02/10/2026
Mythological Mushrooms đ
Psychedelic Assisted Therapy:
*D &
:
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PAT combines psychoactive substances with structured to treat Mental Health conditions. In this report we examine five substances. L*D, psilocybin ( ), DMT (and its traditional preparation ayahuasca), and ketamine covering current clinical research, mechanisms of action, treated conditions, comparative efficacy, safety, legal status, and integration practices. We draw on recent systematic reviews and trials, emphasizing up-to-date evidence (2022â2025).
Mechanisms of Action:
Each substance produces its effects via distinct neuropharmacology. L*D is a classic serotonergic psychedelic, acting as a strong agonist at multiple 5-HT (especially 5-HTâA) receptors and also at dopamine D1, D2, and D4 receptors. Psilocybin is a prodrug converted in vivo to psilocin, which primarily stimulates 5-HTâA receptors (often via a 5-HTâAâmGluRâ receptor complex). DMT likewise is a potent 5-HTâA agonist, but is unique in binding other targets â for example, DMT also activates trace amine-associated receptors (TAARs) and sigma-1 receptors, contributing to neuroplastic and neuroprotective effects. Ayahuasca is a botanical brew containing DMT and MAO-inhibiting β-carbolines (harmine, harmaline) from the Banisteriopsis caapi vine. The MAOIs render DMT orally active by blocking its metabolic breakdown, extending the DMT experience to ~4â6 hours (versus ~20â30 minutes for smoked or IV DMT). Finally, ketamine is an atypical psychedelic: a non-competitive NMDA glutamate receptor antagonist. By blocking NMDA receptors, ketamine triggers a glutamate surge that rapidly stimulates synaptogenesis and increases brain-derived neurotrophic factor (BDNF), accounting for its fast-acting antidepressant effects. (Notably, NMDA antagonism is also thought to contribute to the effects of classic psychedelics like DMT.)
Current Clinical Research and Therapeutic Applications:
-Psilocybin has emerged as the most extensively studied classical psychedelic. Recent RCTs show robust antidepressant effects. For example, one JAMA trial of two guided psilocybin sessions in major depressive disorder found a mean reduction in depression scores significantly greater than placebo (niacin) at 6 weeks. In that study, 41.7% of psilocybin patients had sustained symptom response versus 11.4% for control (25.0% vs 9.1% remission). Longer-term follow-up from Johns Hopkins suggests these effects can persist: 75% of subjects remained responders and 58% in remission at 12 months post-treatment. Psilocybin-assisted therapy is also being tested for end-of-life anxiety (cancer, HIV), smoking cessation and other addictions, OCD, and alcohol use disorder. The FDA has granted psilocybin âbreakthroughâ status for treatment-resistant depression and for cancer-related anxiety, and phase 3 trials are underway.
-L*D research is less active today but shows promise in select areas. A systematic review of historical RCTs (1950sâ70s) found that L*D-assisted therapy yielded positive outcomes especially in alcohol use disorder. Other small trials (mostly older) explored L*D for anxiety, depression, and psychosomatic conditions. Recently, âcompassionate useâ programs in Switzerland have allowed L*D-assisted psychotherapy under strict controls. Current trials are examining L*D (and an L*D analog semisynthetic L*D, âML-120â) for cluster headache and other conditions. In general, L*Dâs long duration (8â12 hours) makes it more challenging in clinical settings, so research has been more limited than for psilocybin.
-DMT/Ayahuasca: Pure DMT therapy is in early stages. A Phase 1 trial (SPL026) showed IV DMT to be well-tolerated (no serious adverse events) at escalating doses in healthy volunteers, and a Phase 2 study of DMT fumarate in depression is planned. IV DMTâs ultra-short duration (sub-30 minutes) could allow multiple sessions in a day. Ayahuasca (oral DMT+MAOI) has been studied in both naturalistic and small clinical trials. Observational research suggests frequent ceremonial use may lower long-term depression/anxiety scores and reduce substance use. In a controlled trial of treatment-resistant depression, a single dose of ayahuasca (with supportive setting) produced significant symptom reductions within 1â2 weeks. Ayahuasca has also been applied for alcohol and drug dependence, anxiety, and eating disorders in ritual contexts. However, RCT evidence is limited.
-Ketamine: This dissociative anesthetic is the most widely used âpsychedelicâ in psychiatry today, thanks to its rapid effects in depression. Its intranasal form (esketamine, brand Spravato) was FDA-approved in 2019 for treatment-resistant depression (TRD) when combined with an oral antidepressant. Dozens of trials show ketamine infusions produce fast (within hours) relief of depressive symptoms, even suicidality. Beyond depression, meta-analyses report ketamine can significantly reduce PTSD and OCD symptom scores and can reduce alcohol craving and increase abstinence in alcohol use disorder. Ketamine-assisted therapy (combining infusions with psychotherapy) is being tested for PTSD and substance use. In one large alcohol use disorder protocol, a structured ketamine-assisted regimen achieved 86% abstinence at 6 months. (However, ketamine effects tend to wane after days or weeks without repeated dosing, and long-term protocols are still being refined.)
Conditions Treated
Therapeutic applications overlap but vary by drug. Depression is a key target: ketamine has demonstrated efficacy in TRD, psilocybin has rapid antidepressant effects in major depression and mood disorders, and early data suggest ayahuasca/DMT may also reduce depressive symptoms. PTSD: Ketamine trials show symptom improvement, and M**A (not covered here) is close to approval. Research on psilocybin or L*D for PTSD is scant. Anxiety: Psilocybin is effective for cancer-related existential anxiety and general anxiety. Small studies suggest L*D and ayahuasca may reduce anxiety in serious illness or bereavement. Addiction: Psilocybin has shown promise in smoking cessation and alcohol/drug relapse prevention. L*D therapy has a long history in alcoholism treatment, with systematic reviews confirming beneficial effects. Ketamine-assisted therapy also appears to curb cravings in alcohol use disorder. Obsessive-compulsive disorder (OCD): Preliminary trials of psilocybin and ketamine reported reduced OCD symptoms (small samples). Other conditions: L*D and psilocybin have been tried for OCD, cluster headaches, and migraines. Ayahuasca has been explored for eating disorders. Overall, most evidence (and regulatory momentum) is for depression, anxiety, and substance-use disorders; other indications remain investigational.
Efficacy Comparisons:
Direct head-to-head trials of different psychedelics are lacking. However, meta-analyses give a rough sense of relative effect sizes. A recent systematic review found that psilocybin produced the largest effect on reducing mood disorder symptoms (Hedgesâ gââ1.49), comparable to ayahuascaâs (DMTâs) gââ1.34, while L*Dâs effect was smaller (gââ0.65). (These are pooled pre-post depression/anxiety outcomes from small trials.) Another meta-analysis of ketamine found robust immediate improvements in TRD and PTSD, but with variable durability. Notably, ketamineâs effects are usually rapid but somewhat shorter-lived, whereas classic psychedelics often yield lasting benefit from one or two sessions. In clinical contexts, psilocybin and ayahuasca sessions typically require intensive therapy support but can produce enduring remission, whereas ketamine often needs repeated dosing or maintenance sessions. L*Dâs efficacy data are less robust by comparison. Overall, psilocybin and ayahuasca appear at least as effective as other treatments for depression and addiction, and stronger (by effect size) than L*D, but cross-study comparisons should be made cautiously.
Practices & Models:
All modern psychedelic therapies emphasize set and setting and ongoing psychotherapy. The typical model (adopted by MAPS, Johns Hopkins, etc.) involves three phases: (1) Preparation, where therapists build rapport and educate the patient; (2) the Dosing Session, where the substance is administered in a comfortable, supervised environment with therapeutic support; and (3) Integration, a series of follow-up sessions to help the patient process the experience and apply insights to life. This model is applied to all substances in clinical research. Licensed clinicians monitor vital signs during sessions and guide the psychological experience as needed. Integration therapy may include talking, journaling, mindfulness, and even bodywork or art, to ensure insights endure.
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