." "Treatment with statins consistently increased the expression of vesicular monoamine transporter 2 (VMAT2), synaptogyrin-3 (SYNGR3) and synaptic vesicles glycoprotein 2C (SV2C) (Schmitt et al., 2016)"

Class I HDAC inhibitor TC-H 106 increased VMAT2 expression

PACAP38 increases VMAT2 expression and attenuates methamphetamine toxicity

Nurr1 agonists upregulate TH, VMAT, DAT, AADC and GDNF

GM1 administration increases the density and expression of the synaptic membrane dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) and enhances DA synaptic membrane uptake and basal, K-stimulated, and amphetamine carrier-mediated DA release in the midbrain and striatum of aged Sprague–Dawley rats.

Osmotin upregulates Nurr1 transcription, tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2).
Lithium increases VMAT2 expression in rats

Activation of Peroxisome Proliferator-Activated Receptorα increases Nurr1 expression; which has downstream upregulation at AADC, TH, DAT, and VMAT2

Credit to gubb1ns for the research on VMAT2

Serotonergic System

5-HT1A

Agonists like DMT, buspirone (can crash some PSSD patients), creatine (probably 5-HT1A autoreceptor/presynaptic antagonist but postsynaptic agonist considering it "enhances" the efficacy of antidepressants), agmatine, evodiamine, ginger, J147, and low-dose zinc (but not high). Maybe berberine but usually NOT recommended to activate this receptor if you have PSSD as it can crash you. Instead, upregulate 5-HT1A with CBG, CBD (high doses only), SJW (probably the most effective in this list), cyproheptadine, ginkgo (agonist that upregulates it ironically), inositol (maybe), rhodiola, berberine, evodiamine, buspirone microdose and curcumin.

CB1 agonists can downregulate 5-HT1A, whereas inhibiting FAAH or inhibiting endocannabinoid uptake can actually increase 5-HT1A function. Estrogen desensitizes 5-HT1A according to this study, but many PSSD patients find relief from increasing E2 ironically. T3 hormone also does the same thing.

Effects of anabolic-androgens on brain reward function

Hypothalamic 5-HT1A increases dopamine, β-endorphin, and oxytocin there. 5-HT1A activation also inhibits NMDA activity (good for anxiety and depression usually), but inhibits substance P which can be bad for mood for certain individuals. This receptor is a mixed bag as to whether you should activate it or block it. Oxytocin is released when 5-HT1A is activated (limonene can be good for this). Blue lotus extract upregulates 5-HT1A. SJW and TCAs, including clomipramine and amitriptyline, upregulate postsynaptic 5-HT1A receptors. Zeolite seems to upregulate serotonin receptors as well.

It is theorized that SSRIs produce antidepressant effects by gradually desensitizing presynaptic 5-HT1A, which is why it's said SSRIs take many weeks work, despite extremely questionable efficacy compared to placebo, likely due to desensitizing beneficial Serotonin receptors leading to a blunting of ALL emotions.

This makes SSRIs outdated and unselective in targeting only the positive effects of 5-HT1A.

To directly compare the efficacy of SSRIs to presynaptic 5-HT1A antagonists at this target, a highly selective presynaptic 5-HT1A silent antagonist (WAY-100635) can block the detrimental effects of presynaptic 5-HT1A without upregulating or increasing sensitivity of them.

5-HT1A used to be a suspected therapeutic target in psychoplastogens, but in fact, highly selective presynaptic 5-HT1A antagonism is significantly more cognitively enhancing by increasing glutamatergic, cholinergic, and dopaminergic activity in the PFC and hippocampus.

Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties

Verbal memory and 5-HT1A receptors in healthy volunteers – A PET study with [carbonyl-11C]WAY-100635

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

To back this with pharmacological data, a 5-HT1A agonist (8-OH-DPAT) does NOT improve the neuroplasticity of psychoplastogens, including ketamine.

Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

Thus, this mechanism is extremely synergistic with psychoplastogens since they both enhance the excitatory activity of pyramidal neurons and regulatory control over subcortical regions, therefore significantly accelerating the antidepressant response.

How does pindolol improve antidepressant action?

Pindolol augmentation of antidepressant response

Unsurprisingly, presynaptic 5-HT1A antagonists are known to uniquely induce a head-twitch response (HTR) on their own, a characteristic that is typically only associated with psychedelics, this demonstrates how directly enhancing DRN serotonergic neurons are to 5-HT2A receptors on Layer V pyramidal neurons, which are the largest with the most extensive dendritic trees, thus the most capable of neuroplasticity. This effect is blocked by a 5-HT2A antagonist (Ketanserin, SR-46349) [x, x].

To further support their synergy, a selective presynaptic 5-HT1A antagonist (WAY-100635) significantly enhances HTR of psychedelics (DOI) [x, x].

Additionally, in a blind study, volunteers reported that a presynaptic 5-HT1A antagonist (Pindolol) potentiated the effects of DMT by 2 to 3 times [x].

Therefore, highly selective presynaptic 5-HT1A antagonists are extremely synergistic with 5-HT2A agonist psychoplastogens, as 5-HT2A is the most expressed Serotonin receptor in the PFC.

Overall, these 5-HT1A mechanisms demonstrate the unique and exceptional potential of presynaptic 5-HT1A antagonists, as it's the most expressed serotonin receptor in the entire brain, for enhancing top-down control, learning, and mood regulation of the PFC.S

Credit to dennison on Discord

Stay away from ashwagandha as it has endless reports of anhedonia, PSSD and depression due to desensitization of 5-HT1A (disastrous). If presynaptic 5-HT1A is desensitized, it will keep the postsynaptic receptors flooded with serotonin.

5-HT1B

Tianeptine can desensitize the presynaptic 5-HT1B heteroreceptor which inhibits acetylcholine release. Agonists can worsen OCD, depression and PSSD. Lithium could be an antagonist/inverse agonist: "the potential of this mode of action is underscored by the 5-HT1B receptor inverse agonist properties of lithium, outlined here. The findings that antidepressant-like effects can be obtained with both antagonists and agonists targeting the receptor likely reflect the heterogeneous localization of 5-HT1B receptors in different neuronal populations where autoreceptors and heteroreceptors may differently modulate depression-like behaviors".

"In the hypothalamus, by contrast, 5-HT1B receptor mRNA expression was high in MDD suicide subjects"

"In a follow-up study, the SSRI-induced reduction of dorsal raphe 5-HT1B receptor mRNA expression was maintained after 8 weeks SSRI administration, but 5-HT1B receptor mRNA levels were rapidly restored upon drug washout. "

“Thus, the regulation of 5-HT1B receptor function by lithium could possibly be mediated via GSK3 inhibition. However, 5-HT1B receptor involvement is not limited to the established antidepressants. In the most promising new line of MDD drug research, a glutamate (AMPA) receptor-dependent increase in 5-HT1B receptor binding in the nucleus accumbens and ventral pallidum has been demonstrated in response to ketamine in nonhuman primates"

"Furthermore, there was a trend of increased 5-HT1B receptor mRNA in projection areas after chronic SSRI administration in rats (Neumaier et al. 1996). Interestingly, in both humans and rats, 5-HT1B receptor measurements were reduced in raphe nuclei with SSRI (Neumaier et al. 1996; Nord et al. 2013)."

5-HT1D

Antagonists include cyproheptadine, trazodone and metergoline. Agonists can worsen OCD, depression and PSSD.

The 5-HT1D receptors are primarily located on presynaptic neurons. When activated, they inhibit the release of various neurotransmitters, including serotonin itself, dopamine, and glutamate. This autoregulatory mechanism helps maintain neurotransmitter balance within the synaptic cleft.

The 5-HT1D receptors are found on blood vessels within the brain. Activation of these receptors causes vasoconstriction, which is thought to counteract the vasodilation associated with migraine attacks. This property makes 5-HT1D receptor agonists (such as triptans) effective in the acute treatment of migraines.

Activation of 5-HT1D receptors inhibits the release of pro-inflammatory neuropeptides, such as calcitonin gene-related peptide (CGRP), which are involved in the pathophysiology of migraines.

By inhibiting serotonin release through presynaptic 5-HT1D autoreceptors, these receptors play a role in mood regulation. Dysregulation of 5-HT1D receptor function can contribute to mood disorders, including depression and anxiety.

Some studies suggest that 5-HT1D receptor activation may have neuroprotective effects, potentially by reducing excitotoxicity and oxidative stress. This could have implications for neurodegenerative diseases, although more research is needed in this area.

5-HT1E

Antagonists like cyproheptadine and metergoline. Agonists can possibly worsen OCD, depression and PSSD.

5-HT1F

Antagonists like metergoline. Agonists can possibly worsen OCD, depression and PSSD.

5-HT2A

Credit to Denzel (u/mastermind_genius)

5-HT2A are Gq-protein coupled excitatory receptors, when activated, it causes Gq-protein to release stored intracellular Ca2+ and activates PKC, a crucial ion and kinase in neuronal signaling [x].

And Gβγ-protein opens/closes nearby ion channels resulting in a net increase of positive electrical charge.

PKC enhances AMPA/NMDA neurotransmission by phosphorylating NMDA (GluN2A/B) and AMPA (GluA1/2) [x, x].

Additionally, Src kinase phosphorylates NMDA (GluN2A), potentiating NMDA neurotransmission.
5-HT2A and NMDA are located very close to each other, allowing for these unique localized interactions.

To highlight the potency of 5-HT2A over 5-HT2B/C since they’re all Gq-protein coupled 5-HT receptors; a 5-HT2A antagonist and inverse agonist (Ketanserin, M100907, SR-46349B) blocks this potentiation, a 5-HT2C antagonist (RS-102221) doesn’t block it, and neither a 5-HT2B or 5-HT2C agonist (BW-723C86, MK212) is able to replicate 5-HT2A’s significant enhancement of excitatory activity [x, x, x].

Furthermore, it was found that genetic reduction of 5-HT2A causes a significant impairment in NMDA activity due to the lack of PKC activity which heavily relies on Gq-protein from 5-HT2A, 5-HT2A activation increases AMPA signaling, and that 5-HT2A is essential for associative learning [x, x].

5-HT2A agonist (DOI) significantly enhances NMDA neurotransmission and associative learning

It can be concluded that 5-HT2A acts as the PFC's major enhancer in AMPA/NMDA neurotransmission and not other receptors due to being a highly expressed Gq-protein coupled receptor in the PFC and has unique localized enhancement of AMPA/NMDA through Src kinase/PKC.

In summary, with all these unique mechanisms, desirable circuitry, and extremely high expression in the PFC, 5-HT2A is the best overall target for cognitive enhancement and therapeutic purposes due to its role in neurotransmission and top-down control.

There are two important forms of the 5-HT2A receptor; the 5-HT2A - mGluR2 heterodimer and intracellular 5-HT2A.

The 5-HT2A - mGluR2 heterodimer excels at stimulation and cognitive enhancement, whereas intracellular 5-HT2A is the most efficacious therapeutic target for long-lasting neuroplasticity and restoring top-down control.

The 5-HT2A - mGluR2 heterodimer: Cognitive enhancement, stimulation, and motivation

mGluR2 is the main presynaptic inhibitory Glutamate receptor of pyramidal neurons that inhibits the production of cAMP from ATP, inhibiting the release of Glutamate.

It can form a heterodimer with 5-HT2A which significantly impairs 5-HT2A's Gq-protein signaling as a regulatory mechanism.

Serotonin (5-HT) has significantly reduced 5-HT2A Gq-protein signaling in the heterodimer, but psychedelics (DOI) uniquely inhibit mGluR2 to significantly reestablish Gq-protein signaling bias

In the 5-HT2A - mGluR2 heterodimer, psychedelics bind to 5-HT2A which causes a unique inhibitory shape change to the mGluR2 receptor right beside it which prevents the inhibitory function of mGluR2 [x], allowing for a substantial increase in Glutamate release and creating a stimulatory effect on the PFC leading to heightened perception/processing speed, attention, logical thinking, working memory, etc.

A well-known non-hallucinogenic psychedelic, Tabernanthalog, is still known to promote neuroplasticity substantially, but is not known for any potent cognitive enhancement or stimulating effects.

This is expected as non-hallucinogenic psychedelics don’t produce head-twitch response (HTR) as mGluR2 inhibition is required to produce HTR, discussed in more detail later in the post [x, x].

mGluR2 is the most abundantly expressed presynaptic Gi-protein coupled receptor in Layer V, while other inhibitory Gi-protein coupled receptors are scarce [x].

mGluR2 is also expressed in Layer II/III, making mGluR2 a targeted way to enhance Glutamate release in desirable regions of the PFC [x, x, x, x].

To emphasize the cruciality of increasing Glutamate in the PFC for cognitive enhancement, a study found that a higher Glutamate to GABA ratio is heavily associated with higher working memory index, a strong predictor of PFC function [x].

Additionally, artificially inducing chronic stress with a glucocorticoid (Hydrocortisone) to dysregulate Glutamate signaling in the PFC significantly impairs working memory [x].

Interestingly, the dlPFC which is the most developed and logic-oriented region of the PFC, but not other PFC regions, uniquely enhances dopaminergic pathways in the VTA/NAcc in response to anticipated reward, showing the importance of the dlPFC for generating goal-directed behavior [x].

5-HT2A uniquely stimulates this interaction while preferring Dopamine release in the PFC and NAcc over the VTA.

Circuitry on how 5-HT2A preferentially inhibits the VTA and while enhancing the NAcc, producing a high effort state of lower VTA activity and higher NAcc activity (green)

This is extremely interesting as higher NAcc and lower VTA activity is an accurate predictor of higher effort, suggesting that 5-HT2A is able to produce a high effort state [x].

To support this pharmacological data, this is blocked by a 5-HT2A antagonist (MDL-11939, SR-46349, M100907, Risperidone), but not by a 5-HT2C antagonist (SB-206553) [x, x, x, x].

An interesting comparison of cognitive enhancers would be a new microdosed psychedelic and amphetamines.

The stimulation and cognitive enhancing properties of amphetamines is due to DAT (Dopamine transporter) inhibition in the PFC, thus significantly increasing Dopamine levels.

The major downside of DAT is that it’s expectedly abundantly expressed in dopaminergic regions like the VTA, which is extremely undesirable because overactivity of these regions are responsible for addictive and impulsive nature [x].

So a microdosed psychedelic has way better modulation of the VTA and NAcc to produce a productive/focused state, while increasing both Glutamate and Dopamine levels in the PFC, preferentially Glutamate.

These mechanisms underlie the primary stimulative and cognitively enhancing properties of mGluR2 inhibition by 5-HT2A agonist psychoplastogens, higher Glutamate in the PFC has high synergy with the mechanisms discussed earlier, such as unique potentiation of AMPA/NMDA through Src kinase/PKC.

Basket GABAergic interneurons: Cognitive enhancement through regulation of pyramidal neurons

5-HT2A receptors are also abundantly expressed on (PV+) fast-spiking GABAergic interneurons in the cerebral cortex, but to a lesser extent than on pyramidal neurons [x, x, x].

There are two types of (PV+) fast-spiking GABAergic interneurons which are basket and chandelier.
Basket GABAergic interneurons provide direct negative feedback to pyramidal neurons by releasing GABA to the soma, thus regulating the overall excitatory activity of a pyramidal neuron.

Basket GABAergic interneuron projections to the soma of the pyramidal neuron

Basket GABAergic interneurons are involved in the precise timing of pyramidal neuron activity by providing fast, strong inhibitory signals, to synchronize the firing of pyramidal neurons.

This generates rhythmic oscillations, known as gamma oscillations (30 - 100 Hz).

These gamma oscillations are heavily associated with enhanced cognitive processes like attention, learning, and working memory.

This fast-spiking negative feedback improves signal clarity and reduces undesired noise of the sensory input, enhancing the accuracy of the pyramidal neuron’s signaling.

Additionally, basket GABAergic interneurons prevent excitatory activity from reaching excitotoxic levels, allowing for a higher excitatory range, supporting higher potential neuroplasticity through neuroprotection [x, x, x, x, x, x, x].

Intracellular 5-HT2A are expressed in GABAergic interneurons can do this the most effectively which is explained in the next section [x, x, x, x].

These are the main reasons why providing neuroplasticity to basket GABAergic interneurons is extremely desirable for cognitive enhancement.

Intracellular 5-HT2A to effectively activate mTORC1: The best neuroplastic & therapeutic target

A significant amount of 5-HT2A receptors in pyramidal neurons and GABAergic interneurons are intracellular, for the most part in the golgi apparatus.

The golgi is acidic unlike the basic pH extracellular space, this acidity allows for sustained 5-HT2A signaling long after its activation [x, x, x].

Extracellular 5-HT2A on the neuron’s membrane (white), intracellular 5-HT2A (blue), and both (overlay)

Neuroplasticity is the brain's ability to reorganize itself by forming new neural pathways, helping to replace unhealthy circuitry responsible for negative thought patterns that lead to chronic stress and depression.
This restructuring ability, which is far too low in depression, can be most effectively reactivated by neuronally permeable 5-HT2A agonist psychoplastogens.

The required target of psychoplastogens to achieve a significant increase on neuroplasticity is mTORC1.

In terms of the true root problems of depression and related neuropsychiatric diseases, they are often viewed as stress-related disorders, this includes depression, anxiety, addiction, bipolar disorder, schizophrenia, and PTSD given the fact that they can be triggered or worsened by chronic stress.

From a well-established pharmacological perspective, chronic stress results in the prolonged release of Norepinephrine, stress hormones (glucocorticoids, CRH, ACTH), and inflammatory cytokines (1β, IL-6, TNF-α).

This causes the amygdala to strengthen while inducing synergistic neurodegeneration to the PFC’s circuits essential for regulating mood, particularly Layer V pyramidal neurons, destroying the PFC’s top-down control.

More detail on the amygdala is in the next section.

Layer V is the most important cortical layer as it contains the largest pyramidal neurons with the most extensive dendrites and connects the PFC to the amygdala.
These characteristics make them extremely capable of significant dendritic and synaptic changes to restore stress-induced deficits and top-down control.

Top-down control by the PFC over subcortical regions (amygdala, VTA/NAcc, DRN, dPAG)

Thus, extensive evidence points to the destruction of the PFC’s Layer V regulatory circuits over subcortical regions, mainly the noradrenergic amygdala, that regulate emotional behaviors such as depression, anxiety, and impulse being the convergence point underlying many neuropsychiatric disorders and diseases.

Downstream signaling to activate mTORC1

Patients with stress-related neurodegenerative mood disorders are found to have lower BDNF and TrkB levels, reduced cortical neuron size, lower synaptic protein (AMPA/NMDA, ion channels) levels, and fewer dendritic spines/synapses in the PFC, all problems which stem from reduced mTORC1 activity [x].

The resulting structural damage is the retraction of dendrites and the loss of dendritic spines and synapses, the exact opposite of neuroplasticity.

mTORC1 is necessary for the synthesis of key plasticity-inducing genes (c-Fos, EGR-1/2), neurotrophic factors and neuropeptides (BDNF, GH, β-Endorphin, Oxytocin), synaptic receptors (AMPA/NMDA), and ion channels, leading to the induction of neuroplasticity and directly addressing the deficits found in depression [x, x, x].

It’s very interesting that Rheb and Rab1A, which are important activators of mTORC1, are localized on the golgi, meaning that 5-HT2A can effectively activate both Rheb and Rab1A through localized interactions as they’re all in the golgi.

Additionally, the golgi and lysosomes, where mTORC1 is at, form contact sites with each other for effective interaction [x, x, x].

These localized intracellular interactions show that the golgi, which expresses 5-HT2A, is an extremely targeted way to effectively activate mTORC1.

Rheb, Rab1A, and 5-HT2A are on the golgi apparatus and mTORC1 is on the lysosomes

Interestingly, intracellular 5-HT2A is colocalized with microtubule-associated protein (MAP1A) [x].

To back mTORC1’s cruciality in neuroplasticity with pharmacological data, a neuronally permeable 5-HT2A antagonist (Ketanserin), genetic deletion of 5-HT2A, and an inhibitor of mTORC1 (Rapamycin), completely blocks the neuroplasticity of psychoplastogens [x, x, x].

An antagonist of TrkB (ANA-12), the receptor of BDNF which is the main neurotrophic factor released by mTORC1, completely reverses neuroplasticity [x].

To ensure neuronal permeability is in fact the required trait in 5-HT2A agonist psychoplastogens; the non-membrane permeable 5-HT2A agonists (TMT, Psy N+) induce insignificant neuroplasticity as expected, but with electroporation which allows any compound to permeate the membrane, they obtain similar neuroplasticity as membrane permeable 5-HT2A agonists (DMT, Psi) by accessing intracellular 5-HT2A.

And the membrane permeable 5-HT2A antagonist (KTSN), which is able to block intracellular 5-HT2A, significantly reduces the neuroplasticity of DMT.

The non-membrane permeable 5-HT2A antagonist (MKTSN N+), only being able to block extracellular 5-HT2A, slightly reduces the neuroplasticity of DMT, but with electroporation, MKTSN N+ completely reverses the neuroplasticity of DMT by blocking intracellular 5-HT2A like KTSN [x].

DMT and Psilocin - membrane permeable 5-HT2A agonists

TMT and Psilocybin (N+) - non-membrane permeable 5-HT2A agonists because of the N+

KTSN - membrane permeable 5-HT2A antagonist, Ketanserin

MKTSN (N+) - non-membrane permeable 5-HT2A antagonist because of the N+, Methylketanserin

Electroporation - a quick electric pulse that opens pores in neuronal membrane, allowing any compound to permeate the membrane

These results prove that intracellular 5-HT2A induces the majority of neuroplasticity in 5-HT2A agonist psychoplastogens and 5-HT2A agonist psychoplastogens access intracellular 5-HT2A by being neuronally permeable.

Another interesting mechanism unique to psychedelics at 5-HT2A is that they use Gq/s/i-protein for plasticity-inducing gene expression, while non-hallucinogenic 5-HT2A agonists like Serotonin can only use Gq-protein. This is evidenced by psychedelics uniquely increasing early growth response-1 (EGR-1) expression which is a plasticity-inducing gene which relies on Gi-protein from mGluR2 [x, x].

Psychedelics biased for β-arrestin 2 signaling at 5-HT2A such as LSD or 25I-NBOMe counteracts head-twitch response (HTR) and induces significantly higher downregulation [x, x, x, x].

G-protein coupled receptors (GPCRs) are primarily expressed on the neuron surface with an extreme few exceptions which are 5-HT2A, MOR, and mGluR5 [x, x].

The clear purpose of intracellular expression is causing extended signaling, explained earlier.

This makes a lot of sense for MOR to desirably extend the pain-relieving effect of opioids and endorphins are conveniently synthesized intracellularly by the endoplasmic reticulum.

For mGluR5, it’s also highly expressed on the apical dendrites of Layer V pyramidal neurons and is a Gq-protein coupled receptor like 5-HT2A [x].

Evolution itself chose to make 5-HT2A intracellular to leverage its extremely desirable circuitry and high expression in Layer V of the PFC to effectively activate mTORC1 through localized interactions.
It's not a question that intracellular 5-HT2A is the brain’s best neuroplasticity target.

Layer V chandelier GABAergic interneurons: Best top-down control target

The amygdala is a noradrenergic primitive brain region responsible for automatic emotional responses like the fight-or-flight response; it plays a crucial role in quickly processing potential threats, including task-related anxiety.

This reflexive anxiety processing was essential for detecting threats and ensuring human survival in the past.

However, in modern times, the amygdala's inability to distinguish between real and perceived threats often results in irrational social anxiety and its illogical input regarding task-related anxiety leads to unwanted procrastination.

This is a good simplified video by Dr. Kanojia for newbies on the topic of procrastination.
"Analysis paralysis" (aka task analysis) refers to the subconscious anxiety-induced procrastination when considering the effort of a task perceived as unpleasant.

When the amygdala senses there are environmental stressors, the brain releases high levels of Norepinephrine, stress hormones (glucocorticoids, CRH, ACTH), and inflammatory cytokines (1β, IL-6, TNF-α), which weakens PFC processing and activates the amygdala, engaging its fight-or-flight response causing involuntary anxiety and conditioned fear, switching the brain into a more primitive state [x, x].
This is why amygdala activity has a direct relationship with anxiety.

These stressors are detrimental long-term, as prolonged exposure to norepinephrine, stress hormones, and inflammatory cytokines have combined synergistic neurotoxicity and deteriorates the brain over time, explaining how chronic stress leads to a higher chance of a neurodegenerative disease later in life.

PFC is active in healthy conditions, whereas the amygdala is active and the PFC is inactive in chronic stress

Thus, social anxiety and procrastination can be characterized by a reduced ability of the Layer V pyramidal neurons of the mPFC to regulate the amygdala [x, x].

To further support this, both social and generalized anxiety disorder have been associated with fewer synaptic connections between the mPFC and the amygdala, compromising the PFC’s ability to regulate fear response [x].

The amygdala's illogical counterproductive input should be silenced in most situations, particularly when it's completely unnecessary when it comes to socialization and being productive.

5-HT2A agonists directly block this, as Layer V chandelier GABAergic interneurons which express 5-HT2A release GABA to GABAA receptors specifically on the pyramidal neuron's axon initial segment which sends signals to the amygdala, thus precisely inhibiting excessive signaling to the amygdala [x, x, x].

Layer V chandelier GABAergic interneuron projecting to the axon initial segment of a pyramidal neuron

To support this with pharmacological data, this amygdala inhibiting mechanism is only blocked by a 5-HT2A antagonist (Ketanserin), but neither 5-HT2B (BW-723C86) or 5-HT2C agonist (WAY-629) can replicate it [x, x, x].

Therefore, 5-HT2A specifically on Layer V chandelier GABAergic interneurons inhibits the undesirable perception of excessive task difficulty and illogical social anxiety by blocking the input of the amygdala as it’s the subcortical region responsible for contributing to feelings of anxiety.

This is the same mechanism on how the mPFC’s chandelier GABAergic interneurons regulates overactivity in the VTA which is a dopaminergic region, blocking potential addictive and impulsive input of this subcortical region [x, x].

Conclusion: Intracellular 5-HT2A is the best neuroplastic & therapeutic target, 5-HT2A - mGluR2 is a great cognitive target, and extra comments

In terms of choosing the most efficacious type of psychoplastogen, psychedelics are the best because they most effectively activate mTORC1 with localized interaction through intracellular 5-HT2A.

Neuronal permeability is the greatest factor in creating the best possible psychoplastogen to be able to access the maximum 5-HT2A possible to take full advantage of neuroplasticity and top-down control.

	Psychedelics	Dissociatives	Deliriants

Popular examples	DMT, Psilocybin, LSD	Ketamine, DXM, PCP, Xenon, Nitrous Oxide	Scopolamine (Datura), Diphenhydramine (Benadryl)
Mechanism to activate mTORC1	Intracellular 5-HT2A activation on the golgi apparatus	NMDA antagonism on GABAergic interneurons to release Glutamate to activate AMPA/NMDA	M1 antagonism on GABAergic interneurons to release Glutamate to activate AMPA/NMDA

To support this with pharmacological data, all Tryptamine psychedelics (Psilocin, DMT, 5-MeO-DMT) are actually all partial agonists because they have lower Gq-protein efficacy at 5-HT2A than the full agonist, Serotonin, since the endogenous agonist is considered the maximum response.

Whereas many Phenethylamine psychedelics (2C-I, DOI, 25I-NBOMe, LSD) are full agonists with high Gq-protein efficacy and an extremely high affinity, thus their doseage is in the mcg (microgram) range, but their high β-arrestin 2 signaling induces rapid tolerance and undesirably counteracts HTR.

Interestingly, these non-hallucinogenic psychedelics (Lisuride, 2-Br-LSD, 6-MeO-DMT, 6-F-DET) all have low Gq-protein efficacy, this is because they don't sufficiently inhibit mGluR2, so mGluR2's Gi-protein has higher signaling bias rather than Gq-protein at the 5-HT2A - mGluR2 heterodimer, resulting in a lack of HTR, Glutamate release, and hallucinations [x].

On top of that, not only do Psilocin and LSD have higher Gq-protein and β-arrestin efficacy than DMT, they also have higher affinity, yet DMT is the strongest psychedelic [x].

.	5-HT2A affinity (Ki)	Gq-protein efficacy (300 min)	β-arrestin efficacy (300 min)

DMT	127.0 nM	7.00	6.72
Psilocin	107.2 nM	7.58	7.14
LSD	3.5 nM	10.00	9.53

So it can be ruled out that neither higher affinity or higher Gq-protein efficacy at 5-HT2A are the most effective approaches to finding the best possible 5-HT2A agonist psychoplastogen.

To identify the key factor in making the most effective psychoplastogen, out of all tested Tryptamine analogues; DMT is the most neuronally permeable, followed by 5-MeO-DMT, Psilocin (4-HO-DMT), then Bufotenin (5-HO-DMT).

In contrast, Serotonin (5-HO-Tryptamine, aka 5-HT) is completely impermeable [x].

The neuronal permeability of Methylethyltryptamine (MET) is somewhere in between DMT and Bufotenin [x].

.	No Methyls	N-Methyl	N,N-Dimethyl

Tryptamines	-1.06 (Tryptamine)	1.20 (NMT)	1.59 (DMT)
5-MeO-Tryptamines	0.51	1.25	1.53 (5-MeO-DMT)
4-HO-Tryptamines	-0.66	0.79	1.51 (Psilocin, 4-HO-DMT)
5-HO-Tryptamines	-2.25 (Serotonin, 5-HT)	-1.95	1.31 (Bufotenin, 5-HO-DMT)

Clearly any modification, even if small like MET, to the original DMT molecule undesirably loses permeability, loses potency, or induces rapid tolerance [x].

DMT is the smallest and simplest Tryptamine, making it the most neuronally permeable.

Therefore, the unique major difference making DMT stronger out of all the psychedelics is neuronal permeability.

To make the best 5-HT2A agonist psychoplastogen possible, maximizing neuronal permeability to access as much 5-HT2A as possible has to be the biggest priority.

Evolution has figured out DMT is the most efficacious to activate these intracellular 5-HT2A receptors due to it having the highest neuronal permeability, as the INMT enzyme was provided to create DMT from Tryptamine.

The main substrate of INMT is Tryptamine, but not other modified Tryptamines as they result in less permeable N,N-Dimethyl analogues.

The highest INMT expression in the human brain is found in the cortical layers of the cerebral cortex [x].
Interestingly, INMT is localized in close proximity to sigma-1, suggesting that INMT is there to effectively activate sigma-1 with DMT [x].

N,N-Dimethyltryptamine is the most neuronally permeable, synthesis of Serotonin and DMT starting from L-Tryptophan

In conclusion, Layer V pyramidal neurons and chandelier GABAergic interneurons form the regulatory circuitry over subcortical regions, especially the amygdala.

Intracellular 5-HT2A is extremely abundant in the PFC, particularly in Layer V, and effectively activates mTORC1 through localized interactions to significantly induce neuroplasticity for these Layer V neurons, reestablishing top-down control, thus making intracellular 5-HT2A the most efficacious therapeutic target.

DMT, as the highest neuronally permeable 5-HT2A agonist, takes full advantage of this because both the Layer V pyramidal neurons and chandelier GABAergic interneurons of course express these intracellular 5-HT2A receptors [x, x, x, x], whereas LSD and Psilocybin aren’t as efficacious due to lower neuronal permeability.

The significantly higher efficacy of psychedelics (Psilocybin) over Ketamine and SSRIs (Fluoexetine) reflects these targeted mechanisms of intracellular 5-HT2A as psychedelics produce much faster and greater week 1 antidepressant results [x].

Ketamine lacks the direct interactions between intracellular 5-HT2A on the golgi and mTORC1 on lysosomes, limiting its efficacy, whereas SSRIs can't access intracellular 5-HT2A at all since Serotonin is completely impermeable, explaining questionable efficacy of SSRIs.

Antidepressant efficacy of a placebo/control (red), the SSRI Fluoxetine (blue), Ketamine (purple), and the psychedelic Psilocybin (orange)

A new microdosed DMT based psychoplastogen designed to enhance neuronal permeability will activate as much intracellular 5-HT2A as possible to take full advantage of the neuroplasticity, top-down control, potentiation of AMPA/NMDA neurotransmission (Gq-protein, Src kinase/PKC) properties of 5-HT2A, while having the cognitive enhancement of higher Glutamate release from mGluR2 inhibition in the PFC, these mechanisms are very synergistic, creating the most efficacious single drug therapeutically and cognitively.

This can't be achieved with non-hallucinogenic psychedelics, as they have low Gq-protein efficacy due to not inhibiting mGluR2 as discussed in detail earlier, thus insufficient PKC activity which heavily relies on Gq-protein from 5-HT2A, resulting in a weaker potentiation of AMPA/NMDA neurotransmission and insignificant Glutamate release.

This is why LSD and Psilocybin aren't perceived as cognitive enhancers, only because they hit the threshold for hallucinations too soon without sufficiently activating enough intracellular 5-HT2A.

The approach described above takes the therapeutic potential further by improving focus and attention, making it beneficial for conditions like ADD/ADHD, the majority would prefer this approach over the recent biotech company trend of non-hallucinogenic psychedelics.

In mid 2024, Cybin's CYB003 (Deuterated Psilocin) and MindMed's MM120 (LSD Tartrate) got fast track designation status from the FDA after impressive human trial results with rigorous clinical trial design.

The real potential of 5-HT2A just hasn’t been realized yet because a good 5-HT2A agonist hasn’t been made.

Since DMT exists, LSD and Psilocybin aren't near what could be the best.

Other comments

Antagonists disinhibit dopamine release but come with downsides so high dose partial agonist usage occasionally is preferrable. Cortical 5-HT2A increases dopamine release to the NAc. You can upregulate 5-HT2A with CB2 agonists like β-caryophyllene/CBD, SJW, inositol, piracetam/noopept and lithium to reverse tolerance to 5-HT2A agonists like psychedelics (ie. LSD, psilocybin and DMT). 5-HT2A activation increases the amount of an enzyme PKC (Protein Kinase C).

One of PKC functions is serotonin reuptake inhibition; it does this by phosphorylating the cell receptor instead of blocking it. This increases the amount of serotonin in the synapse and the length of time the serotonin stays in the synapse, so you wouldn’t want to be on an agonist daily.

Chromium, however, decreases sensitivity of 5-HT2A receptors; and ginkgo too. Ebelin lactone found in Bacopa monnieri enhances 5-HT2A transmission (claimed to be a 5-HT2A PAM, but this is not exactly proven). Activation of 5-HT2A and 5-HT2C happens to facilitate oxytocin secretion just like 5-HT1A as well.

CC in rs6311 of HTR2A, robustly increased risk of suicidal behavior and depression. 3.6x increased risk of sexual dysfunction when taking SSRI Antidepressants.

5-HT2B

Antagonists like bromocriptine, metergoline, lisuride or 10-MeO-Harmalan. 5-HT2B activation is required for the development of fibrosis.

5-HT2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition

Agonism is therefore cardiotoxic. Stay away from cabergoline and other 5-HT2B agonists (Many serotonergic psychedelics are 5-HT2B agonists).

5-HT2C

Inverse agonists like SB-243213, cyproheptadine (cycle because it’s anticholinergic), metergoline, nortriptyline/tricyclic antidepressants, trazodone and mirtazapine help with mood.

Agomelatine works too but is weak and antagonism is less ideal than inverse agonism for this receptor because 5-HT2C receptors have 'constitutive' activity in vivo, meaning they can activate effectors in the absence of an agonist. Both lead to slow wave sleep benefits + more pleasant dreams, dopamine + norepinephrine + GABA disinhibition (anxiolytic, anti-depressant, pro-motivation/ADHD), partially counters the sexual side-effects of SRIs + last longer in bed as well, and appetite enhancement. Metergoline is the best antagonist. Agonists will exacerbate anxiety and anhedonia.

SB-243213, a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile, lacks tolerance and withdrawal anxiety.

5-HT3A to 5-HT3E

Antagonists like memantine, tropisetron, mirtazapine, cyproheptadine or lamotrigine seem to improve cognition, lower anxiety (especially OCD) and nausea. Research into subtypes of this receptor is still in its infancy. It is not recommended to block this receptor unless you have nausea or treatment-resistant OCD as activation of this receptor is necessary for σ1 (sigma-1) activation. σ1 is a very important receptor that is explained in a few pages below. Take ginger if 5-HT3 antagonists make you too constipated.

Full and partial agonists induce distinct desensitized states of the 5-HT3 receptor

5-HT4

Antagonists like metergoline or berberine. 5-HT4 serotonin receptors are anxiogenic and contractile (constricting) thus activating this receptor is ideal for PSSD/sexual dysfunction and anxiety. It is responsible partially for indirect dopamine release but also responsible for transient rise in mineralocorticoid secretion (stress hormone). Some partial agonists like tropisetron may improve cognition.

5-HT5A

Antagonists like metergoline help with mood and anxiety.

5-HT5B

Antagonists like metergoline help with mood and anxiety.

5-HT6

Antagonists like metergoline and cyproheptadine help with mood and anxiety. Rosa rugosa extract is a potent 5-HT6 antagonist which disinhibits dopamine, norepinephrine, acetylcholine, and glutamate release in the PFC.

5-HT6 receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

5-HT7

There are advantages to both antagonists and agonists. Antagonism of this receptor induces instant antidepressant effects. Examples of potent antagonists include metergoline and cyproheptadine. Curcumin reduces expression of this receptor. Activation, however, promotes an increase in TrkB receptor expression and phosphorylation which is desirable, and consequently promotes growth of serotonin neurons by increasing BDNF. NSI-189 is also most likely a 5-HT7 antagonist.

Experimental data suggest the role of 5-HT7 antagonism in the pro-cognitive actions of the antipsychotic drugs amisulpride and lurasidone."

"Additionally, the antagonism of 5-HT7 may contribute to the mechanisms underlying the pro-social action of amisulpride in rats. It cannot be excluded that the 5-HT7 may be involved in pro-cognitive effects of other antipsychotic drugs (for example clozapine) that also possess high affinities for the 5-HT7".

Dopaminergic System

D1-D2 heteromer

D1-D2 heteromer increases as a result of aging through cannabis and cocaine abuse. It is thought to be one of the mechanisms behind cannabis-induced anhedonia. TAT-D1 peptide inhibits the formation of this heteromer, and reverses age and drug related neurochemical changes.

D1

PAM like ASP4345 (untested clinically in humans) or DETQ or Mevidalen (PAMs don’t build tolerance as fast as agonists). Upregulate with ALCAR and phenylpiracetam.

Preclinical testing with D1 PAMs has been found effective to some degree, however the high dosage of current compounds and limited efficacy has made direct targeting using an allosteric mechanism seem not very worth the cost compared to other pathways.

D2

Weak antagonists (ie. tricyclic antidepressants, blue lotus) sensitize the postsynaptic receptors to phasic dopamine release in accordance with external stimuli. PAMs like intranasal/subcutaneous MIF1 are great for mood. Agonism long-term is associated with an increase in impulsivity and pleasure-seeking behavior. Upregulate with cordyceps, forskolin and ALCAR. MIF1 shifts affinity to D2L over D2S (inhibitory) which is good. Inositol happens to upregulate D2 in the long-term as well. NAC lowers homocysteine, which is a NAM at this receptor. Salvinorin A is a D2 partial agonist. The D2-family receptors inhibit cAMP.

D3

Weak antagonists (ie. tricyclic antidepressants, nuciferine) sensitize the postsynaptic receptors to phasic dopamine release in accordance with external stimuli; or PAM. Pramipexole and piribedil are the most effective dopamine agonists but the latter is about as effective with less side effects. D3 is an inhibitory receptor so it should be downregulated. However, D3 activation can also be neurotrophic by enhancing BDNF and GDNF.

The way agonists like pramipexole work for depression/anhedonia is by downregulating the autoreceptors in the long-term which increases influx of dopamine to the postsynaptic receptors leading to enhanced dopaminergic neurotransmission. Unfortunately, there is a risk of developing DAWS so they are not recommended as anything but last-resort.

D4

Weak antagonists sensitize the postsynaptic receptors to phasic dopamine release in accordance to external stimuli; or PAM like intranasal MIF1 (can be taken indefinitely since it’s endogenous in humans already, and neuroprotective).

D5

Agonists like lisuride occasionally could be fine; or PAM theoretically.

Do NOT take dopamine agonists if you don’t have a need for them (like treatment resistant depression, anhedonia, restless legs syndrome or PSSD) because they down-regulate dopamine receptors in the very long-term.

Adrenergic System

α2

Agonists like guanfacine or CBG helps with long COVID symptoms and treat hypofrontality. It most likely does this because guanfacine enhances dlPFC delay cell firing, and COVID causes elevated GCP-II and KAT-II which most likely leads to lowered dlPFC delay cell firing in long COVID and acute COVID. Clonidine, another agonist like guanfacine, potentiates the antidepressant effects of MAOIs in mice indicating a pro-dopaminergic effect and increased blood flow to the prefrontal cortex, although guanfacine is superior for working memory performance and cognition. Agonists also stimulate growth hormone secretion which is indicative of an upstream dopaminergic increase. Guanfacine happens to be an hTAAR1 full agonist as well.

Up to 50% of treatment-resistant ADHD or major depression patients show symptoms of hypofrontality and might not respond to treatment until they add an α2 adrenergic agonist like guanfacine to their stack. If you suspect you have ADHD, download Redbox RX and try to get guanfacine ER prescribed. You would have to do a 5 minute video call with a doctor. Inform the doctor that you can’t focus and have hyperactivity (ADHD), and emphasize that you do not use recreational drugs (or alcohol). Stay away from antagonists as they increase hypofrontality.

β1

Given its localization in inhibitory neurons of layer III dlPFC, and its casual role in mediating stress induced cognitive impairment, antagonists like nebivolol would help with PFC dysfunction and have anxiolytic effects. B1 but not B2 also plays a role in fear responses thus antagonists being beneficial for PTSD. Propranolol, though unselective to B2, synergistically enhances attentional benefits from nicotine. Advisable to use occasionally unless having hypertension or CVD risk.

β2

Agonists like higenamine and slightly more riskier clenbuterol. Antagonists usually have cognitive impairing properties whereas agonists are somewhat beneficial for certain cognitive aspects like working memory, neurogenesis and TBI. β2 agonists are also anabolic, pro testosterone and cardioprotective unlike β1.

Enzymes

MAO

Inhibited ideally (tranylcypromine fully inhibits MAO at only 30 mg). Above that it gets more serotonergic and also starts inhibiting norepinephrine reuptake. At very high doses (100 mg+), it seems to be a dopamine releaser akin to amphetamines (it is a substituted amphetamine after all). Best reversible MAOI is 9-methyl-β-carboline followed by harmine or harmaline (5-HT2A agonists as well). Vitamin B2 is a cofactor for MAOA, required for it to function properly.

Valproic Acid Induces Monoamine Oxidase A via Akt/Forkhead Box O1 Activation

Sustained antidepressant effect of PEA replacement

Beware interactions (ie. SRIs and serotonin releasers ie. kanna and MDMA).

COMT

Inhibited with myricetin (0.2μm Ki), quercetin (~2-5 μM Ki), EGCG (5α-reductase inhibitor and hepatotoxic in high doses, not recommended for PFS or PSSD), rhodiola and maybe lithium. Fisetin is probably the most potent over-the-counter natural COMT inhibitor.

Acetylcholinesterase

Inhibited ideally, but if inhibited too much it may increase irritability. Huperzine A is a good acetylcholinesterase inhibitor. Donepezil is a prescription one that’s stronger but I do NOT recommend it due to side effects. Not an important target for mood but definitely helps cognition. Nigella sativa also happens to be an acetylcholinesterase inhibitor. If you want to increase the activity of this enzyme however, you should take something like forskolin (ideally 5%+ extract).

Butyrylcholinesterase

It is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it is made in the liver, found mainly in blood plasma, and encoded by the BCHE gene.

It is very similar to the neuronal acetylcholinesterase, which is also known as RBC or erythrocyte cholinesterase.

Known inhibitors include CBD, CBG, CBN, ibogamine and ibogaine.

Tryptophan Hydroxylase

This enzyme can be inhibited with fenclonine to reduce conversion of tryptophan into serotonin, which is useful for disorders where serotonergic signaling is excessive (ie. PSSD). On the other hand, if you would like to increase this enzyme’s function long-term epigenetically, you can take pinealon. However, it can cause sexual dysfunction and other negative effects induced by high serotonin.

Dopamine Beta-hydroxylase

Hypericin is an inhibitor of dopamine beta-hydroxylase, which is the enzyme responsible for converting dopamine into norepinephrine. Disulfiram and carnosine are DβH inhibitors.

5α-reductase

Enzymes involved in neurosteroid metabolism like allopregnanolone. These enzymes are inhibited by finasteride, dutasteride, mushrooms like reishi/lion’s mane, and others. Inhibition of this enzyme leads to a reduction in DHT downstream, and less neurosteroids being produced. There are 3 subtypes for this enzyme, each concentrated in different locations in the body. 5α-R1 is mostly in the brain, such as the cortex as well as the liver, and non-genital skin; while 5α-R2 is mostly located in genital tissue, facial and chest hair follicles, liver and brain. Not much is known about type 5α-R3.

5AR inhibitors can lead to unwanted side effects in susceptible people like depression, libido loss and erectile dysfunction which is why they are STRONGLY not recommended.

GSK3β

Lithium, zinc and curcumin are potent inhibitors of this enzyme.

FAAH

Inhibited by macamides, AM404 (paracetamol’s metabolite), lavender oil and URB597 (no safety trials in humans) for reduced pain (both physical and mental) and anxiolytic effect. But can increase anhedonia in some people due to tyrosine hydroxylase downregulation. Palmitoylethanolamide (PEA) inhibits FAAH but is also a substrate (good for pain too, and increases allopregnanolone levels downstream).

Another FAAH inhibitor that is harmful and NOT recommended is myristicin (nutmeg). It has no therapeutic value but can be recreational. It is extremely anticholinergic and neurotoxic so do NOT abuse.

PDE
Non-selective inhibition: phosphodiesterases are enzymes that break down cAMP and cGMP. Inhibition of those enzymes would lead to increased cAMP and cGMP mediated effects. Non-selective PDE inhibition is generally not desirable however there are few ways to achieve it. Methylxanthines are commonly known to inhibit phosphodiesterase with caffeine and paraxanthine being common ones. Caffeine is a non-selective PDE inhibitor that is very accessible and safe. It produces various metabolites which are known to inhibit PDE like paraxanthine (major metabolite; PDE9i) and theophylline (can be toxic when taken directly).

PDE1i: PDE1 is subdivided into PDE1A, PDE1B and PDE1C with inhibition of 1A being responsible for cognition while 1B is generally for dopaminergic effects as it’s expressed in areas with strong dopaminergic innervation such as dentate gyrus, striatum, and in prefrontal cortex. Inhibition of PDE1B can cause indirect D1 stimulation through increasing prefrontal cAMP and cGMP. PDE1B knockout seemingly produces an increase in spontaneous locomotion (PDE10A and PDE4 knockout decreases) and also potentiates psychostimulants suggesting potent dopaminergic effects. Non selective PDE1 inhibition reduces both positive and negative symptoms of schizophrenia suggesting some antipsychotic action. However, non selective inhibition might be counterintuitive due to allosteric activation of PDE2 causing decreased AMPA expression. Vinpocetine is primarily a PDE1B inhibitor, but also inhibits other PDE1 subtypes but also an AMPA antagonist, while ITI214 is an experimental PDE1 inhibitor.

PDE4i: PDE4 is primarily cAMP specific and all of them are widely distributed, but PDE4C is somewhat restricted to olfactory bulb while PDE4B being relevant for dopaminergic enhancement as it is detected highest in nucleus accumbens. PDE4i increases dopamine synthesis through increased TH phosphorylation, potentiates D1 (increased DARPP32 phosphorylation) albeit slightly weaker than PDE10i. Mesembrine found in kanna is a weak PDE4 inhibitor. COX inhibitors downregulate PDE4D expression as well which is pro-cognitive and pro-mood. Rolipram is a pharmaceutical drug that inhibits PDE4. The problem with rolipram is its unselectivity and lack of allosteric affinity, which means that it completely inhibits PDE4D at large enough doses, leading to potential issues and side effects. Roflumilast is a more selective inhibitor in comparison.

PDE4D inhibition specifically (with allosteric inhibitors specifically) is most likely the most procognitive method of modulating PDEs with the evidence available. This is mostly due to its selective location in pyramidal neurons of the dlPFC (it is 285% more located there than elsewhere), however PDE4D also affects other regions of the brain such as the hippocampus. Neurons in this region specifically are thought to underlie a very large part of working memory and spatial cognition. PDE4D inhibition has been found incredibly effective at enhancing cognition in mammal studies in terms of memory and spatial ability.

PDE5i: inhibition of PDE5 both increases blood circulation to the penis, increases nitric oxide production (pro-dopaminergic in the long-term) and, funnily enough, also provides an antidepressant effect. Best PDE5 inhibitor is tadalafil. Highly recommend taking 5-10 mg tadalafil daily if you have erectile dysfunction or PSSD as it upregulates 5α-reductase in the long-term which helps with sexual function (and mood to a lesser extent). If you want to upregulate nitric oxide, check out pomegranate juice which upregulates/increases nNOS mRNA on an epigenetic level. Avoid combining pomegranate juice with PDE5i or other PDE5i with BP lowering substances. Should synergize well with forskolin.

PDE10i: PDE10/PDE10A has higher affinity for cAMP than cGMP and is expressed in areas that are rich in dopaminergic neurons like nucleus accumbens, striatum (MSNs) and olfactory bulb making it a desirable target for dopaminergic dysfunction. Papaverine, a PDE10i robustly increases DARPP32 (indicator of D1 activation) and increases dopamine synthesis (increased TH phosphorylation). PDE10A inhibition generally produces antipsychotic actions. Tofisopam inhibits PDE10

COX2

Inhibited ideally (400-1500 mg white willow bark once weekly is good for this) to increase dopaminergic signaling downstream. Ibuprofen and other COX-2 inhibitors (ie. white willow bark or celecoxib) help with neuroprotection of dopaminergic neurons too.

Do NOT take COX-2 inhibitors daily as they can be harmful to the stomach and other organs. COX inhibitors downregulate PDE4D expression as well which is pro-cognitive and pro-mood.

AMPK

Activate with berberine, metformin, resveratrol, ALCAR or quercetin. Activation stimulates energy generating processes such as glucose uptake and fatty acid oxidation and decreases energy consuming processes such as protein and lipid synthesis.

Histone Deacetylase (HDAC)

DNA is wrapped around histones, which look like donuts, while in the nucleus. It’s a way for DNA to be condensed and organized. DNA must be loosened from the histone for transcription (gene expression) to occur, and also for the DNA to be copied before cell replication. HDAC inhibitors can have long-term if not permanent positive effects in relation to fear extinction.

Best inhibitors are crebinostat , vorinostat, thymoquinone (found in black seed oil), sodium butyrate/tributyrin, EGCG, sulforaphane, curcumin, emodin and adamantane. Valproate is not recommended due to side effects. Crebinostat is the most potent HDAC inhibitor, but vorinostat is much easier to get. As a side note, TrkB and NMDA agonists are fear extinctives along with CB1, MOR, GABAB, 5-HT1A and H2 agonists.

Adamantanes are also powerful HDAC inhibitors that are easily obtainable. ALCAR indirectly inhibits HDAC as explained before (donates acetyl groups to deacetylated proteins which acts similar to an HDAC inhibitor). PRL-8-53 is hypothesized to be an HDAC inhibitor but this is unconfirmed. If it is an HDAC inhibitor, then it is definitely one of the most cost-effective HDAC inhibitors around. Valproate, another HDAC inhibitor, has been shown to reopen critical-period learning of absolute pitch which should theoretically apply to other potent HDAC inhibitors like vorinostat and butyrate.

6 g of butyrate is roughly equivalent in potency to 250 mg of vorinostat in terms of HDAC inhibition, but keep in mind half life of butyrate is only 15 minutes compared to vorinostat’s ~2 hours. However, even a few hours of exposure after sodium butyrate administration can result in H4 histone hyperacetylation. This effect can persist beyond withdrawal however chronic exposure is required to exert more stable long term epigenetic changes, particularly in the context of its neurogenic effects. In a study of cerebral ischemia, 14 days of treatment with sodium butyrate enhanced markers of neurogenesis in the frontal cortex, whilst only 7 days did not. This was a function of butyrate maintaining H3 acetylation, which was lost in the control group not exposed to butyrate. Tributyrin is an ester of butyric acid that has a much longer half life because it is hydrolyzed gradually by lipases, allowing for sustained release. Its half life is around 1 day, which makes it superior.

Vorinostat corrects inhibitory synaptic deficits caused by missense epilepsy mutations to the GABAA receptor γ2 subunit. Since vorinostat is very potent, stick to 15-150 mg strictly. Don’t go above that and take it only once a week.

Only 5.5% of vorinostat crosses the BBB, so it is best to administer it intranasally to maximize absorption by the CNS. The effects from vorinostat become permanent either through repeated sessions of low dosages of 15 mg to 50 mg, or through one session of a regular dosage, which would be from 50 mg to 150 mg. Sessions need to be separated by a few days, because if you take too high a dosage or take too many doses in a row too much HDAC can be inhibited, which prevents chromatin from condensing and consequently arrests the cell cycle. Vorinostat and other HDAC inhibitors also happen to chelate zinc.

Curcumin also promotes HDAC2 in heart failure models, but pan-inhibits Class I and II in normal conditions (including HDAC2). Because of its possible HDAC2-promoting attribute, it probably isn't healthy to take curcumin if you're a smoker or have recently smoked.

EGCG is the most powerful and thoroughly-inhibiting of the natural HDAC inhibitors that have been studied so far, but even as the most potent HDAC inhibitor on paper, its HDAC inhibiting effects are still relatively weak, and overshadowed by its other properties, making most natural HDAC inhibitors not useful for the kind of work mentioned in the above studies. You'll get the benefits, but they will be weaker and shorter-lasting.

It is encouraged to take natural HDAC inhibitors, though, because, as they are only weak HDAC inhibitors, you can take them everyday and reap the benefits of having some HDAC inhibition daily, along with all the other benefits that come from EGCG, resveratrol, cocoa, etc. supplementation. You won't be able to get the full fear-extinguishing effects, and won't get the full long-term memory enhancing effects. For these to occur, more potent and more selective HDAC inhibition is needed.

HDAC inhibition is also anti inflammatory, neuroprotective, enhances the expression of nuclear receptors (ER/AR), neurotrophic, up regulates dopamine genes TH, DAT, C-Fos, Nurr1 etc. Lithium and valproate increase MOR sensitivity by lowering Let-7 (a miRNA that represses MOR).

Another alternative to HDAC inhibitors for demethylating the genome is upregulating TET1. Estradiol does that, and so does GHK-Cu. HDAC inhibition also directly upregulates TET1. The antidepressant-like effect of sodium butyrate (HDACi) is associated with an increase in TET1 and in 5-hydroxymethylation levels in the BDNF gene. HDAC inhibition would induce active de-methylation through GADD45 --> TET1 activation. HDAC inhibition increases ER sensitivity, which increases ERE-mediated TET1/2 upregulation.

Pregnancy reprograms large-conductance Ca2+-activated K+ channel in uterine arteries: roles of TET-mediated active demethylation

Refer to this section for more details on HDAC inhibition.

Enkephalinase

Semax, selank and epitalon inhibit enkephalinase which increases the levels of enkephalins binding to opioid receptors. This leads to theoretical benefits to mood, stress tolerance and many other benefits. Inhibitors of this enzyme should be synergistic with enkephalin precursors like DLPA.

Glutamatergic System

NMDA

Antagonized occasionally with memantine or amantadine (less NMDA antagonism, is an antiviral and increases dopamine release) or adamantane (similar to memantine with longer half life, also an HDAC inhibitor) ideally for mood benefits and potentiation of other nootropics in the stack. NMDA receptors can be upregulated with piracetam, L-theanine, pinealon, sarcosine, glycine, ALCAR, nobiletin, magnesium L-threonate and D-cycloserine or minocycline if you want to reverse tolerance to NMDA antagonists (dissociatives). Harmine enhances reuptake of glutamate.

L-theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry

There is evidence suggesting that vitamin C and zinc can modulate the activity of NMDA receptors. It may act as a cofactor or modulator at these receptors, influencing their responsiveness to glutamate, the primary excitatory neurotransmitter in the brain. This modulation can impact synaptic strength and plasticity.

Zinc Effects on NMDA Receptor Gating Kinetics

Neboglamine, sarcosine, magnesium, D-serine, H1 antagonists, Zelquistinel (& predecessors) and neurosteroids also modulate NMDA transmission; which seems to be hypoactive in most schizophrenics and anhedonic patients (but some are the opposite).

NMDA subunit PAMs theoretically should be good for the hypo-active type, while NMDA antagonists (memantine and ketamine) work wonderfully for the hyperactive type. NMDA agonists are usually neurotoxic and should be avoided. Riluzole is also interesting. Noopept seems to be an NMDA glycine site ligand too, with some sources claiming it is an antagonist and others an agonist. It potentiates psychedelics and ketamine so I would bet it is an antagonist.

H1 antagonists like tricyclic antidepressants and mirtazapine indirectly lower NMDA transmission downstream. Δ-9THC is the same story through the CB1 pathway which could possibly explain why it helps some people with depression/anhedonia in the short-term (not long-term).

Piracetam upregulates NMDA receptors. ADHD brains seem to show hyperactivity of glutamatergic transmission. If you think you are hyper glutaminergic, correcting mGluR2 may suffice (and is easier/more accessible) with something like ALCAR or other HDAC inhibitors.

Ampakines like phenylpiracetam act on NMDA receptors and tend to help ADHD too.

To reduce excessive glutamate: retinol (or retinyl acetate/retinyl palmitate), zinc, copper, magnesium, improving ATP production by treating hypothyroidism, taking methylene blue, creatine, IN SkQ1, idebenone, fixing nutritional deficiencies that are compromising ATP synthesis and getting enough carbohydrates. Minocycline and D-cycloserine might help with fear extinction and NMDA hypofunction. Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity, so be sure to keep your selenium levels in check.

Acute administration of lithium increases levels of glutamate via activation of the NMDA receptor. Chronic administration, however, leads to NMDA receptor downregulation with glutamate reuptake

upregulation resulting in lowered levels of glutamate which explains the mood stabilization effect.

NMDA downregulation upregulates DA/NE/5-HT release through the AMPA receptor. More dopamine is released in the nucleus accumbens and prefrontal serotonin when NMDA is less active.

Methylation and its effect on NMDA function

Sarcosine is a cure, but… : r/SCT

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

GABA

ENX-102, kavalactones, chamomile/apigenin, black seed extract, magnolia bark extract, and agmatine are the best GABA modulators overall.. Kavalactones, BPC157, memantine, selank, HDAC inhibitors, afobazole, fasoracetam, bacopa, cerebrolysin and homotaurine upregulate GABA receptors which helps with resetting tolerance of GABAergics like phenibut. Linalool in lavender (and some cannabis strains) enhances GABA transmission.

Etifoxine can increase neurosteroids like allopregnanolone which is a GABA PAM. Other ways to increase allopregnanolone are oral pregnenolone, HCG, or direct allopregnanolone drops although these are not very bioavailable. Zuranolone is an analog that was made to be more bioavailable than direct allopregnanolone, and has been approved for postpartum depression. PEA (palmitoylethanolamide) can increase allopregnanolone via PPARα activation.

Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone

GABAergics like benzodiazepines inhibit microglial signaling. Those who respond to benzos for anhedonia should investigate inflammatory/immune causes, as they are not sustainable long term. Phenelzine is also an option as it inhibits GABAT in addition to being an MAOI, but has many side effects like sexual dysfunction and constipation/lowered motility.

GABAA negative allosteric modulators induce a tonic glutamate rush. Examples include DHEA and ginkgo. Serotonergic psychedelics (DMT, psilocybin, etc) as well as NMDA antagonists induce a phasic glutamate rush. If you have a high tonic glutamate already, you won't respond to phasic glutamate increase, and GABAA negative allosteric modulators will make you feel worse (as well as intense training).

AMPA

PAM like TAK-653, noopept (has AMPA agonist affinity however) or piracetam (AMPA PAMs potentiate dissociatives and psychedelics). Ketamine activates AMPA too indirectly. IDRA-21 is an AMPA PAM, AMPA agonist, NR2B antagonist, and has a very short half-life; but cognitive-enhancing effects last for up to 3 days because the nootropic effects are actually from LTP induction in the hippocampus and elsewhere. It has the risk of inducing seizures though as AMPA agonism can be excitotoxic. Lithium acts as an AMPA agonist, which is responsible for most of its antidepressant effect.

mGluR (Metabotropic Glutamate Receptors)

Fasoracetam and psychedelics activate mGluR and its subunits, which might be why they cause HPPD in vulnerable individuals. Pramiracetam, noopept and oxiracetam may be helpful too. mGluR2 activation in the 5-HT2A-mGluR2 heteromer has the same effect as 5-HT2A antagonism, and regulation of it has been implicated in the same disorders. If you think you are hyper glutaminergic, correcting mGluR2 may potentially suffice (and is easier/more accessible) with something like ALCAR or other HDAC inhibitors (ie. vorinostat upregulates mGluR2), though their affinity may be limited.

mGluR3 is very important for cognition, mood, executive dysfunction and many other disorders. It is one of the main receptors whose activity is downregulated with aging and especially with neurological conditions such as Alzheimer's Disease. mGluR3 interacts with an enzyme named GCP-II/PSMA, which largely controls the receptor’s function. Inhibition of GCP-II increases mGluR3 significantly (through NAAG), and also increases short/long term memory significantly. Inhibiting GCP-II also is anti-addictive through directly modulating the dlPFC-Limbic pathway, enhancing top-down control and mental autonomy. Inhibiting GCP-II has also been effective at attenuating Alzheimer's and TBI in rodents, on top of other neurological disorders, and this is mediated through mGluR3. ZJ-43 is a GCP-II inhibitor: nootropic, analgesic, anticarcinogen, antipsychotic.

Most compounds that modulate mGluR3 directly also modulate mGluR2, which leads to a less clean effect profile and more glutamate inhibition. Therefore modulating mGluR3 through the GCP-II–NAAG–mGluR3 pathway is likely more effective and easier considering there is not competition for other mGluRs as it does not interact directly. By the way, fun fact, NAAG is the third-most-prevalent neurotransmitter in the mammalian nervous system, so it is quite important (and underrated for modulation).

mGluR5 is involved in various neural processes and has complex roles depending on the brain region and neuronal types involved.

For example, in the cortex, mGluR5 is mostly present on GABA interneurons and its increased expression suppresses pyramidal neuronal activity. This is achieved through the enhancement of long-term depression in excitatory synapses and the loss of presynaptic modulation by mGluR5. Selective cortical excitation of mGluR5 present on glutamate neurons is anti-depressive. Ketamine causes a rapid reduction in cortical mGluR5 expression, with cortical mGluR5 being pro-depressive and limbic mGluR5 being pro-hedonic.

mGluR5 generally acts as a pro-hedonic receptor but becomes depressive when it inhibits glutamate through GABA interneurons. D2 agonism inhibits cortical mGluR5, leading to an antidepressant effect by disinhibiting cortical glutamate firing. Estradiol potentiates mGluR5, improving the hedonic response and increasing dopamine signaling, which leads to a reduction of the cortical type of mGluR5 present on GABAergic neurons. Increased expression of mGluR5 in the hippocampus may reflect compensatory changes to imbalanced glutamate neurotransmission, especially in the context of NMDA receptor hypoactivation, as seen in schizophrenia. mGluR5 mediates the potentiation of NMDA responses in neurons, and its downregulation occurs following chronic activation, such as in addiction. NMDA antagonists can lead to a compensatory upregulation of mGluR5. Chronic morphine treatment increases mGluR5 expression, while lithium decreases it. SSRIs increase p11, a protein that potentiates mGluR5 through 5-HT1B agonism.

The best method of potentiating cognition via mGluR5 is through potentiating mGluR5-Gαq selectively with a PAM, such as VU0409551. This is because increasing mGluR5 generally, especially with something like an agonist, has a likelihood of neurotoxicity and seizures mainly due to its NMDA interactions. Using a PAM on mGluR5-Gαq does not enhance NMDA which avoids this issue, while keeping a procognitive effect.

mGluR5 modulates dopamine transporter activity in the striatum, affecting dopamine-induced long-term potentiation (LTP) and cravings/addiction. mGluR5 in the medial prefrontal cortex plays a role in determining pain and ensuing depression, indicating its involvement in mood and affective disorders. Estradiol potentiates the mGluR1-mGluR5 complex, enhancing drug-induced euphoria and making females more vulnerable to addiction. This effect is mediated by ERalpha.

Increased mGluR5 signaling is associated with OCD-like behaviors and striatal circuit abnormalities. Moreover, sleep deprivation increases mGluR5 availability, which correlates with its antidepressant efficacy. mGluR5 activation can initiate a signaling pathway involving PLC, DAG, PKC, and Src, leading to tyrosine phosphorylation of NMDA receptors and their functional potentiation.

Opioidergic System

μ-opioid MOR

Sinomenine is a natural agonist (maybe venlafaxine/desvenlafaxine as well) which helps with both pain relief and anhedonia. High doses of antagonists like naltrexone are known to induce anhedonia however, but it upregulates MOR in the long-term. This receptor is very important for anhedonia and is shown to be dysfunctional in such patients.

Patients with depression and anhedonia should find great benefit by taking ibogaine which resets MOR sensitivity back to baseline. This helps stop opioid withdrawal symptoms, addictive tendencies and anhedonia. It is, by far, the most powerful opioidergic drug if not psychoactive drug in general and should be used with care. Ibogaine is neither an antagonist nor an agonist at MOR. It is considered a “modulator” since the mechanism of action is unique, poorly understood and cannot be described easily in a phrase.

Another way to indirectly activate this pathway without downregulating it is through administration of enkephalinase inhibitors like semax, selank and epitalon.

Oxytocin is a PAM (positive allosteric modulator) at this receptor. CBD is also another PAM at this receptor too. Thymoquinone in black seed oil (nigella sativa) is a PAM as well. Pregabalin helps some with anhedonia possibly due to indirect modulation of μ-opioid receptors.

δ-opioid DOR

Ibogaine and mitragynine are agonists which help with pain relief and anhedonia. Antagonists like nalmefene and low-dose naltrexone (not high-dose) also ironically help some people with anhedonia. Δ-9THC and CBD are both PAMs of this receptor, but Δ-9THC is not recommended for anhedonia as it downregulates eCB receptors in the long-term. Semax and its analogs are indirect agonists at this receptor due to inhibition of breakdown of enkephalins which are endogenous agonists. Only semax is a safe agonist for this receptor in the long-term.

κ-opioid KOR

Partial agonists like erinacineE disinhibit dopamine release after the κ-opioid receptor is downregulated. An antagonist like nor-BNI can be used once a week at 200 mcg. Ibogaine is an agonist that downregulates κ-opioid in the rebound. SalvinorinA is another κ-opioid receptor agonist although it does NOT seem to downregulate κ-opioid receptor with usage as much as other agonists. Mirtazapine is also a κ-opioid receptor partial agonist but has bad side effects so I don't recommend it. Nor-BNI is theoretically the most effective ligand (antagonist) out of the bunch since it downregulates κ-opioid receptors for a month after a single dose, but there are no safety trials in humans.

KOR antagonists upregulate SERT.

Keep in mind that κ-opioid antagonism is recommended for depersonalization/derealization disorder (DPDR) and not agonism or partial agonism as activating this receptor results in dissociation and dysphoria. Aticaprant is an interesting κ-opioid receptor antagonist in clinical trials for treatment of depression and DPDR.

Kappa agonism for anhedonia

Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics

Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase

Kappa opioid receptor modulation of excitatory drive onto nucleus accumbens fast-spiking interneurons

The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors

Modulation of serotonin transporter function by kappa-opioid receptor ligands

Endocannabinoid System

CB1

Pregnenolone (and CBD) are NAMs. THC enhances and upregulates 5-HT2A through CB1 but not 2-AG or anandamide since it’s blocked by CB2 agonist but is cognitively impairing. Not recommended for most people, but can help anhedonia in rare cases although still not ideal. It is cognitively impairing and downregulates dopamine in the long term. SalvinorinA, yangonin (a kavalactone) and EGCG (hepatotoxic) act on this receptor too. Acetaminophen and ibuprofen somehow show cannabinoid activity as well which could explain why they help pain.

High doses of THC often induce psychosis, especially in males younger than 25 with AKT1 (cc variant) and COMT (val/val) genes.

CB1 agonists tend to induce euphoria in a subset of people and temporarily alleviate anhedonia. However this is likely to develop into an addiction (chronic marijuana use is bad for the brain). WWB potentiates analgesic effects of CB1 agonists. AM404, the metabolite of paracetamol, is an endogenous cannabinoid reuptake inhibitor that mediates its anticonvulsant effects through CB1 receptors, and also happens to be an anandamide transport inhibitor. L-theanine is a CB1 antagonist which helps upregulate CB1 after marijuana abuse. Voacangine is another lesser-known antagonist. Rutin externalizes CB1 which is good for recovering from THC-induced cognitive decline.

Naloxone, a μ-opioid receptor antagonist, inhibited THC-induced Fos immunoreactivity in several regions of the rat central nervous system, including the ventral tegmental area, hypothalamus, caudate-putamen, and periaqueductal gray. Conversely, naloxone and THC had an additive effect on Fos immunoreactivity in the amygdala, stria terminalis, insular cortex, and paraventricular nucleus of the thalamus

DHEA and EPEA are both cannabinoid CB1 and CB2 receptor agonists.

A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice

There is some evidence that tropisetron upregulates CB1 which explains its analgesic properties.

CB2

β-caryophyllene is an agonist at this receptor which is anti-psychotic and pro-mood. Agonists upregulate 5-HT2A downstream through ERK1/2 signaling which is useful for potentiating psychedelics and reversing their tolerance, but can worsen mood. CBD is an antagonist in presence of CB1 and CB2 agonists; happens to be a trkA agonist as well. THCV activates CB2 and blocks CB1. Yangonin in kava is another agonist.

An Endocannabinoid Uptake Inhibitor from Black Pepper Exerts Pronounced Anti-Inflammatory Effects in Mice

Cholinergic System

Nicotinic aChR α1 to β4

Partial agonists like tropisetron (α7), or ABT-089/phenylpiracetam (α4β2 agonists, the latter has affinity of 5.86 μM) for cognitive enhancement. Bifemelane is an agonist at some nAChRs too. Partial agonists are preferable to avoid receptor desensitization.

Molecular insights into the benefits of nicotine on memory and cognition (Review)

Muscarinic aChR M1 to M5

Avoid anticholinergics as the side effects are horrific (plus they are anti-cognitive). Both agonists (ie. ALCAR indirectly through increasing acetylcholine levels which is an endogenous agonist), and antagonists (ie. tricyclic antidepressants, diphenhydramine, cyproheptadine and scopolamine) could be antidepressant depending on your genetic makeup. If you have excess acetylcholine, stack piracetam (acetylcholine sponge) and acetylcholinesterase inducers like forskolin or coluracetam; and agmatine.

Acetylcholine also reduces distractibility by increasing signal to noise ratio and reducing processing of irrelevant stimuli in the environment. M3 antagonism triggers remyelination of neurons, so it can be good in moderation (especially for PSSD/SFN folk). M1 is an interesting muscarinic receptor; it is optimally targeted using PAM compounds rather than agonists.

Diphenhydramine, a potent M1 and M4 antagonist, increases dopamine and oxytocin release through blockage of the mentioned receptors in limbic areas.

Melanocortin System

MC1 to MC4

Antagonize with MIF1 ideally or semax. Melanocortin receptor dysfunction is implicated in anhedonia and mood disorders. Avoid agonists like melanotan-II, bupropion and PT-141 as they can cause anhedonia. Administration of MC4 antagonists (ie. semax and its analogs) is associated with a significant increase in the pleasurable effects of opioids including endogenously-produced types such as enkephalins.

A Dissociation of the Acute Effects of Bupropion on Positive Emotional Processing and Reward Processing in Healthy Volunteers

Calcium and Potassium Channels

Sodium and Calcium Channels

Blockers like kavalactones, phenibut and pregabalin/gabapentin can help anhedonia for some people.

T-Type Calcium Channels

SAK3 as a Cav3.1 and Cav3.3 agonist, promotes dopamine, acetylcholine and serotonin release. It has anxiolytic (lasts up to 2 weeks post withdrawal), antidepressant (through increasing neurogenesis) and stimulant effects.

KCNQ2/3 Potassium Channels

Openers like ezogabine show potential in treating anhedonia but come with severe side effects.

GIRK (G-protein-activated Inwardly Rectifying K+ Potassium Channels)

Inhibited by reboxetine and atomoxetine which are noradrenergic. Upregulating this receptor through antagonism causes 5-HT1A to sensitize, which is useful for PSSD and sexual dysfunction.

Hormone Receptors

ERα

Estrogen receptors are heavily involved in oxytocin receptor modulation. Oxytocin, in turn, is responsible for mu opioid receptor sensitivity across the CNS. High tonic serotonin release leads to rapid oxytocin receptor downregulation and anorgasmia. ERα activation upregulates 5-HT1A receptors and induces oxytocin receptor expression both in the brain and periphery. High ERα signaling can lead to OCD, anxiety, and hypersexuality -- this is because ERα directly upregulates mGluR5 which is the receptor involved in OCD. ERα also upregulates the mesolimbic dopamine pathways so potently, making people overall way more hedonistic and hypersexual / hyper-emotional.

Usually it is due to either vitamin D deficiency or an abnormal VDR allele, which is also very common among PSSD sufferers. This could also be why people often crash miserably from vit D3 supplementation, since it reduces ERα signaling even further.

ERα induces oxytocin receptor expression centrally and peripherally. ERβ induces hypothalamic oxytocin release and could have antidepressant effects there.

Progesterone works through sensitizing ERα mainly within the mPOA. Progesterone has different effects on ERα depending on tissue type, but what's important for us is the mPOA.

ERβ

ERβ activation induces hypothalamic oxytocin release. Oxytocin neurons of the paraventricular and supraoptic nuclei express GPR30, so activation of GPR30 causes oxytocin release, which might mediate estradiol's rapid antidepressant effect.

ERβ activation upregulates 5-HT2A receptors. Activation of 5-HT2A receptors increases protein kinase C (PKC), which in turn desensitizes presynaptic 5-HT1A autoreceptors, resulting in increased postsynaptic 5-HT1A heteroreceptor activation. Furthermore, estradiol directly desensitizes hypothalamic 5-HT1A receptors, possibly through GPR30.

HCG according to some studies downregulates ERβ mRNA expression. HDAC inhibition sensitizes ERβ more than it does ERα.

Although ERβ and ERα can have some antagonistic effects to each others (i.e. tryprophan hydroxylase, or mGluR5), working ERβ is essential for hedonic ability.

Mitochondria

PQQ, NSI-189, methylene blue, inosine, idebenone, carnosic acid, J147 (also happens to be a 5-HT1A agonist) and IN SkQ1 are good for mitochondrial health. Do not take them all at once obviously. Only two or three are enough, and beware of methylene blue’s MAOI action at 10 mg/kg + doses. NSI-189 + IN SkQ1 + methylene blue is a good stack.

mTOR

Activate with ketamine or agmatine for enhanced synaptic pruning. Some people like to inhibit mTOR with rapamycin, metformin or berberine because it can be antidepressant. IN insulin is another activator. Chromium picolinate probably indirectly activates mTOR through restoring insulin sensitivity.

TrkB, mTOR, and 5-HT2A signaling underlie psychedelic-induced plasticity.

Sigma-1 σ1

PAM (like E1R) or agonists like DMT, memantine, opipramol, fluoxetine, allopregnanolone, fluvoxamine, PRE084, DXM (neurotoxic and is an SRI), 3-MeO-PCP, cariprazine, donepezil (60% occupancy at 5 mg) and SJW are the most desirable ligands for this receptor. Both PAMs and agonists potentiate dopaminergic transmission (which can be synergistic with stimulants). σ1 receptors modulate dopamine, μ-opioid, κ-opioid, NMDA and LTP transmission. Fluvoxamine and opipramol are the most potent σ1 agonists available. σ1 activation also improves plasticity by potentiating NMDA and Ca2+ transmission.

Fluvoxamine is an SSRI so it’s not recommended, but perhaps microdosing it just enough to increase neurosteroid synthesis without inhibiting SERT can be good. Combined 5-HT reuptake inhibition and σ1 receptor activation has a synergistic effect on prefrontal dopaminergic transmission, along with NMDA antagonists + σ1 agonism and AChEi’s. Fluvoxamine works better with patients suffering from psychotic depression compared to antidepressants without σ1 receptor agonist properties.

Anecdotes of activation of this receptor seems to point towards it helping with depersonalisation/derealization sometimes, and might be the receptor behind neuroplasticity induced by psychedelics.

The most effective SSRIs have actually been found to have a relatively significant σ1 affinity, leading to the hypothesis that σ1 affinity underlies the beneficial effects of many compounds that may have been much less effective without. Another compound that may be an example is memantine, which is an NMDA antagonist, which usually is undesirable, however some may benefit from the σ1 potentiation, albeit better options for increasing σ1 are likely available.

Psychedelic’s ability to enhance consciousness and perception may somewhat be mediated via σ1, one example being DMT and 5-MeO-DMT.

σ1 knockout mice maintained on a high fat diet have lower fat mass compared to wildtype controls, but do not differ in metabolism, indicating that σ1 is important for diet-induced adiposity.

Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine

The σ1-protein interacts with μ-opioid and trkB-receptors, whereas in preclinical experiments σ1-agonists reduce μ-receptor desensitization and improve trkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone.

1) NMDA antagonist already sensitizes μ-opioid receptor

2) σ1 ligands also prevents desensitization of μ-opioid receptor

R-ketamine can probably go well with low dose buprenorphine or tianeptine.

Neurotrophic Factors BDNF, NGF, GDNF, CDNF, MANF, etc

Can be upregulated with bromantane, NSI-189, lion’s mane (5α-reductase - 5α-R inhibitor, beware if you have PSSD or PFS), TAK-653, ketamine, semax, and cerebrolysin. 9-methyl-β-carboline (especially GDNF) and lithium orotate also upregulate neurotrophic factors. Psychedelics upregulate neurotrophic factors as well. Tabernanthalog is the best non hallucinogenic psychedelic analog. Blueberry vinegar can also be used to increase neurotrophic factors.

Dihexa and ISRIB (or its potentially safer derivative ABBV-CLS-7262/Fosigotifator) are experimental RCs that are the most effective at raising neurotrophic factors, but aren’t studied in humans. MANF is generally more selective and better at repairing dopaminergic neurons; and CDNF is even better than MANF (CDNF ≥ MANF ≥ GDNF). 9-methyl-β-carboline is the only substance so far to increase CDNF; 9-methyl-β-carboline, lithium, piperine and CBD can enhance MANF.

MT1 and MT2

Agomelatine is good for sleep (hepatotoxic). Aside from that not much is known about this receptor family in terms of effects.

HIF1

Agonists like noopept (also AMPA agonist) or roxadustat possibly have positive mood benefits according to some early research.

A2A-adenosine

Antagonists like istradefylline and caffeine upregulate D2 and D3 receptors downstream. Chronic blockade of adenosine A2A prevents the memory deficits induced by cannabinoids. A2A blockade attenuates cannabinoid-mediated impairments in hippocampal LTP. Pentoxifylline is primarily a non selective PDE inhibitor and A2A antagonist.

cAMP

Forskolin increases it (which also has cardiovascular effects). Kanna (mesembrenone specifically) indirectly increases it through general weak PDE4 inhibition. Intranasal Administration of Forskolin and Noopept Reverses Parkinsonian Pathology in PINK1 Knockout Rats. The D2-family receptors inhibit cAMP.

TrkA and TrkB

Agonists like 7,8-DHF, 4'-DMA-7,8-DHF, lion’s mane, NA-semax-amidate, β-caryophyllene and myricetin increase neurogenesis. Aim to upregulate trkB with polygala and NA-semax-amidate for maximum neurogenesis over the long-term. This receptor happens to be very important for antidepressant action, and could be one of the main reasons why amitriptyline (trkA-B agonist) is always at the top of most antidepressant effectiveness meta-analysis studies.

TrkB activation by BDNF upregulates several dopamine receptors as well as 5-HT1A and SERT. Tropomyosin receptor kinase B has also been shown to upregulate estrogen receptors, particularly ERα, in certain cellular contexts. This interaction is especially relevant in the treatment of PSSD, and cancer research such as in breast cancer and neural tissues. TrkB activation can enhance estrogen receptor expression through signaling pathways like PI3K/Akt and MAPK/ERK. Conversely, studies have demonstrated that estrogen can directly upregulate BDNF expression via the ERα-dependent genomic pathway, indicating that estrogen signaling can influence the BDNF/TrkB pathway. ACD-855 and ACD-856 are both trkB PAMs.

Study suggests the majority of antidepressant compounds and psychedelics are direct TrkB PAMs

GLP1

Glucagon-like peptide 1 (GLP1) drugs have been shown to have effects on neurotransmitters, particularly dopamine, serotonin, GABA , and glutamate. GLP1 and GLP1 receptor agonists (GLP1 agonists) can modulate the release of these neurotransmitters and regulate their balance in the brain. GLP1 are distributed throughout the brain, including the mesolimbic reward system, such as the ventral tegmental area, accumbens core, and lateral septum. GLP1 is also found outside the mesolimbic reward system, including the hippocampus.

GLP1 and GLP1 agonists have been shown to regulate drug-motivated behaviors and improve the behavior of laboratory rodents exposed to many psychostimulants such as cocaine, alcohol, nicotine, and amphetamine. GLP1 drugs have also been shown to reduce food intake and body weight. GLP1 modulates dopamine levels and glutamatergic neurotransmission, which results in observed behavioral changes. GLP1 drugs have shown promise in treating addiction, including alcohol and opioid use disorder. Myricetin is an example of a compound that increases GLP1.

Cerebral Activity

Indeloxazine and bifemelane are interesting cerebral activators. For some reason only Japan is interested in researching this class of drugs.

Catecholaminergic Activity

Selegiline sublingually or transdermally enhances catecholaminergic activity; but do not combine it with tranylcypromine as it’s redundant. BPAP and PPAP are also catecholaminergic activity enhancers, but possess no safety data in humans. Rasagiline boosts DA and PEA levels in the brain significantly and promotes regeneration of substantia nigra dopaminergic neurons in Parkinsonian mice, but isn’t quite a catecholaminergic activity enhancer (not as good as BPAP, PPAP or selegiline).

OXR1

The OXR1 gene plays a key role in maintaining brain health and prolonging life with diet. Restricting food to 10% of a typical diet activates this gene, improving neuronal protection. A Buck Institute study on fruit flies and human cells suggests how strategies such as interval fasting can affect OXR1 and promote brain health and longevity. Calorie restriction affects the gene, enhancing the protein sorting mechanism in cells and emphasizing the importance of diet in slowing brain aging.

TAAR1

WIP

Nootropic Stacks

Highlighted in red are research chemicals and ones in magenta are hepatotoxic.

Hepatotoxic chemicals should be avoided, but if necessary then they should be stacked with hepatoprotectors like black seed oil, NAC, TUDCA, Na-R-ALA/R-ALA, NovaSOL curcumin (with bioperine ideally), schisandra and/or milk thistle.

NOTE: you don’t have to take all of them. Just 5 or so are enough. These are only to highlight theoretical synergies and lack of interactions.

Comprehensive Anhedonia and PSSD Stack

15 mg 9-methyl-β-carboline for 60-150 days (ideally in the winter because of UV photosensitivity) then switch to tranylcypromine/kanna/SJW Ze 117/ibogaine microdosing + 100-300 mcg 10-MeO-Harmalan/≤5 mg metergoline/≤200 mcg lisuride as serotonin antagonist/partial agonist + ≤30 mg memantine + 1500 mg acetyl L-carnitine (to upregulate D2 and D3) + 1 drop weekly of Energin (or active vitamin B complex) + 200 mcg nor-BNI once a week for κ-opioid receptor downregulation + 250 mg intranasal agmatine sulfate + 1-30 mg (elemental) lithium + 25 mg zinc + 100 mg magnesium (threonate ideally) + IN 10 mg MIF1 (D2 and D4 PAM, also increases oxytocin) + 50 mg neboglamine/Zelquistinel + CBD full-spectrum oil sublingually or vaped (more bioavailable) + 1000 mg NAC (divide by 10 for NACET dose) + 300 mg myricetin + 1000 mg black seed oil + 25 mg J147

Outlined Treatment Strategies for Treatment-Resistant Anhedonia (work in progress)

Class: compound, dose, ROA, frequency

Overview

Many experience significant symptom relief, sometimes achieving complete remission, through monotherapy with several of the mentioned antidepressants. If monotherapy proves insufficient, combining two or more agents could be considered. For those experiencing symptoms characterized by agitation rather than inhibition, a tricyclic antidepressant (TCA) may be of particular interest due to its sedating and anxiolytic effects. On the other hand, those struggling with inhibition and lethargy may find psychostimulatory agents more suitable.

Compounds within the same class can typically be substituted interchangeably, considering factors such as equivalent dosing and duration of action between the different compounds. Keep common sense in mind, and ALWAYS double-check for potential drug-interactions. Below I will include a few reference stacks by symptom hallmarks.

Agitated Depression, or where significant anxiety is present: n/a

Inhibited Depression, with severe presentation, or melancholia: n/a

Dysthymia: n/a

It's important to recognize that "Treatment-Resistant Depression" isn't a distinct subtype of depression but rather a reflection of current treatment limitations, with its prevalence directly corresponding to the effectiveness, or lack thereof, of available options at the time.

Tricyclic Antidepressants

Specifics regarding their pharmacological mechanisms is outlined here.

TCAs are often derivatives of the phenothiazines, a class of compounds that includes antihistamines such as Chlorpromazine, Promethazine, and Promazine. Due to their structural resemblance with phenothiazines, the majority of tricyclic antidepressants share similar pharmacological characteristics and target sites. There are a few exceptions however, such as Tianeptine.

Imipramine

Imipramine (known as G-22355 during development) was introduced as an antidepressant in Europe in 1958, marketed as Tofranil. Its discovery as an antidepressant is often regarded as serendipitous. Initially explored for treating schizophrenia without success and was later abandoned for this indication, it did however show promise for depression in a 1955 trial where….. However, its efficacy was later questioned as assessments at the time relied heavily on subjective observations of symptoms by raters, rather than through standardized scales like the Hamilton Depression Rating Scale (HAM-D), first introduced in 1960 by Max Hamilton.

Its efficacy as an antidepressant appears…

Amineptine

Amineptine stands out among other TCAs due to its notable, albeit relatively mild and short lasting (t1/2 of 0.8-2.5 hours), psychostimulatory effects. It is one of the few TCAs associated with abuse potential and documented cases of misuse, along with Tianeptine.

Clomipramine

Involvement of the microglial NLRP3 inflammasome in the anti-inflammatory effect of the antidepressant clomipramine

“Clomipramine ameliorates depressive-like behaviors, inflammation, the NLRP3 inflammasome, and microglial activation in the hippocampus in LPS-treated mice.”

Amitriptyline

Amoxapine

Monoamine Oxidase Inhibitors (MAOIs)

Specifics regarding their pharmacological mechanisms are outlined here.

Iproniazid, the first MAO-I found to exhibit antidepressant effects, was originally used as an antibiotic for tuberculosis. Its antidepressant effects were discovered serendipitously later on. Although Iproniazid was among the earliest antidepressants on the market, Amphetamine, marketed as Benzedrine from 1935 for the treatment of “mild depression”, predates it.

“Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications) predates it”

MAO-Is, such as Tranylcypromine, completely eliminates REM sleep, which is believed to contribute to its antidepressant effects.

List of MAO-Is (type): Moclobemide (RIMA) 450-1650 mg/day, Bifemelane (RIMA) 150-300 mg/day, Tranylcypromine, Phenelzine, 9-methyl-β-carboline

Psychostimulants

Although the term "psychostimulant" lacks a universally accepted definition. In this text, both "psychostimulant" and "stimulant" will denote a sympathomimetic agent. While outdated, this nomenclature is kept for accessibility and clarity.

Psychostimulants, recognized for their antidepressant efficacy since the early 1930s, represent the first generation of antidepressants, including Amphetamine and Methylphenidate among others. For many individuals with particularly severe treatment-resistant depression, they are sometimes regarded as nothing short of a miracle.

“At the six-month follow-up, the patient still endorsed a very significant relief of depressive symptoms. She stated that her mood is still very much improved, that she feels very stable on dextroamphetamine and amphetamine combination salts and even went as far as to call it “a wonder drug” for her.” - (Small et al., 2022)

“Some 45% described the psychostimulant as the best or equal best to previously prescribed antidepressants, and 48% reported a sustained benefit. Such effectiveness rates in those with TRD are impressive” - (Parker, 2023)

“Over decades, I have given dexamphetamine to hundreds of patients (including many highly educated patients) for prolonged periods ranging from weeks to years, with overt benefits in the vast majority, and with about five complications. Withdrawal effects, if stopped abruptly, consist simply of tiredness or return of depression.” - (Horgan, 2016)

These compounds alleviate symptoms such as psychomotor inhibition, lethargy, and general low mood, offering rapid symptom relief, often within a few hours, for patients suffering from melancholic depression - a particularly difficult-to-treat entity similar to depression. In addition, they could extend the periods between episodes for individuals with recurrent depression, demonstrating high effectiveness even in the most treatment-resistant cases [1,2,3,4,5,6], without significant tolerance development and great tolerability. Methylphenidate also appears to reduce the incidence of suicide attempts and self-harming behavior, along with improving positive interpersonal perceptions in those with dysphoria.

“Methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal- or self-harming behaviour.” - (Rohde et al., 2020)

The positive mood-altering effects of Methylphenidate appear to correspond with how people perceive their interactions with others, especially those experiencing dysphoria.

Psychostimulants can motivate patients to improve and be more optimistic toward their treatment and recovery, addressing one of the most debilitating barriers hindering their recovery - poor executive functioning, lethargy, and lack of motivation.

Many individuals with depression appear particularly responsive to the mood-enhancing effects of psychostimulants

Other Research

In a 2023 meta-analysis of 13 RCTs on the use of psychostimulant augmentation for treating depression, it was found that psychostimulant augmentation effectively alleviates the burden of depressive symptoms without necessarily increasing the odds of remission.

In phase 2 trials, Lisdexamfetamine (Vyvanse, pro-drug to dextroamphetamine) showed promising efficacy in treating depression. However, despite initial success, it was dropped during phase 3 trials after failing to demonstrate the same level of effectiveness. The most common explanation for the disparity between the two trials was that the phase 2 study was underpowered. However, there have been various other hypotheses made as to why this might have happened.

Psychostimulants may improve domains beyond those typically evaluated, such as cognitive symptoms, which are often overlooked by commonly used inventories like variations of the Hamilton Depression Rating Scale (HAM-D) or the Montgomery-Åsberg Depression Rating Scale (MAD-RS).

Treatment of Eating Disorders

There were plans to trial Lisdexamfetamine for another condition, namely Bulimia nervosa, a condition often comorbid with depression. Unfortunately, efforts ended for unknown reasons. However, based on what we know from past preliminary case reports, psychostimulants are NOT to be considered contraindicated for the treatment of restrictive eating disorders such as Bulimia or Anorexia nervosa, and may in fact alleviate symptoms associated with the disorder in those with and without ADHD.

Who is most likely to benefit from psychostimulant therapy for depression?

Based on patient characteristics highlighted in past studies, it appears that those experiencing particularly severe depression or melancholia, characterized by hallmark symptoms such as psychomotor retardation (lethargy, cognitive impairment, and ‘hypoactive delirium’ [1,2]), executive dysfunction, consummatory and anticipatory anhedonia, are the ones most likely to derive benefit from psychostimulants.

How to use

For those benefiting from psychostimulants, continued usage over months to years is often necessary as stopping typically leads to the return of depressive symptoms. In cases of reduced response to psychostimulants, the addition of Tranylcypromine has been noted to significantly improve both efficacy and duration of remission from Dextroamphetamine in one case-study, after either treatment alone appeared to only be effective in the short-term, with the patient experiencing continuous relapses shortly after each treatment introduction in the past.

Psychostimulants: Dextroamphetamine 10-30 mg/day b.i.d., Lisdexamfetamine 30-70 mg/day (equiv. 10-30 mg/day d-amph sulfate) b.i.d., Methylphenidate (IR) 10-60 mg/day t.i.d., Cyclazodone (and NMC) 20-50 mg/day b.i.d., Methamphetamine 2.5-5 mg/day

Note: N-Methyl-Cyclazodone appears to be a pro-drug of regular Cyclazodone, as described in a 2022 toxicological case-report, where they measured Cyclazodone in the urine of a patient taking N-Methyl-Cyclazodone.

Atypical Psychostimulants: Bromantane ≤36 mg/day IN, Modafinil

Bromantane, being a lipid-soluble compound, is recommended to be dissolved for intranasal use using Caprylic Acid as an excipient.

Nicotinic Receptor Agonists

Catecholamine Depletion

Catecholamine depletors like Reserpine…

“Eleven studies reported depressive effects of reserpine, 13 reported an absence of effect and 11 reported potential benefits for depression symptoms with reserpine.” - (Strawbridge et al., 2023)

Anticholinergics

Anticholinergics like Atropine or Scopolamine….

Anticholinergics suppress REM sleep, which is thought to contribute to the antidepressant effects of other compounds, such as the MAO-Is and tricyclics.

“The old tricyclic antidepressants (such as amitriptyline) were shown over many years to work very well for many people. [...] The side effects are due to various different pharmacologic effects, particularly the blockade of acetylcholine [...].

This suggests another interpretation of the "active placebo" effect: perhaps it is not simply the existence of side-effects that psychologically boosts a placebo effect here, it is that the side-effects themselves are due to a pharmacologic action that is actually of direct relevance to the treatment of depression.

While this is an interesting--though far from proven-- treatment idea, it is very important to be aware of anticholinergic side effects, which at times could be physically and psychologically unpleasant. At worst, cognitive impairment or delirium could occur as a result of excessive cholinergic blockade. Therefore, any attempt to treat psychiatric symptoms using anticholinergics should be undertaken with close collaboration with a psychiatrist.” - (Garth Kroeker, 2009)

Sleep Deprivation Therapy

Sleep Deprivation Therapy, also known as Wake Therapy, is an often overlooked option for those seeking rapid but short-lived relief from symptoms. Despite its impressive response rate of 40-60%, the results are transient, and relapse is common once sleep is resumed. It involves restricting sleep and sometimes methods to alter sleep architecture in an effort to manage depressive symptoms. Basically, it’s a deliberate form of sleep deprivation. It’s the foundation of the REM sleep hypothesis of managing Depression.

“Therapeutic efficacy of REM sleep reduction appeared similar to reported efficacy of imipramine hydrochloride treatment of depression. Eight of nine endogenous patients, unimproved by REM sleep deprivation, did not improve with imipramine. Results suggested (1) that substantial REM sleep reduction has antidepressant activity, and (2) since imipramine and other drug antidepressants reduce REM sleep much more so than non antidepressant drugs, that an antidepressant "mechanism" of drugs resides in their capacity to substantially reduce REM sleep.” - (Vogel et al., 1975)

There are no known serious side-effects from the restriction of REM sleep specifically, but sleep restriction for extended periods of time is known to disrupt regular functioning. Restricting REM does not appear to impair memory consolidation.

Other

Other: Agmatine sulfate, SJW Ze 117, Ibogaine microdosing ≤15 mg, Kanna (MX-16 extract), Black seed oil, nor-BNI IN, MIF1 SQ, Lithium orotate, β-caryophyllene, CBD, Nicotine

SJW Ze 117/9-methyl-β-carboline/≤15 mg ibogaine microdosing/kanna MX-16 + ≤36 mg IN bromantane + ≤30 mg memantine + cyclazodone/modafinil/methylphenidate/dextroamphetamine/lisdexamfetamine + black seed oil + agmatine sulfate + IN nor-BNI + IN/subQ MIF1 + lithium orotate + beta-caryophyllene + CBD

Out of everything I tried, only pramipexole, memantine, ketamine, bromantane, tranylcypromine, 9-methyl-β-carboline, vyvanse/dextroamphetamine, clomipramine, MIF1, lion’s mane, salvinorinA, lithium, Δ-9THC, β-caryophyllene, limonene, tropisetron, ALCAR, NAC, PE-22-28, creatine, active B complex like AOR's, B12 (methylcobalamin and adenosylcobalamin), low dose naltrexone and agmatine had any noticeable effect on anhedonia for me.

Antipsychotic Stack

CBD + cyproheptadine + β-caryophyllene + neboglamine/sarcosine + lithium + L-theanine + nuciferine (blue lotus) occasionally + NAC/NACET + agmatine sulfate + magnesium L-threonate + pregnenolone + cycle of BPC-157 + cycle of a neurogenic like cerebrolysin

The most effective pathways of modulation are most likely mGluR2/3 enhancers, EAAT2 PAMs & PDE4D NAMs (this is due to most affected protein level).

Stay away from NMDA antagonists, serotonin agonists (especially 5-HT2A and 5-HT2C), opioid agonists, dopamine agonists, and CB1 agonists like Δ-9THC.

Treatment-Resistant Anxiety Stack

Kava (Fiji Vanuatu extract or full spectrum paste are the best extracts) + fasoracetam + NAC/NACET + lithium + dry vaped CBD herb with β-caryophyllene, limonene and linalool + magnolia bark + neboglamine + nor-BNI + guanfacine + taurine + metergoline + SJW Perika or kanna MX-16 or ibogaine microdosing + etifoxine + DHEA/pregnenolone + active B vitamin complex (ie. Energin) + nigella sativa (5% thymoquinone at least) + memantine + magnesium L-threonate/magnesium chloride + URB597 + MIF1 + IN agmatine sulfate + IN vorinostat occasionally

Chronic Pain Stack

1000 mg agmatine + URB597 + WWB/celecoxib + dry vaped CBD herb with β-caryophyllene, limonene and linalool + glyNAC (glycine or derivatives like TMG/sarcosine with NAC) + kava (can replace with pregabalin/phenibut/magnolia bark if you prefer) + black seed oil (5%+ thymoquinone) + low dose naltrexone (≤5 mg) + allopregnanolone/etifoxine/PEA + vitexin + NRI like nortriptyline or reboxetine or MAOI like 9-methyl-β-carboline/tranylcypromine (latter is probably preferable due to NRI action above 40 mg) + L-berberine and/or NovaSOL curcumin w/ bioperine (AMPK activator) + magnesium chloride/L-pidolate/glycinate + DHEA with pregnenolone. Add memantine if still treatment-resistant.

Optionally you can also microdose psychedelics (or take neurogenics) to increase BDNF which helps with pain tolerance. If this stack isn’t enough, replace MAOI (if you were taking one) with amitriptyline or kanna MX-16 extract (not with any MAOI or SRI).

Amphetamine Microdosing Protocol
Credit to jcd3nt
Not recommended except as an absolute last resort for PSSD and anhedonia as it carries some theoretical risks such as developing tics or possibly psychosis.

One way to (possibly) sensitize dopamine receptors is to microdose amphetamine/methamphetamine (latter preferrable) for up to one week with PPARa activators (ie. β-caryophyllene), COX-2 inhibitor like WWB or celecoxib, SKQ1/CoQ10, a MAOB inhibitor like 9-methyl-β-carboline/selegiline/rhodiola/tranylcypromine, and nicotinamide riboside/nicotinic acid (for PGC1A activation), then cycle off with GDNF enhancers + PKC inhibitors like bromantane/amantadine/9-methyl-β-carboline/DNSP-11/NSI-189, PGC1α activators like niacin and lithium (only if you have the COMT val/val gene or respond well to lithium; to downregulate PKC back to baseline) with lots of high-protein food (to keep up with replenishment of neurotransmitters).

And optionally palmitoylethanolamide (PEA) with ALA + vitamin D3 (increases bioavailability of PEA) to increase dopamine in the mesolimbic system. You can also downregulate NR2B with an NMDA antagonist like memantine, ketamine or DXM afterwards periodically (do NOT take DXM with MAOIs or SRIs). This guide is also useful for resetting tolerance to amphetamines/stimulants.

Whether this microdosing protocol actually works or not is up for debate. It is definitely experimental, theoretical and not at all recommended as anything but a last-resort.

Dopamine Agonists for Treatment-resistant Depression

You can also try ≤250 mcg lisuride (D3 agonism), ≤5 mg pramipexole or ≤200 mg piribedil if possible. However, dopamine agonists downregulate D2 and D3 receptors in the long-term which is bad. Hence why this is NOT recommended unless you are very treatment-resistant and absolutely need it. Or if you have high prolactin and/or restless legs syndrome. If you had to choose one dopamine agonist, go for piribedil as it is the only agonist with little to no risk of developing DAWS. Dopamine agonist withdrawal syndrome (DAWS) is not something you would want to experience. Pramipexole especially has been studied to be extremely effective in treatment-resistant depression (both unipolar and bipolar) marked by anhedonia. The problem with pramipexole, however, is that it is a selective presynaptic D2 receptor agonist, which makes it sedating.

Dopamine agonists ranked by efficacy: piribedil > ropinirole > pramipexole > bromocriptine.

Dopaminergic Medications in Treatment-Resistant Depression - Meet the Scientist Webinar

Pramipexole: My Secret Weapon Against Anhedonia and Depression

Microdosing Amphetamine: the Results

The Many (Surprising) Health Benefits of Methamphetamine

Low and high dose methamphetamine differentially regulate synaptic structural plasticity in cortex and hippocampus

3,4‐Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine‐induced damage to dopamine nerve endings: β‐keto amphetamine modulation of neurotoxicity by the dopamine transporter

Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice | International Journal of Neuropsychopharmacology

Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10

Neurological Disorders

Depersonalization/Derealization Disorder

Sarcosine, low dose naltrexone, MIF1, ezogabine, riluzole, lamotrigine, lithium, BPC157 (risky), neboglamine, Zelquistinel, fasoracetam, glycine, Aticaprant, TAK653, piracetam and nor-BNI are the most helpful drugs for DPDR. Antidepressants or MAOIs (ie. 9-methyl-β-carboline, tranylcypromine, methylene blue) can help too. A lot of these may help HPPD as well since both HPPD and depersonalization/derealization disorder (DPDR) mostly involve glutamatergic dysfunction.

Opioid system dysfunction is implicated in depersonalization/derealization disorder (DPDR). NMDA modulators like NAC/NACET, glycine, piracetam, sarcosine, neboglamine and maybe fasoracetam too are likely helpful for DPDR. Avoid NMDA antagonists if you have DPDR. Refer to the KOR section.

PSSD

An Overview of PSSD - the Why and How to Fix It

PSSD stands for Post-SSRI Sexual Dysfunction Disorder, although it can be caused by similarly serotonergic substances like ashwagandha (desensitises 5-HT1A). Its symptoms are varied, ranging from genital numbness and erectile dysfunction to anhedonia and more for mood and sexual function both. There are many hypotheses as to how SSRIs/serotonergics could cause such persisting dysfunction in certain individuals and not others. The main factor behind this is the presence of poor detox and other epigenetic pathways that are difficult to change for a certain subset of the population. A common gene variant found in most PSSD sufferers is VDR, which is the allele that affects metabolism of vitamin D3. Another allele that increases risk of getting PSSD is CC in rs6311 of HTR2A, which also robustly increased risk of suicidal behavior and depression. It increases the risk of sexual dysfunction by 3.6x when taking SSRI antidepressants.

The presence of homozygous polymorphisms of VDR causes ER-alpha signaling to be upregulated before PSSD. This might be caused by vitamin D3 deficiency or a problem with the VDR gene variant (Ghost found a common variant with SNPs compilation). This makes the HPA axis super reactive, and we become hypersexual and hyper emotional. High ER-alpha signaling before PSSD would lead to OCD, anxiety, and hypersexuality -- this is because ER-alpha directly upregulates mGluR5 which is a receptor directly involved in OCD pathophysiology. This is why a lot of PSSD patients seem to have this phenotype of previous hyperemotionality and anxiety. It is therefore theorised that PSSD is the downregulation of ER-alpha signalling, which blunts 5-HT1A transmission (desensitisation) leading to dysfunctional dopamine release, less oxytocin induction (both of which are very important for mood and sexual function) and dysfunctional AR signalling along with methylation of important genes. In fact, without dopamine or oxytocin you would not feel any pleasure from sex. And ER-alpha is mainly responsible for AR induction in the hypothalamus.

Without ER-alpha, you won't have a libido to begin with. The variability in symptoms in PSSD subtypes come essentially from the variable levels of AR/ER methylation/silencing as well location of said silencing. As AR/ER regulates GABA-glutamate balance, dopamine, serotonin, and acetylcholine; a universal cure should target AR/ER silencing first and foremost, in every type of PSSD there is. After that, it's a matter of helping the brain get back to optimal homeostatic functioning over time. Libido is very important for nNOS -> NO induction for the erectile response. Problems that lead to weak erections can be low oxytocin, low dopamine, NMDA-NO-cGMP pathway, inflammation triggering hypoxia, chronic ED leading to structural changes (collagen deposition and hard flaccid).

As for what hypothalamic 5-HT1A does exactly, it increases dopamine, β-endorphin, and oxytocin in the region, and 5-HT1A activation also inhibits NMDA activity (good for anxiety and depression) - leading to the hypothesis that 5-HT1A desensitisation/low dopamine being the main culprit behind PSSD. Estrogen receptors are heavily involved in oxytocin receptor modulation. Oxytocin, in turn, is responsible for mu opioid receptor sensitivity across the CNS. High tonic serotonin release leads to rapid oxytocin receptor downregulation and anorgasmia, which is a result of high tryptophan hydroxylase activity (the enzyme that synthesises serotonin) and downregulated SERT – both of which increase serotonin receptor desensitisation even more.

The desensitisation of 5-HT1A desensitises MOR receptors downstream. This leads to lower release of endogenous pleasure chemicals called endorphins and enkephalins, which are released alongside dopamine during pleasurable activities. This also seems to be partially a result of gut dysbiosis caused by SSRIs and similar serotonergics affecting the gut microbiome - killing certain bacteria strains and/or causing overgrowth of fungus like candida. These bad bacteria release endotoxins which affect the brain and body, making the condition even worse. When the immune system is hyper-activated like in this case, it also attacks endogenous receptors. Quite a few people have been tested for antibodies that attack their own body receptors (the main one being ACE2). The good bacteria in the gut are known to release serotonin, GABA and other neurotransmitters, so when they are killed off, so does neurotransmitter release (and receptor activation changes).

One of the clues towards PSSD being gut-dysbiosis mediated, at least partially, is the presence of many anecdotes of probiotics and antibiotics/antifungals helping. Here are a few:

Almost cured through gut treatment : r/PSSD

Gut Theory - how I’m fixed : r/PSSD

Gut microbiota theory: How I finally cured my PSSD

And ofcourse the nuclear option is going for an FMT (fecal microbiota transplant), which has cured many (PFS and post-accutane are very similar syndromes). The ideal donor would be someone who lived a happy childhood and has no mental or gut issues. A hypersexual donor would be even better, but preferably one of the same sex (it anecdotally matters which makes sense because the gut modulates hormones as well). How this procedure works is that a donor of good health gets their stool sterilised and purified into an enema, which is then taken by the recipient over a week or two (sometimes a month) to colonise the gut and repopulate the microbiome with good bacteria. This actually leads to changes in the mood, sexual health, immune function and even personality. Sometimes the patient sees full remission then dips again. This is sometimes normal and means a second round is necessary (maybe a third or a fourth could be done later). It could also mean an alternative donor should be trialled.

Lipopolysaccharides, which are found in bacteria cell walls, could be the cause of many symptoms found in PSSD/PFS and related conditions. Stressed mice display greater intestinal permeability and circulating levels of this endotoxin. LPS binds to toll-like receptor 4, causing an inflammatory response. It has been shown to be implicated in chronic inflammation, neuroinflammation and associated diseases, making them a reasonable explanation for many symptoms including brain fog, SFN, joint pain, tinnitus, eye degeneration, etc as excessive cytokines are released regularly, preventing the body from healing. TLR4 inhibitors may prove to be therapeutic. Allopregnanolone is a TLR4 inhibitor.

Aside from gut dysbiosis, there is also the methylation of genes that affects body function as mentioned briefly before. DNMT are enzymes that catalyze the transfer of a methyl group to DNA, and when located in a gene promoter, DNA methylation acts to repress gene transcription. Simply put, genes are like switches. Methyl groups turn certain genes off, and there are enzymes in the body (DNMT and HDAC) that facilitate that. This is why HDAC and DNMT inhibitors help with depression and PSSD symptoms. There has been a popular case report of someone curing his post-finasteride syndrome with high doses of androgens and valproate (one of the most potent HDACi). The idea is that demethylating the genome will help reset the body back to the original state, and a 5-αR substrate which is dihydroboldenone would help the body reset its androgen function back to normal. This should work for PSSD too, although probably not in all cases.

Another popular HDACi used for treating PSSD and PFS is lithium. This one works differently from valproate in many ways, namely the fact that its affinity for certain subtypes of HDAC are lower, but it upregulates TET1 unlike valproate. TET1 is another enzyme responsible for demethylating the genome. A simpler supplement to take for inducing this enzyme is liposomal vitamin C, but stacking it with lithium is ideal for treating PSSD and PFS.

Lastly, one area that needs to be looked at in PSSD is neurosteroids. It has been found that allopregnanolone levels especially are altered in PFS and PSSD - usually lower but in some cases it's the complete opposite. Either way, when levels are out of range (too low or too high), problems arise. Simply put, allopregnanolone is an endogenous GABAA PAM which is a substance that enhances the function of a receptor’s endogenous ligand, instead of activating it directly and downregulating it. In most PSSD/PFS cases, this neurosteroid is endogenously underproduced, which leads to the GABA/glutamate ratio being out of balance - favoring glutamate (the excitatory neurotransmitter). The problem with glutamate being out of balance is that it acts against dopamine and GABA (especially in high amounts), which makes it anti-cognitive, anti-sexual and pro-depressive. However, if it’s too low, the neuronal excitability is kept to a minimum which obviously lowers sexual function and mood.

Thankfully, the solution to the neurosteroid balance is simpler than the rest - a 14-day cycle of zuranolone (preferably with an HDACi like tributyrate and proper action to fix gut microbiome including probiotics and antibiotics if necessary) should suffice, especially for milder cases. More severe cases might need more than zuranolone and an HDACi, but it is entirely possible that zuranolone by itself could be enough for a large number of patients.

Experimental PSSD Protocol (Stop at the Step Where You Get Cured):

Step 1 - Fix the Gut

Get tested for SIBO and SIFO first by getting a microbiome test (BiomeSight). If positive for SIBO, take rifaximin 550mg 3 times for 14 days + prebiotics + probiotics (megasporebiotic + InnovixLabs mood + Youtheory spore biotic + Linex Forte) + MegaIGg2000/good quality colostrum + L-glutamine + biofilm breakers (Interfase Plus) + tributyrin

If positive for SIFO instead, stack undecylenic acid with biofilm breakers (Interfase Plus) + good probiotics like Biogaia Osfortis, Youtheory Sporebiotic and/or MegaSporebiotic + colostrum/MegaIgG2000 + L-glutamine + caprylic acid (optional) for 2 months total.

If neither of these procedures succeed, consider at least 1 round of FMT if not more. DIY FMT could be done if you trust the provider/donor.

The reason why this is the first step is that, as mentioned before, gut dysbiosis seems to be the main factor behind most PSSD cases (if not all). This should be the first step. The gut protocol alone should cure many people. Move onto the next step if necessary. If you cannot get FMT, focus on cleaning your gut and colonising it with good bacteria.

Step 2 - Fix the Hormonal Imbalance

Get hormone levels checked and if they aren't ideal then bipolar androgen therapy of 500mg testosterone enanthate once a month + 5-25mg trestolone acetate daily for 3 months + 300-900mg lithium carbonate or 25-50mg zuranolone daily (for GSK3b inhibition) then PCT with 50-100mcg kisspeptin for 40-60 days should be done. SERMs like tamoxifen and clomiphene/enclomiphene are not recommended due to ocular damage risk.

Make sure to get your vitamin D3 levels checked as well. Aim for 60-100 ng/ml blood level if you are homozygous positive or heterozygous for a VDR mutation.

Step 3 - Induce Persistent Neuroplasticity

500-2000mg iboga TA (equivalent of 7.5-30g bark) + 1000mg L-carnitine + 1000mg magnesium oxide to counteract QT prolongation. Out of all psychedelics, ibogaine is by far the most promising for permanently rewiring the brain positively. It has been proven to cure addictions, i.e. opioids and pornography, by reversing the maladaptive neuroplasticity involved in addiction, which is very severe.

Here is a paper summarizing all research on this fascinating compound. Ibogaine reverses the long-term depression (LTD) that's present in PSSD and PFS cases. Unlike psilocybin, ibogaine upregulates not only BDNF but also GDNF, which is the neuro-regenerating material for dopamine, so ibogaine is a superior alternative to psilocybin (although the latter can be used if you are worried about ibogaine’s sides).

After trialling psychedelics, trial zuranolone 25-50mg for 14 days to fix the GABA-glutamate imbalance problem. A lot of patients will be cured by this step. Move on if necessary.

Step 4 - Maintain Neuroplasticity Induction

350-750mg DXM + 100mg CBG daily, and 1g psilocybin/50ug LSD (latter preferrable) trips once every 4 weeks and 100mg IM ketamine once weekly (not simultaneously) with EGCG beforehand to prevent bladder damage. Optionally, ACD-856 (a trkB PAM) could be added to enhance trkB function which increases neurogenesis further.

Step 5 - Fix the Dopamine System Dysfunction

A cycle of 9-Me-BC 15mg sublingual for 150 days + DHEA/pregnenolone mix + up to 30 mg memantine + optionally 500 mcg nor-BNI once a week. If the anhedonia is still treatment-resistant, do start a cycle of dopamine repair peptides like D21 + cyclo-gly-leu + HER-096 + optionally DNSP-11 for 1-3 months.

A weaker dopamine agonist like piribedil or bromocriptine + amphetamine microdosing until supersensitivity to dopamine is also an option as a stack. AVOID pramipexole due to DAWS risk (unless you are absolutely desperate).

Microdosing salvia is also an option to downregulate KOR which disinhibits dopamine release in the limbic areas. A KOR antagonist like nor-BNI should work as well in the long term.

Step 6 - Fix the Mitochondrial Dysfunction

This step will improve fatigue and energy levels the most. Take NMN + SkQ1 + PQQ + optionally ALCAR if you can tolerate it for 3 months then cycle SS-31 at 2-4mg daily for 20 days. Finally, take 2-4 weeks off and proceed to cycle 5mg Mots-C once a week for 4-8 weeks. Repeat this step once or twice if there is room for improvement.

Nuclear options for treatment-resistant depression

If none of the other protocols above worked for your depression, these two protocols down below can work.

The first one is stacking trans-ISRIB-A17 and/or dihexa with tranylcypromine and nootropics of your choice that do not bind to trkB (too much neurogenesis is bad/not ideal at least). Both ISRIB and dihexa should be used with caution as they are research chemicals, but they have good anecdotes for treating traumatic brain injuries and lifelong cases of depression. Tranylcypromine is the second oldest antidepressant on the market so it is about as well studied as it gets. Objectively the best antidepressant bar none for anyone who does not have severe social anxiety/eating disorders. In those cases, replace tranylcypromine with phenelzine, but there is a tiny risk of inducing PSSD with phenelzine due to some mysterious mechanism that tightens the pelvic floor and ruins the gut microbiome (for some people).

The other one would be stacking drugs that manipulate the epigenome. This includes a good HDACi like crebinostat once daily (source and dose TBD), potent GSK3b-inhibitor like zuranolone for 14 days or tideglusib daily until cured (source TBD) and an estrogenic agent whether it's injecting E2 benzoate (RISKY and only recommended for females or males that do not tolerate the BP increase from roids) or trestolone/trenbolone (the latter is only recommended if trestolone doesn't work for you). Keep in mind trenbolone's metabolites are HPTA suppressive for up to a year, so your balls will stay shrunken for at least a year and not PCT will fix it until then. It could also induce permanent neurotoxicity in many areas in the brain, and most likely will change your personality a lot -- for the worse unfortunately. A not as uncommon as you would think side effect would be, I kid you not, turning gay (thanks to being a strong progestin).

Anhedonia/Melancholia

Melancholic depression or hypodopaminergic phenotype of depression is known as anhedonia. Some argue that it should be considered its own separate entity to that of depression. It is caused by dopaminergic dysfunction (usually low), opioidergic dysfunction and supersensitivity to serotonin. Avoid serotonergics as much as possible and focus on maximizing dopaminergic transmission. KOR downregulation and psychedelics could be helpful. Sometimes PSSD treatments can work for this disorder as they occasionally share similar roots.

The Sydney Melancholia Prototype Index is commonly used to distinguish melancholic from non-melancholic depression.

MIF-1, 9-Me-BC, vorinostat, pramipexole, psychedelics (especially ibogaine and 5-MeO-DMT), dissociatives (especially DXM and ketamine), amantadine/memantine, bromantane, IM BPC-157, IN PE-22-28, Cerebrolysin, certain serotonin antagonists, NSI-189, dextroamphetamine, VLD amisulpride, buprenorphine, sarcosine + NACET, mesembrine and salvia show the most potential for treating anhedonia.

OCD and Anxiety Disorders

Mostly involve glutamatergic dysfunction and serotonin deficit (in specific regions). Only NMDA antagonists, SRIs and MAOIs work for this disorder because serotonin negatively regulates NMDA transmission (excessive in OCD). Dissociatives, fluvoxamine, tropisetron, clomipramine and psychedelics are the most reliable long-term treatments for this disorder. Other SSRIs can work too, but the two mentioned are usually the most effective. HDAC inhibition might also prove useful for exterminating fear and anxiety.

PTSD and Trauma-Induced Disorders (ie. Borderline Personality Disorder)

Pathophysiology of PTSD is unclear although it seems to be similar to depressive disorders for the most part with a hyperactive amygdala.

Antidepressants, bromantane, fear-extinctives (including URB597, nor-BNI and vorinostat) and psychedelics especially are likely the most useful for these disorders.

HPPD and Visual Snow Syndrome

Tropisetron, vorinostat, nicotine, sigma-1 agonists like opipramol and fluvoxamine and piracetam seem to help. Not much is known about these disorders other than the fact glutamate (excess), acetylcholine and serotonin are involved.

Fibromyalgia

Anti-inflammatories (ie. CBD, β-caryophyllene and WWB), NRIs, antidepressants, psychedelics (especially ibogaine), URB597, magnesium, curcumin, kava, etifoxine, berberine, black seed oil and nor-BNI are the most helpful for this.

Schizophrenia and Psychotic Disorders

NMDA antagonists, serotonin agonists (especially 5-HT2A and 5-HT2C), opioid agonists, dopamine agonists, and CB1 agonists like Δ-9THC exacerbate psychotic symptoms.

Stay away from those and stick to this stack.

Brain Regions (WIP)

dlPFC

The dorsolateral prefrontal cortex (dlPFC or DL-PFC) is an area in the prefrontal cortex of the primate brain. It is one of the most recently derived parts of the human brain. It undergoes a prolonged period of maturation which lasts into adulthood.[1] The DLPFC is not an anatomical structure, but rather a functional one. It lies in the middle frontal gyrus of humans (i.e., lateral part of Brodmann's area (BA) 9 and 46).

Many neurological disorders have significant dysfunction in the dlPFC, such as schizophrenia, ADHD, addiction, Alzheimer's, OCD (via dlPFC-OFC relationship), etc.

The dlPFC is also a very promising target for cognitive enhancement because of its position to control other brain regions and also because of its density of pyramidal neurons and other factors.

The dlPFC is also the single most important neuronal correlate of consciousness.

vlPFC

The ventrolateral prefrontal cortex (vlPFC) is a section of the prefrontal cortex located on the inferior frontal gyrus, bounded superiorly by the inferior frontal sulcus and inferiorly by the lateral sulcus. It is attributed to the anatomical structures of Brodmann's area (BA) 47, 45 and 44 (considered the subregions of the vlPFC – the anterior, mid and posterior subregions).

Functionally, it acts similar to the dlPFC, acting somewhat as a side-processing unit for the dlPFC. It has similarly been implicated in executive function, albeit somewhat less important.

In schizophrenia, the vlPFC most likely assumes the role of the dlPFC due to the dlPFC’s high level of dysfunction. This means people with schizo-related disorders are more likely to rely on their vlPFC for executive function than the dlPFC.

The vlPFC may also be implicated in multiple hallucination disorders if dysfunction arises.

Hypothalamus

The hypothalamus is a small but crucial region in the brain located just below the thalamus and directly above the brainstem. Despite its small size, the hypothalamus plays a pivotal role in many important functions, acting as a link between the endocrine and nervous systems.

Key Functions of the Hypothalamus

Hormone Regulation

The hypothalamus produces several releasing and inhibiting hormones that control the secretion of various other hormones from the pituitary gland. These hormones regulate metabolism, stress responses, temperature regulation, fluid balance, and other critical bodily functions.

Homeostasis

It helps maintain the body's internal balance by regulating temperature, hunger, thirst, sleep, mood, and the circadian rhythms. For instance, it detects changes in body temperature and activates mechanisms to bring it back to a set point.

Autonomic Control

The hypothalamus has a significant influence over the autonomic nervous system, which controls involuntary body functions such as heart rate, digestion, and respiratory rate. This control is crucial for responding to stress and emotional stimuli.

Appetite and Weight Control

It plays a role in controlling appetite by regulating the sensations of hunger and satiety. The hypothalamus receives signals from the body that indicate nutritional status, and it adjusts food intake accordingly.

Sexual Behavior and Reproductive Functions

The hypothalamus is involved in controlling sexual behavior and also regulates the hormones necessary for reproduction and the menstrual cycle.

Sleep-Wake Cycle

It controls sleep patterns by regulating various neurotransmitters that are involved in wakefulness, arousal, and sleep.

The hypothalamus is also involved in more complex functions such as memory and emotional expression. Its importance in the overall functioning of the endocrine and nervous systems cannot be overstated, with its actions profoundly affecting overall health and well-being.

Cerebral Cortex

Serotonin heavily regulates cortical glutamate. Potassium channels heavily regulate GABA/glutamate in cortical areas. Serotonin also regulates cortical GABA/glutamate interneurons; especially NMDA.

The cerebral cortex is the outermost layer of the brain, responsible for complex cognitive processes such as reasoning, language, and memory. It is characterized by a distinctive wrinkled appearance, with folds (gyri) and grooves (sulci), which increase its surface area, allowing for a greater number of neurons within a limited space.

Structure

The cerebral cortex is typically divided into two hemispheres: the left and the right, connected by a band of nerve fibers known as the corpus callosum, which facilitates interhemispheric communication. Each hemisphere is further divided into four lobes:

Frontal Lobe: Located at the front of the brain, this lobe is associated with reasoning, planning, parts of speech, movement, emotions, and problem-solving.

Parietal Lobe: Situated behind the frontal lobe, it handles sensory information from various parts of the body, understanding spatial orientation, and the manipulation of objects.

Temporal Lobe: Found beneath the lateral fissure, this lobe is involved in perception and recognition of auditory stimuli, memory, and speech.

Occipital Lobe: Located at the back of the brain, it is primarily responsible for visual processing.

Function

The cerebral cortex plays a key role in numerous high-level brain functions including:

Perception: Making sense of various sensory data such as visual inputs from the eyes or touch information from the skin.

Attention: Governing the ability to process potential stimuli and focusing on specific tasks or sensory inputs.

Memory: Storing and recalling information both in the short term and the long term.

Thought: Enabling abstract thinking, understanding, and problem-solving.

Consciousness: Providing the capacity for awareness of self and surroundings.

Language: Different areas of the cortex are involved in various aspects of understanding and producing language.

Neuronal Make-up

The cerebral cortex is made up of gray matter, which contains the cell bodies of neurons. Below this layer is the white matter, composed of axons, which facilitate communication between different brain areas both within the cortex and between the cortex and other parts of the nervous system.

Cerebral Cortex Plasticity

The cortex is not static but highly plastic; it can reorganize itself functionally and physically in response to learning, experience, and injury. This plasticity allows for the adaptation of cognitive and motor functions, especially important in instances of brain damage.

Overall, the cerebral cortex is critical for the integration of complex cognitive, sensory, and motor functions, making it essential for the sophisticated behavioral responses that are characteristic of human beings.

Nucleus Accumbens

The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, acting as a major component of the mesolimbic pathway. This area is a key site for the brain's processing of reward, pleasure, reinforcement learning, motivation, and pleasure-including laughter. It influences our motivation to repeat behaviors that lead to reward through the release of dopamine, which is commonly associated with feelings of pleasure and reward.

Functionally, the nucleus accumbens has a significant role in reward cognition, including reinforcement of rewarding stimuli and substance use disorder. It integrates dopaminergic inputs from the ventral tegmental area (VTA) and glutamatergic inputs from various regions of the brain to influence motor functions related to reward-related behavior. When activated, it promotes positive reinforcement and reward-related behaviors, but when dysfunctional, it is implicated in the pathology of several addictive and psychiatric disorders.

Dysregulation or alterations in the activity of the nucleus accumbens are linked to several psychiatric and neurological disorders, such as depression, addiction, and schizophrenia. Changes in the neurotransmitter systems affecting the nucleus accumbens, such as dopamine and glutamate, play crucial roles in the pathophysiology of these disorders. For instance, reduced activity in the nucleus accumbens has been observed in individuals suffering from depression, which is associated with a decreased ability to experience pleasure, a condition known as anhedonia.

Brain Stimulation

tDCS

Transcranial Direct Current Stimulation (tDCS) is a form of neurostimulation that uses a constant, low current delivered directly to the brain area of interest via electrodes on the scalp. tDCS is non-invasive and is used to modulate neuronal activity.

Basic Principles of tDCS:

Current and Electrodes:

tDCS involves the application of a small electric current (usually between 1 and 2 milliamperes) through two or more electrodes placed on the scalp. One electrode acts as the anode (positive), and the other acts as the cathode (negative).

Neuronal Effects:

The direct current influences neuronal activity by altering the electrical environment of the brain cells. Anodal tDCS tends to increase neuronal excitability by depolarizing the neuronal membrane, which can facilitate firing. Conversely, cathodal tDCS tends to decrease neuronal excitability by hyperpolarizing the membrane, making neurons less likely to fire.

Applications of tDCS:

Cognitive Enhancement:

Research has explored tDCS as a tool for enhancing cognitive functions, such as memory and attention, in healthy individuals as well as those with brain disorders.

Mood Regulation: It has been studied for its potential to improve symptoms of depression, with some studies showing that it can modulate mood and emotional responses.

Rehabilitation:

tDCS is being investigated as a therapy for stroke rehabilitation, specifically in aiding motor recovery and aphasia (language and communication recovery).

Pain Management:

It may be used to alleviate chronic pain, including neuropathic pain, by modulating the pain signals and pathways in the brain.

Safety and Side Effects:

tDCS is generally considered safe when guidelines are followed. The most common side effects are mild and may include itching, tingling, or a mild burning sensation under the electrodes during stimulation. Slight headaches and fatigue may also occur after treatment. However, serious side effects are rare.

rTMS

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive technique used primarily for treating depression and certain other neurological and psychiatric disorders. It involves placing a magnetic coil on the scalp near the forehead. This coil generates brief magnetic pulses, which pass through the skull and induce small electrical currents in the brain. These currents activate nerve cells in the targeted brain region, which is often the prefrontal cortex for depression treatment.

The theory behind rTMS is that it can influence the activity of the neural circuits in the brain, which can become dysfunctional in conditions like depression. By targeting these circuits, rTMS may help to alleviate symptoms. The treatment is typically administered over multiple sessions, and its effects can accumulate over time, potentially leading to significant improvements in mood and cognitive function in some patients.

rTMS is considered particularly valuable because it can be targeted very specifically to affected brain regions with relatively few side effects compared to medications. It's been approved by health authorities in various countries, including the FDA in the United States, for treatment-resistant depression and has shown promise in other areas such as anxiety, PTSD, and chronic pain.

More on HDAC Inhibition

“How I overcame my social anxiety using vorinostat” - a removed Reddit post

So I struggled with severe social anxiety for a few years, granted it did become slightly better with age.

It used to be absolutely debilitating, walking down school hallways became nearly impossible without breaking a sweat. I'd deliberately eat my lunch outside of school facilities because I simply couldn't bear the thought of eating in the presence of so many others. Eye contact was a thing of fiction, it's as if it killed me to look others in the eyes, so I never did.

Fast forward a few years, I graduated and it did become a little better with time but it was still very draining. So I went looking for possible treatments, I didn't consider visiting a doctor or anything like it. Maybe I should've but you know, social anxiety and all that.

Anyway, since I've always held an interest in biochemistry and pharmacological drugs I did some extensive research into anxiolytics. I did try pregabalin which worked rather well for me but it was a short-term fix, so I wasn't very keen on it.

Eventually, stumbled across vorinostat, an HDAC inhibitor. Essentially, vorinostat wipes any learned fear after a memory is recalled or a situation is experienced, causing the memory/situation to be permanently stripped of its learned fear-response-inducing attributes. This Reddit post elaborates on it.

So, I was hooked. After some research, I managed to find a somewhat reputable source, bought some, and tried it. (The drug isn't FDA-approved for this purpose, just something to note).

I can only call the experience life-altering. I would say there's me pre-vorinostat and me, post-vorinostat. This substance changed me on a fundamental level. Truly.

Speaking to those suffering from severe, chronic social distress, you'll identify that discomfort you so often experience as part of you as an individual. After all, it's pretty much all you've ever known. It's hard to imagine a future where you do not find yourself uneasy in certain social situations.

Well, I am here to tell you that although that used to be the case for me, it is no more. It's nearly akin to a miracle. The effects might not be instantaneously obvious but after some intervals, I noted myself unable to experience the discomfort I used to in certain contexts. Once this realization was set into place that's when the magic happened.

Knowing that the extreme unease felt before won't pop up regardless of my environment has been very freeing. I now initiate interactions I evaded before, and look people in the eyes where I didn't in the past. The best thing, arguably, is the permanence of its effects. I took it a few times, spaced some weeks apart and the effects remained.

Again, I do have to reiterate that this isn't an FDA-approved drug for anxiolytic purposes, so I can't advise anyone to take this without knowing the risks and doing their due diligence. Just sharing my unconventional battle with social anxiety.

---------------------------------------

“When DNA needs to be read it is unraveled from the histone and held open with acetyl groups. Histone deacetylase (HDAC) then takes the acetyl groups back off after the dna is read. An HDAC inhibitor, then, lowers the amount of available HDAC to take acetyl groups back off the DNA, leaving the DNA open a bit longer for transcription. This, in effect, increases transcription with things HDAC is implicated in, from creating memories to changing the number of receptors based on the environment in the body. Children have lower HDAC than adults, and the amygdala has more HDAC than the rest of the brain. HDAC inhibitors could then be used to learn things like children do, or reshape fears from traumatic events that are usually untouchable through conventional therapy due to evolution not wanting us to forget fearful situations (like a lion attack, but in today's world this is unnecessary and only presents itself as debilitating PTSD).

Edit: To expound on your case, there aren't any studies on remaking one's habits or sort of personality you could say, overcoming long standing habits and beliefs that stem from childhood, simply because this isn't a clinical problem, but it my and others' experience HDAC inhibitors help do exactly what you want, which is change the way you act much faster than you would normally be able to (and sometimes help you change things otherwise you normally would never be able to). For example, I had social anxiety from smoking pot for several years -- it's just how I reacted. I was looking for a solution for so long, and practiced different habits as well. When I found vorinostat, however, (this was before I knew about black seed oil, so I ordered vorinostat from a manufacturer) I was dumbfounded that the first few times I took it the anxiety just wasn't there, because it wasn't real and the HDAC inhibitor let my mind write over the old fear memories with clean new ones. It was almost weird, however, because at that point I was so used to this anxiety that when it wasn't there I didn't really know how to act. But, after a few sessions of vorinostat I was very comfortable and making great headway on making a new self. It was easy to be outgoing, and I started learning new things. The benefit of HDAC inhibitors is that it makes permanent changes to your memories, and so permanently changes your thoughts and who you are.” - from longecity

---------------------------------------

Vorinostat potentiates alot - r/Nootropics

---------------------------------------

“As I've investigated the use of HDAC inhibitors for fear extinction, I've also looked into how certain memories are formed, including fear, anxiety, negative reinforcement, positive reinforcement, reward, love, attachment, etcetera. The way different memories are made in the brain and what controls them is very important. HDAC doesn't control all memory, and if the ones it does oversee it doesn't control them all equally. There are many other transcription factor targets, as well as many other epigenetic regulator targets that affect various kinds of memory other than HDAC. For example, DNMT3a affects addiction and, to some extent, certain types of reward, as seen in this study:

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens

This is how I understand it from all I've read... Fear and anxiety has totally different mechanisms and pathways in the brain from regular memories, reward, love, and anything else. They build over time, even if the trigger is no longer directly linked to danger. This makes sense evolutionarily if you think about it. You want to make sure that whatever is brought into danger brings up awful feelings so you don't even think about doing it again. The degree to which it brings up fear and the degree to which you can actively combat it probably depends on the person, hence some people are prone to anxiety, PTSD, etc. and some people are less prone. This is key to understanding how HDAC inhibitors work... the fears associated with certain memories and situations are often overblown by our brain compared to how we should actually be reacting to the memory/situation. This is a protective trait built up throughout evolution. If you did something and a lion came up out of nowhere, you're brain is making sure you never want to do that again, even if you never even see another lion in your life... walking to that part of the desert is always going to bring up that fear, and may even build over time, even if you never see another lion. This happens in different parts of the brain, too, with certain pathways dedicated specifically to fear, and there have been studies showing that HDAC is upregulated or downregulated in specific parts of the brain depending on whether there's been a fear-inducing situation that has taken place. I'll try to find that study.

To answer the first question, HDAC selectively resets the anxiety and fear switch because, 1, HDAC happens to have a built-in propensity toward acting on transcription factors and parts of the brain having to do with negative reinforcement, fear, anxiety, avoidance, etc... it just doesn't act towards other emotions, because these are handled by different pathways in the brain and perhaps might not even be regulated by epigenetics as much, as they evolved into lifeforms after fear (love, happiness, connection, empathy, etc.) 2, an HDAC inhibitor works so well at eradicating fear because fear is the most likely emotion to be naturally attributed to a situation and unnaturally built-up. An HDACi, even at a small dosage, increases the priority of the present, so no matter what you've felt about the present situation (brought up through meditation or an actual experience) in the past, what the situation is doing in the present moment will be given full priority, which is usually felt as "nothing". In real time, how an HDACi feels is like nothing. No extreme, built-up emotions from the past come up. You can remember them if you try, you can remember everything that happened, but unless you're about to be hit by a bus, there will be no tightness in your chest, no anxiety, etc. Even if you were hit by a bus on an HDACi, as long as you were on it still after being hit, or took it again a couple days later, the fear that was learned from being hit by the bus on the HDACi can also be eradicated, so there should be no fear in using an HDAC. It's getting at the root of memory formation, at the transcription level, so it's impossible to have a "bad trip" or anything like that. It doesn't affect cognition, because it doesn't directly affect neurotransmission or anything upstream of CREB, which is anything above what BDNF is actually doing to DNA. It's really incredible, and nothing else we've used acts like this, so it's hard to wrap your mind around at first. You just have to try it.

To answer your second question, yes, HDACi hyper-acetylate other genes as well, but they're not nearly as sensitive as the brain. If you take high amounts of HDACi for a long period of time, you will arrest the cell cycle even. This is how HDACi are used to kill cancer. Most healthy cells can handle this, however. At the dosages we'd be taking them at the cell cycle won't be arrested... not even close. We just need enough increase in transcription to prioritize the present when it comes to transcribing memories. This is how children are able to learn and adapt so quickly... one of the reasons HDACi are described as "turning back the clock" on memory, or "feeling like a kid again."

To address your third question... The first paragraph is actually wrong. HDAC indirectly affects many things, neurotransmitters and receptors included, but this is nowhere near how it works. This is part of why it's so hard to wrap your head around at first... Trkb, NMDAR, calcium channels, whatever you wanna talk about neurotransmission-wise in a cell above CREB, this isn't how HDACi works. It works at the transcription level by holding open transcription. This is what heightens "resilience," as you say. This is also how exposure therapy is actually brought to work by using HDAC inhibitors. Without HDAC inhibitors, it can be extremely hard for exposure therapy to work for a lot of things, especially PTSD. Even if it does work, the chance of relapse is incredibly high. This is because our fear centers in our brain and fear memories were built to keep fears alive for our protection. They're incredibly hard to overcome, and the only way to do so is to hold open the window of transcription when a memory is reactivated long enough for the present to become stronger than the past. The past will still be remembered, technically, but when you bring the memory up after your HDAC session, the most recent, non-fear-inducing memory will be what you feel.

In my experience, since HDACi helps form long-term memories in general, it has helped me learn how to act socially. Once it gets rid of the fears of the past that used to get in your way, you're free to act in the present however you please, and almost everything is remembered in incredible detail because you're on the HDAC. It's really amazing, and I can't wait to get more vorinostat.

Last question of yours... I don't think StevesPetRat read enough of the anecdotes or my posts because HDAC inhibitors do not bring up the past. It's not therapy through normal cognitive pathways, it's therapy through physical changes in transcription, and to the watcher, you, consciousness, it looks like the fear disappeared and you're left with nothing. Not a bad feeling of nothingness felt with the shitty medications doctors use to blunt people's emotions, but an unencumbered state of no longer being controlled by your past negative emotions and having the room to feel other emotions in a situation once again, as if you were a child.” - longecity

---------------------------------------

“The happiness, pleasure, attraction, and love parts of our brain work differently and utilize HDAC in different ways (or perhaps not at all) than the fear pathways of our brain. It does not dull emotions. Also positive emotions are less likely to artificially build up in our minds like fear does, which is an evolutionary trait to keep us away from harm. Most of the fear that comes up in us is connected to fears that are associated with memories, have built up overtime, and are triggered by various stimuli causing a resurgence and then strengthening of those fears, whether or not the original danger is still there or not. HDAC inhibitors allow the reassessment of these past fears, which usually give the feeling of the fear disappearing. They were technically overpowered and overwritten by the present moment, which, unless you're about to get hit by a train, is not as fear-inducing as the overly-built-up fears from the past. Vorinostat essentially allows growth. It overcomes the built up fear and allows the other emotions we have to surface, hence the breath of fresh air I felt the first time I took vorinostat. In this way it potentiates the positive emotions because it is allowing them a chance by stripping away the built up fear. What makes us truly afraid today is completely different from what instilled fear in us in our younger years, and, because of the way fear works evolutionarily, fear is meant to build up in us over time surrounding certain situations. Since we're not needing to avoid lions anymore, this evolutionary trait usually just manifests itself as weird, crippling anxieties that are at their essence unnecessary in today's world. If they are necessary, they will be kept, as vorinostat doesn't dull any emotion. So, if every time you say something dumb in class you feel anxiety, if you're on vorinostat you will record that anxiety, but it will not allow it to balloon. Any anxiety about that situation that has ballooned over time will be stripped away, so even that bit of necessary anxiety that possibly could remain still feels like a breath of fresh air because now you're feeling all the emotions equally and not just the built up, unnecessary anxiety from all times past.” - longecity

---------------------------------------

"previous work from our laboratory assessed the role of HDAC1 and HDAC2 on synapse maturation and synaptic efficacy in hippocampal neurons and found that individual HDAC2 knockout led to deficits in synaptic efficacy in mature neurons (Akhtar et al., 2009). The depressed synaptic input-output curves we observed in the present study may be related to HDAC2’s constitutive impact on synaptic efficacy. In addition, an earlier study from our laboratory observed a similar effect of the HDAC inhibitor trichostatin A (TSA) on synaptic efficacy that could be reversed by co-incubation with actinomycin D (Nelson et al., 2006). Taken together, these findings suggest that the basal decrease in synaptic efficacy seen after loss of HDAC2 may be the result of a transcriptional effect, rather than a transcriptional-independent pathway, however further experiments are needed to test this hypothesis."

"Based on a limited number of studies including our own, deleterious effects of postnatal HDAC2 knockout remain to be found. One important exception is that conditional HDAC2 deletion in adult neural stem cells leads to deficits in neurogenesis in the dentate gyrus subregion of the hippocampus, suggesting a continued role for HDAC2 in cell differentiation in adult brain (Jawerka et al., 2010). Deficits in adult hippocampal neurogenesis have been implicated in mood disorders as well as in a lack of an appropriate behavioral response to antidepressants in animal models suggesting that the therapeutic potential of targeting HDAC2 for cognitive disorders may be limited in some cases (Hanson et al., 2011). It is conceivable that while enhanced plasticity manifests as advantageous in experimental settings in which animals are trained chronologically in distinct learning tasks, in nature such rapid inhibition of responding to CS-US associations could prove maladaptive. As one example, CTA is an adaptive response to ingested poisons, therefore near immediate extinction to the CS following limited experience in which the US is not present may be considered detrimental. One role of endogenous HDAC2 in the adult brain may therefore be to promote and maintain the stability of learned associations when an organism is faced with new and competing associations, however this hypothesis demands further study. Recent data suggests that a postnatal forebrain KO of the class II HDAC, HDAC4, impairs learning and LTP, demonstrating dissociable roles for class I versus class II HDACs in cognition and synaptic plasticity (Kim et al., 2012). "

https://www.ncbi.nlm...17/#!po=55.2632Page 11:

Knockdown of HDAC2 but not HDAC1 decreases synaptic activity in mature hippocampal neurons:

Together, these findings indicate that maintenance of miniature excitatory transmission in mature neurons requires the activity of HDAC2, which targets the presynaptic release machinery but not the number or maturation state of synapses.

"To further investigate the role of HDAC2-mediated effects on synaptic transmission in mature neurons, we infected C57BL/6 hippocampal neurons at 7 DIV with lentivirus expressing HDAC2 (Fig. 7A). We found that overexpression of HDAC2 in mature neurons produced a significant increase in mEPSC frequency with no change in their amplitudes (Fig. 7B–D). The significant increase in mEPSC frequency with HDAC2 overexpression, coupled with the significant decrease in mEPSC in HDAC2 null neurons, suggests that HDAC2 plays a critical role in mediating synaptic transmission in mature neurons and changes in its expression can profoundly impact synaptic function" - longecity

---------------------------------------

Cannabis-induced anhedonia requires a slightly different approach. Highly recommend BDNFan’s guide to recover from cannabis-induced anhedonia.---------------------------------------

---------------------------------------

Pharmaceuticals & Nootropics

Other Pharmaceuticals

IN Deferoxamine

VLD Amisulpride

VLD Buprenorphine

Ezogabine/XEN-1101/BHV-7000

Zuranolone

Mechanisms of Action

Bacopa Monnieri

Guanfacine

Nor-BNI

Lion’s Mane (Erinacines and Hericinones)

Erinacines

Hericenones

Modafinil and Methylphenidate

Melatonin

Rosemary and Carnosic Acid

Sulbutiamine and Other Vitamin B1 Derivatives

Introducing Peptide Mastery, decoded from over 200 scientific research papers, giving you the most in-depth and accurate knowledge of peptides ever made available to the public

Peptides for Mood Improvement

Advanced

Possible Other Mechanisms of Action (Speculation)

Sarcosine + NAC/NACET

Trimethylglycine + L-tryptophan

Piracetam

Noopept

Kavalactones

ACD-856

Minerals, Hormones & Supplements

Minerals

Vitamins

Vitamin A, C, E and D3 + K2

Vitamin B1, B2, B3, B5, B7 and B12

Vitamin B6, specifically Pyridoxal 5'-phosphate (P5P)

B8 Inositol

B9 Methylfolate

B12 Adenosylcobalamin/Methylcobalamin

Nicotinic Acid or NMN or Nicotinamide Riboside (NR)

Supplements

R-ALA/NA-R-ALA

Gut Health

Other good probiotics:

S-tier prebiotics:

Hormones

T3 for Hypothyroid (Including Subclinical)

HCG

Testosterone

Anabolic Steroids

Hallucinogens & Psychedelics

Psychological and Emotional Benefits

Neurological and Physiological Benefits

Sociocultural and Spiritual Benefits

Risks and Considerations

Psychoactive Effects

Mechanism of Action

Cultural and Traditional Use

MDMA: Ecstasy in a Pill

2C-B: Shulgin’s Personal Favorite

DOM: the Psychedelic Amphetamine

Hallucinogenic Psychedelic Classes

Others

Non-psychedelic Hallucinogens

Cannabinoids

Dissociatives

Terpenoids

Non-hallucinogenic Analogs

Memantine: the Little-Known Dissociative Adamantane

Dextromethorphan: the Dissociative Cough Syrup

Diet & Fitness

Diet

Cannabis-induced anhedonia requires a slightly different approach. Highly recommend BDNFan’s guide to recover from cannabis-induced anhedonia.
---------------------------------------