Compounds within the same class can typically be substituted interchangeably, considering factors such as equivalent dosing and duration of action between the different compounds. Keep common sense in mind, and ALWAYS double-check for potential drug-interactions. Below I will include a few reference stacks by symptom hallmarks. Agitated Depression, or where significant anxiety is present: n/a Inhibited Depression, with severe presentation, or melancholia: n/a Dysthymia: n/a It's important to recognize that "Treatment-Resistant Depression" isn't a distinct subtype of depression but rather a reflection of current treatment limitations, with its prevalence directly corresponding to the effectiveness, or lack thereof, of available options at the time. Tricyclic Antidepressants Specifics regarding their pharmacological mechanisms is outlined here. TCAs are often derivatives of the phenothiazines, a class of compounds that includes antihistamines such as Chlorpromazine, Promethazine, and Promazine [a] . Due to their structural resemblance with phenothiazines, the majority of tricyclic antidepressants share similar pharmacological characteristics and target sites. There are a few exceptions however, such as Tianeptine. Imipramine Imipramine (known as G-22355 during development) was introduced as an antidepressant in Europe in 1958, marketed as Tofranil. Its discovery as an antidepressant is often regarded as serendipitous. Initially explored for treating schizophrenia without success and was later abandoned for this indication, it did however show promise for depression in a 1955 trial where…[b] .. However, its efficacy was later questioned as assessments at the time relied heavily on subjective observations of symptoms by raters, rather than through standardized scales like the Hamilton Depression Rating Scale (HAM-D), first introduced in 1960 by Max Hamilton. Its efficacy as an antidepressant appears…
Amineptine Amineptine stands out among other TCAs due to its notable, albeit relatively mild and short lasting (t1/2 of 0.8-2.5 hours), psychostimulatory effects. It is one of the few TCAs associated with abuse potential and documented cases of misuse, along with Tianeptine. Clomipramine Amitriptyline Amoxapine Monoamine Oxidase Inhibitors (MAOIs) Specifics regarding their pharmacological mechanisms are outlined here. Iproniazid, the first MAO-I found to exhibit antidepressant effects, was originally used as an antibiotic for tuberculosis. Its antidepressant effects were discovered serendipitously later on. Although Iproniazid was among the earliest antidepressants on the market, Amphetamine, marketed as Benzedrine from 1935 for the treatment of “mild depression”, predates it. “Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications) predates it” MAO-Is, such as Tranylcypromine, completely eliminates REM sleep, which is believed to contribute to its antidepressant effects. List of MAO-Is (type): Moclobemide (RIMA) 450-1650 mg/day, Bifemelane (RIMA) 150-300 mg/day, Tranylcypromine, Phenelzine, 9-methyl-β-carboline Psychostimulants
Although the term "psychostimulant" lacks a universally accepted definition. In this text, both "psychostimulant" and "stimulant" will denote a sympathomimetic agent. While outdated, this nomenclature is kept for accessibility and clarity. Psychostimulants, recognized for their antidepressant efficacy since the early 1930s, represent the first generation of antidepressants, including Amphetamine and Methylphenidate among others. For many individuals with particularly severe treatment-resistant depression, they are sometimes regarded as nothing short of a miracle. “At the six-month follow-up, the patient still endorsed a very significant relief of depressive symptoms. She stated that her mood is still very much improved, that she feels very stable on dextroamphetamine and amphetamine combination salts and even went as far as to call it “a wonder drug” for her.” - (Small et al., 2022) “Some 45% described the psychostimulant as the best or equal best to previously prescribed antidepressants, and 48% reported a sustained benefit. Such effectiveness rates in those with TRD are impressive” - (Parker, 2023) “Over decades, I have given dexamphetamine to hundreds of patients (including many highly educated patients) for prolonged periods ranging from weeks to years, with overt benefits in the vast majority, and with about five complications. Withdrawal effects, if stopped abruptly, consist simply of tiredness or return of depression.” - (Horgan, 2016) These compounds alleviate symptoms such as psychomotor inhibition, lethargy, and general low mood, offering rapid symptom relief, often within a few hours, for patients suffering from melancholic depression - a particularly difficult-to-treat entity similar to depression. In addition, they could extend the periods between episodes for individuals with recurrent depression, demonstrating high effectiveness even in the most treatment-resistant cases [1,2,3,4,5,6], without significant tolerance development and great tolerability. Methylphenidate also appears to reduce the incidence of suicide attempts and self-harming behavior, along with improving positive interpersonal perceptions in those with dysphoria. “Methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal- or self-harming behaviour.” - (Rohde et al., 2020) The positive mood-altering effects of Methylphenidate appear to correspond with how people perceive their interactions with others, especially those experiencing dysphoria. Psychostimulants can motivate patients to improve and be more optimistic toward their treatment and recovery, addressing one of the most debilitating barriers hindering their recovery - poor executive functioning, lethargy, and lack of motivation. Many individuals with depression appear particularly responsive to the mood-enhancing effects of psychostimulants
Other Research In a 2023 meta-analysis of 13 RCTs on the use of psychostimulant augmentation for treating depression, it was found that psychostimulant augmentation effectively alleviates the burden of depressive symptoms without necessarily increasing the odds of remission. In phase 2 trials, Lisdexamfetamine (Vyvanse, pro-drug to dextroamphetamine) showed promising efficacy in treating depression. However, despite initial success, it was dropped during phase 3 trials after failing to demonstrate the same level of effectiveness. The most common explanation for the disparity between the two trials was that the phase 2 study was underpowered. However, there have been various other hypotheses made as to why this might have happened. Psychostimulants may improve domains beyond those typically evaluated, such as cognitive symptoms, which are often overlooked by commonly used inventories like variations of the Hamilton Depression Rating Scale (HAM-D) or the Montgomery-Åsberg Depression Rating Scale (MAD-RS). Treatment of Eating Disorders There were plans to trial Lisdexamfetamine for another condition, namely Bulimia nervosa, a condition often comorbid with depression. Unfortunately, efforts ended for unknown reasons. However, based on what we know from past preliminary case reports, psychostimulants are NOT to be considered contraindicated for the treatment of restrictive eating disorders such as Bulimia or Anorexia nervosa, and may in fact alleviate symptoms associated with the disorder in those with and without ADHD.
Who is most likely to benefit from psychostimulant therapy for depression? Based on patient characteristics highlighted in past studies, it appears that those experiencing particularly severe depression or melancholia, characterized by hallmark symptoms such as psychomotor retardation (lethargy, cognitive impairment, and ‘hypoactive delirium’ [1,2]), executive dysfunction, consummatory and anticipatory anhedonia, are the ones most likely to derive benefit from psychostimulants. How to use For those benefiting from psychostimulants, continued usage over months to years is often necessary as stopping typically leads to the return of depressive symptoms. In cases of reduced response to psychostimulants, the addition of Tranylcypromine has been noted to significantly improved both efficacy and duration of remission from Dextroamphetamine in one case-study, after either treatment alone appeared to only be effective in the short-term, with the patient experiencing continuous relapses shortly after each treatment introduction in the past.
Psychostimulants: Dextroamphetamine 10-30 mg/day b.i.d., Lisdexamfetamine 30-70 mg/day (equiv. 10-30 mg/day d-amph sulfate) b.i.d., Methylphenidate (IR) 10-60 mg/day t.i.d., Cyclazodone (and NMC) 20-50 mg/day b.i.d., Methamphetamine 2.5-5 mg/day Note: N-Methyl-Cyclazodone appears to be a pro-drug of regular Cyclazodone, as described in a 2022 toxicological case-report, where they measured Cyclazodone in the urine of a patient taking N-Methyl-Cyclazodone. Atypical Psychostimulants: Bromantane ≤36 mg/day IN, Modafinil Bromantane, being a lipid-soluble compound, is recommended to be dissolved for intranasal use using Caprylic Acid as an excipient. Nicotinic Receptor Agonists Catecholamine Depletion Catecholamine depletors like Reserpine…[c] “Eleven studies reported depressive effects of reserpine, 13 reported an absence of effect and 11 reported potential benefits for depression symptoms with reserpine.” - (Strawbridge et al., 2023) Anticholinergics Anticholinergics like Atropine or Scopolamine…. [d] Anticholinergics suppress REM sleep, which is thought to contribute to the antidepressant effects of other compounds, such as the MAO-Is and tricyclics. “The old tricyclic antidepressants (such as amitriptyline) were shown over many years to work very well for many people. [...] The side effects are due to various different pharmacologic effects, particularly the blockade of acetylcholine [...]. This suggests another interpretation of the "active placebo" effect: perhaps it is not simply the existence of side-effects that psychologically boosts a placebo effect here, it is that the side-effects themselves are due to a pharmacologic action that is actually of direct relevance to the treatment of depression. While this is an interesting--though far from proven-- treatment idea, it is very important to be aware of anticholinergic side effects, which at times could be physically and psychologically unpleasant. At worst, cognitive impairment or delirium could occur as a result of excessive cholinergic blockade. Therefore, any attempt to treat psychiatric symptoms using anticholinergics should be undertaken with close collaboration with a psychiatrist.” - (Garth Kroeker, 2009) Sleep Deprivation Therapy Sleep Deprivation Therapy, also known as Wake Therapy, is an often overlooked option for those seeking rapid but short-lived relief from symptoms. Despite its impressive response rate of 40-60%, the results are transient, and relapse is common once sleep is resumed. It involves restricting sleep and sometimes methods to alter sleep architecture in an effort to
manage depressive symptoms. Basically, it’s a deliberate form of sleep deprivation. It’s the foundation of the REM sleep hypothesis of managing Depression. “Therapeutic efficacy of REM sleep reduction appeared similar to reported efficacy of imipramine hydrochloride treatment of depression. Eight of nine endogenous patients, unimproved by REM sleep deprivation, did not improve with imipramine. Results suggested (1) that substantial REM sleep reduction has antidepressant activity, and (2) since imipramine and other drug antidepressants reduce REM sleep much more so than non antidepressant drugs, that an antidepressant "mechanism" of drugs resides in their capacity to substantially reduce REM sleep.” - (Vogel et al., 1975) There are no known serious side-effects from the restriction of REM sleep specifically, but sleep restriction for extended periods of time is known to disrupt regular functioning. Restricting REM does not appear to impair memory consolidation. Other Other: Agmatine sulfate, SJW Ze 117, Ibogaine microdosing ≤15 mg, Kanna (MX-16 extract), Black seed oil, nor-BNI IN, MIF1 SQ, Lithium orotate, β-caryophyllene, CBD, Nicotine SJW Ze 117/9-methyl-β-carboline/≤15 mg ibogaine microdosing/kanna MX-16 + ≤36 mg IN bromantane + ≤30 mg memantine + cyclazodone/modafinil/methylphenidate/dextroamphetamine/lisdexamfetamine + black seed oil + agmatine sulfate + IN nor-BNI + IN/subQ MIF1 + lithium orotate + beta-caryophyllene + CBD Out of everything I tried, only pramipexole, memantine, ketamine, bromantane, tranylcypromine, 9-methyl-β-carboline, vyvanse/dextroamphetamine, clomipramine, MIF1 , lion’s mane, salvinorinA, lithium, Δ-9THC, β-caryophyllene, limonene, tropisetron, ALCAR, NAC, PE-22-28, creatine, active B complex like AOR's, B12 (methylcobalamin and adenosylcobalamin) and agmatine had any noticeable effect on anhedonia for me. Antipsychotic Stack CBD + cyproheptadine + β-caryophyllene + neboglamine/sarcosine + lithium + L-theanine + nuciferine (blue lotus) occasionally + NAC/NACET + agmatine sulfate + magnesium L-threonate + pregnenolone + cycle of BPC-157 + cycle of a neurogenic like cerebrolysin The most effective pathways of modulation are most likely mGluR2 /3 enhancers, EAAT2 PAMs & PDE4D NAMs (this is due to most affected protein level). Stay away from NMDA antagonists, serotonin agonists (especially 5-HT2A and 5-HT2C), opioid agonists, dopamine agonists, and CB1 agonists like Δ-9THC.
Treatment-Resistant Anxiety Stack Kava (Fiji Vanuatu extract or full spectrum paste are the best extracts) + fasoracetam + NAC/NACET + lithium + dry vaped CBD herb with β-caryophyllene, limonene and linalool + magnolia bark + neboglamine + nor-BNI + guanfacine + taurine + metergoline + SJW Perika or kanna MX-16 or ibogaine microdosing + etifoxine + DHEA/pregnenolone + active B vitamin complex (ie. Energin) + nigella sativa (5% thymoquinone at least) + memantine + magnesium L-threonate/magnesium chloride + URB597 + MIF1 + IN agmatine sulfate + IN vorinostat occasionally Chronic Pain Stack 1000 mg agmatine + URB597 + WWB/celecoxib + dry vaped CBD herb with β-caryophyllene, limonene and linalool + glyNAC (glycine or derivatives like TMG/sarcosine with NAC) + kava (can replace with pregabalin/phenibut/magnolia bark if you prefer) + black seed oil (5%+ thymoquinone) + low dose naltrexone (≤5 mg) + allopregnanolone/etifoxine/PEA + vitexin + NRI like nortriptyline or reboxetine or MAOI like 9-methyl-β-carboline/tranylcypromine (latter is probably preferable due to NRI action above 40 mg) + L-berberine and/or NovaSOL curcumin w/ bioperine (AMPK activator) + magnesium chloride/L-pidolate/glycinate + DHEA with pregnenolone. Add memantine if still treatment-resistant. Optionally you can also microdose psychedelics (or take neurogenics) to increase BDNF which helps with pain tolerance. If this stack isn’t enough, replace MAOI (if you were taking one) with amitriptyline or kanna MX-16 extract (not with any MAOI or SRI). Sexual Function (Maximizing Nitric Oxide Production Mainly) Stack Agmatine + 9-methyl-β-carboline + beet root + L-citrulline + tadalafil + forskolin + black seed oil (5%+ thymoquinone) + DHEA and pregnenolone + androsterone + vitamin C, D3 and K2 MK4 + zinc + boron + B6 P5P and B12 if levels aren’t high + creatine (monohydrate) + tribulus extract + cordyceps + caffeine ADHD Stack 9-methyl-β-carboline + bromantane + lithium orotate + tropisetron + ALCAR + lion’s mane + zinc + magnesium + agmatine + guanfacine +
cyclazodone/amphetamine/methylphenidate/amantadine + NA-semax-amidate + TAK-653 + optionally 10 mg IN deferoxamine for 7 days (very experimental and risky, you should stack with IN NAC for protection against mucormycosis) Neurogenesis and Cognition Stack NA-semax-amidate + IN cerebrolysin (10x 2 ml) + lion’s mane + bromantane + 9-methyl-β-carboline + NSI-189 + psychedelic microdose (ie. LSD/2C-B/DMT/psilocybin/mescaline) or non-hallucinogenic psychoplastogen like lisuride or tabernanthalog + noopept + lithium + novaSOL curcumin + optionally dihexa and/or trans-ISRIB + IN agmatine sulfate + DHA + optionally ketamine/memantine occasionally (abuse is neurotoxic) + polygala Post-Cannabis Abuse Recovery Stack CBG + CBD + THCV + β-caryophyllene + cordyceps + curcumin + L-theanine + white willow bark extract + pregnenolone + liposomal vitamin C + NAC + IN cerebrolysin / sublingual NSI-189 Sleep Stack DSIP + melatonin + cyproheptadine + CBD Amphetamine Microdosing Protocol Credit to jcd3nt Not recommended except as an absolute last resort for PSSD and anhedonia as it carries some theoretical risks such as developing tics or possibly psychosis. One way to (possibly) sensitize dopamine receptors is to microdose amphetamine/methamphetamine (latter preferrable) for up to one week with PPARa activators (ie. β-caryophyllene), COX-2 inhibitor like WWB or celecoxib, SKQ1 /CoQ10 , a MAOB inhibitor like 9-methyl-β-carboline/selegiline/rhodiola/tranylcypromine, and nicotinamide riboside/nicotinic acid (for PGC1A activation), then cycle off with GDNF
enhancers + PKC inhibitors like bromantane/amantadine/9-methyl-β-carboline/DNSP-11/NSI-189, PGC1α activators like niacin and lithium (only if you have the COMT val/val gene or respond well to lithium; to downregulate PKC back to baseline) with lots of high-protein food (to keep up with replenishment of neurotransmitters). And optionally palmitoylethanolamide (PEA) with ALA + vitamin D3 (increases bioavailability of PEA) to increase dopamine in the mesolimbic system. You can also downregulate NR2B with an NMDA antagonist like memantine, ketamine or DXM afterwards periodically (do NOT take DXM with MAOIs or SRIs). This guide is also useful for resetting tolerance to amphetamines/stimulants. Whether this microdosing protocol actually works or not is up for debate. It is definitely experimental, theoretical and not at all recommended as anything but a last-resort. Dopamine Agonists for Treatment-resistant Depression You can also try ≤250 mcg lisuride (D3 agonism), ≤5 mg pramipexole or ≤200 mg piribedil if possible. However, dopamine agonists downregulate D2 and D3 receptors in the long-term which is bad. Hence why this is NOT recommended unless you are very treatment-resistant and absolutely need it. Or if you have high prolactin and/or restless legs syndrome. If you had to choose one dopamine agonist, go for piribedil as it is the only agonist with little to no risk of developing DAWS. Dopamine agonist withdrawal syndrome (DAWS) is not something you would want to experience. Pramipexole especially has been studied to be extremely effective in treatment-resistant depression (both unipolar and bipolar) marked by anhedonia. The problem with pramipexole, however, is that it is a selective presynaptic D2 receptor agonist, which makes it sedating. Piribidel followed by ropinirole then bromocriptine are the best dopamine agonists on paper. Dopaminergic Medications in Treatment-Resistant Depression - Meet the Scientist Webinar Pramipexole: My Secret Weapon Against Anhedonia and Depression Microdosing Amphetamine: the Results
The Many (Surprising) Health Benefits of Methamphetamine Low and high dose methamphetamine differentially regulate synaptic structural plasticity in cortex and hippocampus 3,4‐Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine‐induced damage to dopamine nerve endings: β‐keto amphetamine modulation of neurotoxicity by the dopamine transporter Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice | International Journal of Neuropsychopharmacology Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10 Neurological Disorders Depersonalization/Derealization Disorder Sarcosine, low dose naltrexone, MIF1 , ezogabine, riluzole, lamotrigine, lithium, BPC157 (risky), neboglamine, Zelquistinel, fasoracetam, glycine, Aticaprant, TAK653 , piracetam and nor-BNI are the most helpful drugs for DPDR. Antidepressants or MAOIs (ie. 9-methyl-β-carboline, tranylcypromine, methylene blue) can help too. A lot of these may help HPPD as well since both HPPD and depersonalization/derealization disorder (DPDR) mostly involve glutamatergic dysfunction. Opioid system dysfunction is implicated in depersonalization/derealization disorder (DPDR). NMDA modulators like NAC/NACET, glycine, piracetam, sarcosine, neboglamine and maybe fasoracetam too are likely helpful for DPDR. Avoid NMDA antagonists if you have DPDR. Refer to the KOR section. PSSD It is caused by high tryptophan hydroxylase activity, low dopamine, gut dysbiosis and dysfunctional VDR/MTHFR.
Fenclonine, rifaximin, cyproheptadine, ibogaine, memantine, SJW Ze 117 and NA-semax-amidate are the most helpful for this disorder. Anhedonia/Melancholia Melancholic depression or hypodopaminergic phenotype of depression is known as anhedonia. Some argue that it should be considered its own separate entity to that of depression. It is caused by dopaminergic dysfunction (usually low), opioidergic dysfunction and supersensitivity to serotonin. Avoid serotonergics as much as possible and focus on maximizing dopaminergic transmission. KOR downregulation and psychedelics could be helpful. Sometimes PSSD treatments can work for this disorder as they occasionally share similar roots. The Sydney Melancholia Prototype Index is commonly used to distinguish melancholic from non-melancholic depression. MIF-1, 9-Me-BC, vorinostat, pramipexole, psychedelics (especially ibogaine and 5-MeO-DMT), dissociatives (especially DXM and ketamine), amantadine/memantine, bromantane, IM BPC-157, IN PE-22-28, and Cerebrolysin, serotonin antagonists, NSI-189, dextroamphetamine, VLD amisulpride, buprenorphine, sarcosine + NACET, mesembrine and salvia show the most potential for treating anhedonia. OCD and Anxiety Disorders Mostly involves glutamatergic dysfunction and serotonin deficit. Only NMDA antagonists, SRIs and MAOIs work for this disorder because serotonin negatively regulates NMDA transmission (excessive in OCD). Dissociatives, fluvoxamine, tropisetron, clomipramine and psychedelics are the best treatments for this disorder. HDAC inhibition might also prove useful for exterminating fear and anxiety. PTSD and Trauma-Induced Disorders (ie. Borderline Personality Disorder) Pathophysiology of PTSD is unclear although it seems to be similar to depressive disorders for the most part. Antidepressants, bromantane, fear-extinctives (including URB597, nor-BNI and vorinostat) and psychedelics especially are likely the most useful for these disorders. HPPD and Visual Snow Syndrome Tropisetron, vorinostat, nicotine, sigma-1 agonists like opipramol and fluvoxamine and piracetam seem to help. Not much is known about these disorders other than the fact glutamate (excess), acetylcholine and serotonin are involved.
Fibromyalgia Anti-inflammatories (ie. CBD, β-caryophyllene and WWB), NRIs, antidepressants, psychedelics (especially ibogaine), URB597, magnesium, curcumin, kava, etifoxine, berberine, black seed oil and nor-BNI are the most helpful for this. Schizophrenia and Psychotic Disorders NMDA antagonists, serotonin agonists (especially 5-HT2A and 5-HT2C), opioid agonists, dopamine agonists, and CB1 agonists like Δ-9THC exacerbate psychotic symptoms. Stay away from those and stick to this stack. Brain Regions dlPFC The dorsolateral prefrontal cortex (dlPFC or DL-PFC) is an area in the prefrontal cortex of the primate brain. It is one of the most recently derived parts of the human brain. It undergoes a prolonged period of maturation which lasts into adulthood. [1] The DLPFC is not an anatomical structure, but rather a functional one. It lies in the middle frontal gyrus of humans (i.e., lateral part of Brodmann's area (BA) 9 and 46). Many neurological disorders have significant dysfunction in the dlPFC, such as schizophrenia, ADHD, addiction, Alzheimer's, OCD (via dlPFC-OFC relationship), etc. The dlPFC is also a very promising target for cognitive enhancement because of its position to control other brain regions and also because of its density of pyramidal neurons and other factors. The dlPFC is also the single most important neuronal correlate of consciousness. vlPFC The ventrolateral prefrontal cortex (vlPFC) is a section of the prefrontal cortex located on the inferior frontal gyrus, bounded superiorly by the inferior frontal sulcus and inferiorly by the lateral sulcus. It is attributed to the anatomical structures of Brodmann's area (BA) 47, 45 and 44 (considered the subregions of the vlPFC – the anterior, mid and posterior subregions). Functionally, it acts similar to the dlPFC, acting somewhat as a side-processing unit for the dlPFC. It has similarly been implicated in executive function, albeit somewhat less important.
In schizophrenia, the vlPFC most likely assumes the role of the dlPFC due to the dlPFC’s high level of dysfunction. This means people with schizo-related disorders are more likely to rely on their vlPFC for executive function than the dlPFC. The vlPFC may also be implicated in multiple hallucination disorders if dysfunction arises. Hippocampus WIP Hypothalamus WIP Cerebral Cortex Serotonin heavily regulates cortical glutamate. Potassium channels heavily regulate GABA/glutamate in cortical areas. Serotonin also regulates cortical GABA/glutamate interneurons; especially NMDA. Nucleus Accumbens WIP Brain Stimulation tDCS WIP rTMS WIP More on HDAC Inhibition
“How I overcame my social anxiety using vorinostat” - a removed Reddit post So I struggled with severe social anxiety for a few years, granted it did become slightly better with age. It used to be absolutely debilitating, walking down school hallways became nearly impossible without breaking a sweat. I'd deliberately eat my lunch outside of school facilities because I simply couldn't bear the thought of eating in the presence of so many others. Eye contact was a thing of fiction, it's as if it killed me to look others in the eyes, so I never did. Fast forward a few years, I graduated and it did become a little better with time but it was still very draining. So I went looking for possible treatments, I didn't consider visiting a doctor or anything like it. Maybe I should've but you know, social anxiety and all that. Anyway, since I've always held an interest in biochemistry and pharmacological drugs I did some extensive research into anxiolytics. I did try pregabalin which worked rather well for me but it was a short-term fix, so I wasn't very keen on it. Eventually, stumbled across vorinostat, an HDAC inhibitor. Essentially, vorinostat wipes any learned fear after a memory is recalled or a situation is experienced, causing the memory/situation to be permanently stripped of its learned fear-response-inducing attributes. This Reddit post elaborates on it. So, I was hooked. After some research, I managed to find a somewhat reputable source, bought some, and tried it. (The drug isn't FDA-approved for this purpose, just something to note). I can only call the experience life-altering. I would say there's me pre-vorinostat and me, post-vorinostat. This substance changed me on a fundamental level. Truly. Speaking to those suffering from severe, chronic social distress, you'll identify that discomfort you so often experience as part of you as an individual. After all, it's pretty much all you've ever known. It's hard to imagine a future where you do not find yourself uneasy in certain social situations. Well, I am here to tell you that although that used to be the case for me, it is no more. It's nearly akin to a miracle. The effects might not be instantaneously obvious but after some intervals, I noted myself unable to experience the discomfort I used to in certain contexts. Once this realization was set into place that's when the magic happened. Knowing that the extreme unease felt before won't pop up regardless of my environment has been very freeing. I now initiate interactions I evaded before, and look people in the eyes where I didn't in the past. The best thing, arguably, is the permanence of its effects. I took it a few times, spaced some weeks apart and the effects remained. Again, I do have to reiterate that this isn't an FDA-approved drug for anxiolytic purposes, so I can't advise anyone to take this without knowing the risks and doing their due diligence. Just sharing my unconventional battle with social anxiety. --------------------------------------- “When DNA needs to be read it is unraveled from the histone and held open with acetyl groups. Histone deacetylase (HDAC) then takes the acetyl groups back off after the dna is read. An HDAC inhibitor, then, lowers the amount of available HDAC to take acetyl groups back off the DNA, leaving the DNA open a bit longer for transcription. This, in effect, increases transcription with things HDAC is implicated in, from creating memories to
changing the number of receptors based on the environment in the body. Children have lower HDAC than adults, and the amygdala has more HDAC than the rest of the brain. HDAC inhibitors could then be used to learn things like children do, or reshape fears from traumatic events that are usually untouchable through conventional therapy due to evolution not wanting us to forget fearful situations (like a lion attack, but in today's world this is unnecessary and only presents itself as debilitating PTSD). Edit: To expound on your case, there aren't any studies on remaking one's habits or sort of personality you could say, overcoming long standing habits and beliefs that stem from childhood, simply because this isn't a clinical problem, but it my and others' experience HDAC inhibitors help do exactly what you want, which is change the way you act much faster than you would normally be able to (and sometimes help you change things otherwise you normally would never be able to). For example, I had social anxiety from smoking pot for several years -- it's just how I reacted. I was looking for a solution for so long, and practiced different habits as well. When I found vorinostat, however, (this was before I knew about black seed oil, so I ordered vorinostat from a manufacturer) I was dumbfounded that the first few times I took it the anxiety just wasn't there, because it wasn't real and the HDAC inhibitor let my mind write over the old fear memories with clean new ones. It was almost weird, however, because at that point I was so used to this anxiety that when it wasn't there I didn't really know how to act. But, after a few sessions of vorinostat I was very comfortable and making great headway on making a new self. It was easy to be outgoing, and I started learning new things. The benefit of HDAC inhibitors is that it makes permanent changes to your memories, and so permanently changes your thoughts and who you are.” - from longecity --------------------------------------- Vorinostat potentiates alot - r/Nootropics --------------------------------------- “As I've investigated the use of HDAC inhibitors for fear extinction, I've also looked into how certain memories are formed, including fear, anxiety, negative reinforcement, positive reinforcement, reward, love, attachment, etcetera. The way different memories are made in the brain and what controls them is very important. HDAC doesn't control all memory, and if the ones it does oversee it doesn't control them all equally. There are many other transcription factor targets, as well as many other epigenetic regulator targets that affect various kinds of memory other than HDAC. For example, DNMT3a affects addiction and, to some extent, certain types of reward, as seen in this study: Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens This is how I understand it from all I've read... Fear and anxiety has totally different mechanisms and pathways in the brain from regular memories, reward, love, and anything else. They build over time, even if the trigger is no longer directly linked to danger. This makes sense evolutionarily if you think about it. You want to make sure that whatever is brought into danger brings up awful feelings so you don't even think about doing it again. The degree to which it brings up fear and the degree to which you can actively combat it probably depends on the person, hence some people are prone to anxiety, PTSD, etc. and
some people are less prone. This is key to understanding how HDAC inhibitors work... the fears associated with certain memories and situations are often overblown by our brain compared to how we should actually be reacting to the memory/situation. This is a protective trait built up throughout evolution. If you did something and a lion came up out of nowhere, you're brain is making sure you never want to do that again, even if you never even see another lion in your life... walking to that part of the desert is always going to bring up that fear, and may even build over time, even if you never see another lion. This happens in different parts of the brain, too, with certain pathways dedicated specifically to fear, and there have been studies showing that HDAC is upregulated or downregulated in specific parts of the brain depending on whether there's been a fear-inducing situation that has taken place. I'll try to find that study. To answer the first question, HDAC selectively resets the anxiety and fear switch because, 1, HDAC happens to have a built-in propensity toward acting on transcription factors and parts of the brain having to do with negative reinforcement, fear, anxiety, avoidance, etc... it just doesn't act towards other emotions, because these are handled by different pathways in the brain and perhaps might not even be regulated by epigenetics as much, as they evolved into lifeforms after fear (love, happiness, connection, empathy, etc.) 2, an HDAC inhibitor works so well at eradicating fear because fear is the most likely emotion to be naturally attributed to a situation and unnaturally built-up. An HDACi, even at a small dosage, increases the priority of the present, so no matter what you've felt about the present situation (brought up through meditation or an actual experience) in the past, what the situation is doing in the present moment will be given full priority, which is usually felt as "nothing". In real time, how an HDACi feels is like nothing. No extreme, built-up emotions from the past come up. You can remember them if you try, you can remember everything that happened, but unless you're about to be hit by a bus, there will be no tightness in your chest, no anxiety, etc. Even if you were hit by a bus on an HDACi, as long as you were on it still after being hit, or took it again a couple days later, the fear that was learned from being hit by the bus on the HDACi can also be eradicated, so there should be no fear in using an HDAC. It's getting at the root of memory formation, at the transcription level, so it's impossible to have a "bad trip" or anything like that. It doesn't affect cognition, because it doesn't directly affect neurotransmission or anything upstream of CREB, which is anything above what BDNF is actually doing to DNA. It's really incredible, and nothing else we've used acts like this, so it's hard to wrap your mind around at first. You just have to try it. To answer your second question, yes, HDACi hyper-acetylate other genes as well, but they're not nearly as sensitive as the brain. If you take high amounts of HDACi for a long period of time, you will arrest the cell cycle even. This is how HDACi are used to kill cancer. Most healthy cells can handle this, however. At the dosages we'd be taking them at the cell cycle won't be arrested... not even close. We just need enough increase in transcription to prioritize the present when it comes to transcribing memories. This is how children are able to learn and adapt so quickly... one of the reasons HDACi are described as "turning back the clock" on memory, or "feeling like a kid again." To address your third question... The first paragraph is actually wrong. HDAC indirectly affects many things, neurotransmitters and receptors included, but this is nowhere near how
it works. This is part of why it's so hard to wrap your head around at first... Trkb , NMDAR, calcium channels, whatever you wanna talk about neurotransmission-wise in a cell above CREB, this isn't how HDACi works. It works at the transcription level by holding open transcription. This is what heightens "resilience," as you say. This is also how exposure therapy is actually brought to work by using HDAC inhibitors. Without HDAC inhibitors, it can be extremely hard for exposure therapy to work for a lot of things, especially PTSD. Even if it does work, the chance of relapse is incredibly high. This is because our fear centers in our brain and fear memories were built to keep fears alive for our protection. They're incredibly hard to overcome, and the only way to do so is to hold open the window of transcription when a memory is reactivated long enough for the present to become stronger than the past. The past will still be remembered, technically, but when you bring the memory up after your HDAC session, the most recent, non-fear-inducing memory will be what you feel. In my experience, since HDACi helps form long-term memories in general, it has helped me learn how to act socially. Once it gets rid of the fears of the past that used to get in your way, you're free to act in the present however you please, and almost everything is remembered in incredible detail because you're on the HDAC. It's really amazing, and I can't wait to get more vorinostat. Last question of yours... I don't think StevesPetRat read enough of the anecdotes or my posts because HDAC inhibitors do not bring up the past. It's not therapy through normal cognitive pathways, it's therapy through physical changes in transcription, and to the watcher, you, consciousness, it looks like the fear disappeared and you're left with nothing. Not a bad feeling of nothingness felt with the shitty medications doctors use to blunt people's emotions, but an unencumbered state of no longer being controlled by your past negative emotions and having the room to feel other emotions in a situation once again, as if you were a child.” - longecity --------------------------------------- “The happiness, pleasure, attraction, and love parts of our brain work differently and utilize HDAC in different ways (or perhaps not at all) than the fear pathways of our brain. It does not dull emotions. Also positive emotions are less likely to artificially build up in our minds like fear does, which is an evolutionary trait to keep us away from harm. Most of the fear that comes up in us is connected to fears that are associated with memories, have built up overtime, and are triggered by various stimuli causing a resurgence and then strengthening of those fears, whether or not the original danger is still there or not. HDAC inhibitors allow the reassessment of these past fears, which usually give the feeling of the fear disappearing. They were technically overpowered and overwritten by the present moment, which, unless you're about to get hit by a train, is not as fear-inducing as the overly-built-up fears from the past. Vorinostat essentially allows growth. It overcomes the built up fear and allows the other emotions we have to surface, hence the breath of fresh air I felt the first time I took vorinostat. In this way it potentiates the positive emotions because it is allowing them a chance by stripping away the built up fear. What makes us truly afraid today is completely different from what instilled fear in us in our younger years, and, because of the way fear works evolutionarily, fear is meant to build up in us over time surrounding certain situations. Since we're not needing to avoid lions anymore, this evolutionary trait usually just manifests
itself as weird, crippling anxieties that are at their essence unnecessary in today's world. If they are necessary, they will be kept, as vorinostat doesn't dull any emotion. So, if every time you say something dumb in class you feel anxiety, if you're on vorinostat you will record that anxiety, but it will not allow it to balloon. Any anxiety about that situation that has ballooned over time will be stripped away, so even that bit of necessary anxiety that possibly could remain still feels like a breath of fresh air because now you're feeling all the emotions equally and not just the built up, unnecessary anxiety from all times past.” - longecity --------------------------------------- "previous work from our laboratory assessed the role of HDAC1 and HDAC2 on synapse maturation and synaptic efficacy in hippocampal neurons and found that individual HDAC2 knockout led to deficits in synaptic efficacy in mature neurons (Akhtar et al., 2009). The depressed synaptic input-output curves we observed in the present study may be related to HDAC2 ’s constitutive impact on synaptic efficacy. In addition, an earlier study from our laboratory observed a similar effect of the HDAC inhibitor trichostatin A (TSA) on synaptic efficacy that could be reversed by co-incubation with actinomycin D (Nelson et al., 2006). Taken together, these findings suggest that the basal decrease in synaptic efficacy seen after loss of HDAC2 may be the result of a transcriptional effect, rather than a transcriptional-independent pathway, however further experiments are needed to test this hypothesis." "Based on a limited number of studies including our own, deleterious effects of postnatal HDAC2 knockout remain to be found. One important exception is that conditional HDAC2 deletion in adult neural stem cells leads to deficits in neurogenesis in the dentate gyrus subregion of the hippocampus, suggesting a continued role for HDAC2 in cell differentiation in adult brain (Jawerka et al., 2010). Deficits in adult hippocampal neurogenesis have been implicated in mood disorders as well as in a lack of an appropriate behavioral response to antidepressants in animal models suggesting that the therapeutic potential of targeting HDAC2 for cognitive disorders may be limited in some cases (Hanson et al., 2011). It is conceivable that while enhanced plasticity manifests as advantageous in experimental settings in which animals are trained chronologically in distinct learning tasks, in nature such rapid inhibition of responding to CS-US associations could prove maladaptive. As one example, CTA is an adaptive response to ingested poisons, therefore near immediate extinction to the CS following limited experience in which the US is not present may be considered detrimental. One role of endogenous HDAC2 in the adult brain may therefore be to promote and maintain the stability of learned associations when an organism is faced with new and competing associations, however this hypothesis demands further study. Recent data suggests that a postnatal forebrain KO of the class II HDAC, HDAC4 , impairs learning and LTP, demonstrating dissociable roles for class I versus class II HDACs in cognition and synaptic plasticity (Kim et al., 2012). " https://www.ncbi.nlm...17/#!po=55.2632Page 11:
Knockdown of HDAC2 but not HDAC1 decreases synaptic activity in mature hippocampal neurons: Together, these findings indicate that maintenance of miniature excitatory transmission in mature neurons requires the activity of HDAC2 , which targets the presynaptic release machinery but not the number or maturation state of synapses. "To further investigate the role of HDAC2 -mediated effects on synaptic transmission in mature neurons, we infected C57BL/6 hippocampal neurons at 7 DIV with lentivirus expressing HDAC2 (Fig. 7A). We found that overexpression of HDAC2 in mature neurons produced a significant increase in mEPSC frequency with no change in their amplitudes (Fig. 7B–D). The significant increase in mEPSC frequency with HDAC2 overexpression, coupled with the significant decrease in mEPSC in HDAC2 null neurons, suggests that HDAC2 plays a critical role in mediating synaptic transmission in mature neurons and changes in its expression can profoundly impact synaptic function" - longecity --------------------------------------- An article on HDAC Inhibitors geared toward the nootropics community - r/Nootropics [a]Add more specifics about its pharmacological effects and targets [b]Add additional information and characteristics from the trial [c]To complete [d]To complete