Biohacking-Bible

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

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, 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. 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 <4.5 like what the standard lab reference ranges say. TSH should be 0.2-1.2 mIU/L, 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? Hallucinogens and 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. 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 potentiation (LTP) that's semi-permanent. Unlike psilocybin, ibogaine upregulates not only BDNF but also GDNF. Microdosing of 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 500-1000 mg of magnesium oxide (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. 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.

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 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. 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 . 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. Co-use of MDMA with psilocybin/LSD/DMT may buffer against challenging experiences and enhance positive experiences 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. 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 WIP Mescaline: the Cactus-derived Phenethylamine WIP 2C-B: Shulgin’s Personal Favorite 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.

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 Allylescaline Escaline Mescaline Methallylescaline Proscaline MDMA (most euphoric drug) 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 2C-T 2C-T-2

2C-T-21 2C-T-7 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 Δ-9THC Δ-8THC

THCA THCP HHC CBG CBD THCV CBN CBC Dissociatives Ketamine Memantine Dextromethorphan (DXM) Phencyclidine (PCP) Eticyclidine (PCE) Deschloroketamine (DCK) 2-Fluorodeschloroketamine (2-FDCK) Methoxetamine (MXE) Deoxymethoxetamine (DMXE) 3-HO-2'-Oxo-PCE (HXE) Methoxpropamine (MXPr) Methoxisopropamine (MXiPr) O-PCE 3-HO-PCP 3-Me-PCP 3-MeO-PCP 4-MeO-PCP 3-HO-PCE 3-MeO-PCE 3-MeO-PCMo Methoxyketamine (MXM) Nitrous oxide Terpenoids SalvinorinA (the only hallucinogenic terpenoid) 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 IV it, but you can take it intranasally (half the bioavailability thus double the dose).

You should try 5-10 infusions (NOT more) and see if it helps your depression/anhedonia. 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 is neurotoxic if abused, and will damage your bladder too. 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. 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 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. 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. Pathways and Ligands Transporters SERT Reuptake should be increased ideally (ie. tianeptine) unless you have OCD/anxiety. Some SRIs like mesembrine and hyperforin can be good (do not combine with MAOIs). DAT Inhibited ideally, modafinil does the job. Methylphenidate, phenylpiracetam and amantadine are other notable DRIs. Inhibition of this transporter leads to an increase in synaptic dopamine, which leads to stimulation (and sometimes euphoria). NET Inhibited ideally if it’s not anxiogenic, otherwise leave it alone. 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. Ca 2+ 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-HT 1A 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 and curcumin. CB1 agonists can downregulate 5-HT1A, whereas inhibiting FAAH or inhibiting endocannabinoid uptake can actually increase 5-HT1A 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. TCAs, including clomipramine, upregulate postsynaptic 5-HT1A receptors. Zeolite seems to upregulate serotonin receptors as well. 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-HT 1B 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-HT 1D

Antagonists like cyproheptadine, trazodone and metergoline. Agonists can worsen OCD, depression and PSSD. 5-HT 1E Antagonists like cyproheptadine and metergoline. Agonists can possibly worsen OCD, depression and PSSD. 5-HT 1F Antagonists like metergoline. Agonists can possibly worsen OCD, depression and PSSD. 5-HT2A Partial agonists occasionally like LSD, psilocybin, DMT, harmine or harmaline are useful for downregulating this receptor and getting antidepressant effects. Antagonists disinhibit dopamine release but come with downsides so 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.

5-HT2B Antagonists like bromocriptine, metergoline, lisuride or 10-MeO-Harmalan. 5-HT2B activation is required for the development of fibrosis. Agonism is therefore cardiotoxic. Stay away from cabergoline and other 5-HT2B agonists. 5-HT2C Inverse agonists like 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. 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. 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 partially agonizing/antagonizing 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. Roga rugosa extract is a potent 5-HT6 antagonist which disinhibits dopamine, norepinephrine, acetylcholine, and glutamate release in the PFC. First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease 5-HT 7 There are advantages to both antagonists and agonists. Antagonism of this receptor induces instant antidepressant effects. Potent antagonists are 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. 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.

Do not take dopamine agonists for longer than 2 months if you don’t need them; ie. for treatment-resistant depression or RLS. 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. Tell them 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.

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). 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).

Dopamine Beta-hydroxylase Hypericin is an inhibitor of dopamine beta-hydroxylase, which is the enzyme responsible for converting dopamine into norepinephrine. Disulfiram is a DβH inhibitor. 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. This can lead to unwanted side effects in susceptible people like depression, libido loss and erectile dysfunction which is why 5AR inhibitors are not recommended. GSK3β Lithium 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. 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. 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 , but pan-inhibits the others (Class I and II). Because of its 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. Refer to this section for more details on HDAC inhibition.

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 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, 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 . 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. This receptor is very important for anhedonia and is shown to be dysfunctional in such patients. Oxytocin is a PAM (positive allosteric modulator) at this receptor. Pregabalin helps some with anhedonia possibly due to indirect modulation of μ-opioid receptors. Thymoquinone in black seed oil (nigella sativa) is a PAM as well. CBD is a PAM at this receptor too. 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. 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 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. 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. Rutin externalizes CB1. 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. 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. 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: the Consciousness Receptor 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. Both PAMs and agonists potentiate dopaminergic transmission (synergetic with stimulants). σ1 receptors modulate dopamine, μ-opioid, κ-opioid, NMDA and LTP. Fluvoxamine and opipramol are the most potent σ1 agonists available. σ1 activation also improves plasticity by potentiating NMDA and Ca 2+ transmission. 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. 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. Famotidine and thiamine inhibit serotonin synthesis. Only cyproheptadine and famotidine work for stopping serotonin syndrome. 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. 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. 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 - 5AR 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. MT 1 and MT2 Agomelatine is good for sleep (hepatotoxic). Aside from that not much is known about this receptor family in terms of effects. HIF 1 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. 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. Upregulate trkB with polygala and NA-semax-amidate. 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. ACD-855 is a trkB PAM. 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. 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. 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/PSSD (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.