Biohacking Bible - A Neuropharmacology Encyclopedia [02-2024 ed.]

Citation preview

Biohacking Bible A Neuropharmacology Encyclopedia by u/ryderlefeg and editors Updated as of 14-02-2024

Check out the GPT bot Biohacker (beta version; free of charge). And don’t forget to check out r/prefrontal as well. --------------------------------------If you want to download or print, you can get it from Gumroad. I also do 1-on-1 consultations on Calendly and Discord. If you booked a consultation on Calendly, contact me on Discord to discuss details afterwards. 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, and pharmacology/neuroscience. I mostly go over the substances that I think would be of most help

to the hypodopaminergic phenotype of neuropsychiatric disorders (ie. anhedonia, depression/anxiety, PSSD, DPDR and ADHD). A lot of pharmacological and neuroscientific concepts are explained in sufficient detail. Poor focus, depression and demotivation are often attributed to low dopamine and norepinephrine but low acetylcholine activity can also contribute sometimes. Acetylcholine is needed to maintain sustained attention and lack of acetylcholine due to low dietary choline can contribute to ADHD symptoms so make sure you eat enough choline-rich food like eggs, or supplement with CDP-choline/alpha-GPC. MAOIs increase concentrations of both dopamine and norepinephrine 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’s 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 go around this is to block specific serotonin receptors. --------------------------------------NOTE: none of this is medical advice. These are mainly my notes I’ve written after years of research. Some of the stuff mentioned in this ebook are experimental and are marked as such. 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 adopt 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 burden on the liver and protect from any hepatotoxic chemicals (including in your food). Safety note - never take TUDCA before alcohol as the combo is very toxic to the liver; and never take NAC after alcohol as the combo is, once again, toxic. This ebook is constantly updated so feel free to check it every once in a while (ie. once a month). And feel free to use the comment feature if you want to give feedback. If any link is down just use the archived mirror. It’s also highly recommended to get your genes tested 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 before you dabble with nootropics.

My ranking of DNA kits would be Nebula/Dante Labs/Sequencing.com > AncestryDNA > 23&Me. 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; and check out r/MTHFR for help. As an under-methylator or over-methylator, it’s recommended to get your methylation status in check before attempting to dabble with pharmaceuticals or nootropics. ---------------------------------------

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

Also highly recommend Adam’s biohacking guide for general health and wellness. ---------------------------------------

Pharmaceuticals and 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, 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. 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-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 enhances dopaminergic transmission downstream, 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: 1. Imipramine, amitriptyline, amoxapine, trimipramine – especially effective against anxiety and melancholic depression. Imipramine cannot be taken with MAOIs. 2. 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. 3. Nortriptyline and desipramine – great for depression marked by lethargy, and great for ADHD. They are safe adjuncts to MAOIs like tranylcypromine. 4. 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. 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 however.

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 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. Combining MAOIs together is also safe, and dietary concerns are very overblown. Just 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 less 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 (MAO-A) and 20-30% of MAO-B,[105] studies evaluating brain occupancy of MAO-A enzymes have shown dosages of 600 mg to only inhibit 74% of MAO-A enzymes[106] and dosages in the 900–1200 mg range to inhibit slightly less MAO-A than Phenelzine (Nardil) at 45–60 mg;[107] subsequently, it is highly plausible that reports of lower efficacy[108] 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 MAOB inhibitor that also happens to be a DAT and NET reuptake inhibitor + σ1 antagonist (bad for cognition and mood). 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 particularly serotonergic phenethylamines (ie. MDMA and 2C-B).

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. Can help depersonalization/derealization disorder too. It causes a deadly rash in rare cases so not recommended generally. Titrate slowly to reduce the risk of getting the rash.

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.

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 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. Can be counteracted with anti-prolactin drugs like metergoline. 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. In this proof-of-concept, unblinded clinical trial, we describe the clinical effect, safety, and tolerability of low-dose buprenorphine for TRD in older adults. 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 guy 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, did 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.

In all likelihood, tianeptine, despite acting on the μ-opioid receptor, will trigger 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.

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 kind of 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 source in my opinion seems to be UltraKanna (MX-16 extract is the best on paper).

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). 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 90-180 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.

Mucuna Pruriens 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: 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 Enkephalin breakdown inhibition, dopamine increase downstream and melanocortin antagonism. Ideal dose is between 200 and 800 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.

Bromantane Upregulates tyrosine hydroxylase in the long-term through multiple complicated mechanisms. 100 mg amantadine is a good alternative as well (same chemical family) that happens to possess D2 agonist action, dopamine releasing action, and tyrosine hydroxylase upregulation as well. Amantadine is one of the few treatments to claim parity of effectiveness with methylphenidate. 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 D2 and D4 PAM, opioid receptor antagonist and increases oxytocin downstream which can be prosocial behavior. Melanocortin antagonist as well which can be good for anhedonia and stress. MIF1 can be administered intranasally in a spray. Ideal dose is between 1 and 10 mg subcutaneously or intranasally.

Metergoline 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 month as it is a dopamine agonist.

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 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) 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. Be careful with lion’s mane however as it is 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 a lot of the other stuff on here obviously). Also bone loss is a possibility with modafinil, its analogs and NRIs in general. 25-100 mg modafinil/analogs like 4-Cl-modafinil (NDRI RC) disinhibit dopamine release downstream (more effective than regular modafinil) but either can work. Armodafinil is an alternative that is also a D2 partial agonist in vivo. Builds tolerance for most people. Modafinil may upregulate VMAT2 significantly. 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. However, this doesn't mean that methylphenidate is neuroprotective in a general sense. 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 Maximize androgen synthesis in the testes.

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 mTOR activation, neurogenic effects, modulation of dopamine circuitry, and many other benefits.

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 good. 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 my 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 Inhibits acetylcholinesterase which inhibits breakdown of acetylcholine, and that increases dopamine downstream. Happens to be a mild NMDA antagonist too.

Rosemary and Carnosic Acid Increases the expression of VDR (vitamin D receptor), via carnosic acid, which in turn makes more dopamine. There seems to be a correlation between dysfunctional VDR and PSSD incidence when taking SRIs, so if you have a VDR mutation I’d stay away from SRIs completely. Carnosic acid is also a potent antioxidant. Lemon balm which contains rosmarinic acid also happens to be a potent GABA-T inhibitor which is potently anxiolytic.

Sulbutiamine and Other Vitamin B1 Derivatives Upregulates D2 and more: ○

○

The Beneficial Role of Thiamine in Parkinson Disease ○ Energin - Liquid B-Complex Vitamin Mix ○ Effect of thiamine deficiency on brain serotonin turnover ○ Serotonin Syndrome and Thiamine: Is There a Connection? Thiamine Deficiency Increases Serotonin Synthesis, Inhibits Uptake ○ DNA Methylation, Aging, And Cancer

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.

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 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.

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. -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 schizoid 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. 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.

Minerals, Hormones and 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. 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

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 A cofactor for tyrosine hydroxylase. 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). 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.

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 I wouldn’t recommend supplementing 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 and aim for ~100 ng/ml as your vitamin D receptors would need more D3 to be activated in that case. K2 MK4 vs MK7

Vitamin B1, B2, B3, B5, B7, B9 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 P5P if you’re taking Phenelzine, instead opt for Pyridoxine

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) Coenzyme for tyrosine hydroxylase and important for longevity and mitochondrial health. Nicotinic acid is the most cost effective supplement to raise NAD+ levels.

Supplements Creatine Monohydrate 5-HT1A activation, 5α-reductase upregulator, recycles ATP, cellular energy enhancement and increases DHT. 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 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. 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)

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 5-25 mcg. Do not take T3 unless you are confirmed hypothyroid as it can be dangerous otherwise. Ideal TSH is 0.2-1.5, not