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Substances

  • MDMA
  • PSILOCYBIN
  • KETAMINE
  • IBOGAINE
  • AYAHUASCA
  • LSD
  • 5-MeO-DMT

MDMA

(3,4-Methylenedioxy-Methamphetamine)

Formula: C₁₁H₁₅NO₂
Classification: Stimulant entactogen/empathogen
Onset of action: 30–45 minutes (orally)
Peak effects: 1.5–3 hours

History

MDMA was first synthesized in 1912 by German chemist Anton Köllisch for the pharmaceutical company Merck. Although it was initially created for pharmaceutical purposes, its psychoactive properties remained unknown for decades.

In the 1970s, American chemist Alexander Shulgin rediscovered MDMA, developing a new synthesis method and recognizing its therapeutic potential. He introduced it to psychotherapist Leo Zeff, who began using it in psychotherapeutic settings and shared it with other therapists.

MDMA was valued for its ability to facilitate emotional openness, communication, and the processing of trauma.

Pharmacology

  • Main classification: Entactogen/Empathogen
  • Psychedelic properties: MDMA can induce mild psychedelic effects in some circumstances, but it is not considered a classic psychedelic like LSD, mescaline, psilocybin, or DMT.

MDMA is classified as a phenethylamine. It has both stimulant and entactogenic properties. It acts mainly by inhibiting the reuptake and promoting the release of serotonin, dopamine, and norepinephrine, thereby increasing their concentration in the brain’s synapses.

The high level of serotonin activates several serotonin receptor subtypes, including 5-HT2A receptors, although this is not considered MDMA’s main mechanism of action (unlike other classic psychedelics). MDMA also stimulates the release of oxytocin, the hormone associated with social attachment and empathy.

This can lead to:

  • Increased empathy and emotional connection
  • Reduction of social anxiety and psychological defenses
  • Feelings of well-being and open-mindedness
  • Reduced fatigue and increased energy

Risks and Benefits

Benefits:

  • Therapeutic efficacy: clinical trials have shown that MDMA-assisted therapy can lead to significant reductions in PTSD symptoms.
  • Lasting effect: improvements may persist over time, reducing the need for long-term treatment.
  • Increased emotional openness: it facilitates the processing of deep trauma in a safe therapeutic environment.
  • Positive effects on anxiety in autistic adults
  • An exploratory analysis of a phase 3 PTSD trial observed a preliminary improvement in alcohol-related risk scores (not in other substance use); dedicated studies are needed to assess efficacy for addiction.

Risks:

  • Physical side effects: increased heart rate and blood pressure, possible muscle tension, and nausea.
  • Psychological effects: anxiety, paranoia, or disorientation in some individuals.
  • Preexisting health problems: MDMA use can negatively affect preexisting health problems such as hypertension, cardiovascular, liver, or kidney disease, diabetes, glaucoma, and epilepsy.
  • High doses: consuming MDMA at high doses increases the risk of experiencing adverse effects.
  • Repeated use at high doses can also lead to serotonin syndrome.

It is essential that MDMA be administered in a clinical setting with qualified professionals to minimize risks.

Administration Protocols and Process

The protocol developed by MAPS for MDMA-assisted therapy, used in the Phase 3 clinical trials, emphasizes the crucial importance of psychotherapy throughout the entire course of treatment.

Treatment Structure:

  • 3 MDMA-assisted psychotherapy sessions (about 8 hours each) with two qualified therapists.
  • 12 non-drug sessions (90 minutes each), divided between preparation and integration.

Protocol Details:

Preparation Phase (First 4 weeks):

  • 3 preliminary sessions without MDMA.
  • Goal: build a solid therapeutic relationship and prepare the patient for the experience.
  • In this phase, the patient’s medications are gradually discontinued (this process can take from a few weeks to several months)

Preparation Phase (first 3 to 5 weeks):
3 preparatory sessions without MDMA are planned, with both therapists.
Goal: to build a safe therapeutic relationship, inform the patient about the MDMA experience, and lay the foundations for psychological exploration.

Note on medications: in clinical trials, discontinuing psychiatric medications (e.g., SSRIs, SNRIs, benzodiazepines) may be necessary for reasons of pharmacological safety and to avoid interactions. However,

  • does not necessarily take place during the clinical preparation phase proper,
  • may begin weeks or months before the first therapy meeting,
  • and is managed case by case by a physician, never by the therapists.

Active Treatment Cycles
3 repeated modules, each consisting of:

  • 1 session with MDMA
  • 3 integration sessions without MDMA

Interval between MDMA sessions: 3 to 4 weeks, to allow the experiences to be processed and integrated.

Integration sessions aim to help the patient integrate and understand the content of the MDMA session.

To practice according to the MAPS protocol, professionals must complete:

  • 100 hours of specialized training in MDMA-assisted therapy.
  • 45 hours of clinical supervision to obtain certification.

Approval Stage and Organizations Involved

MDMA has completed Phase 3 clinical trials for the treatment
of PTSD. In the United States, the Food and Drug Administration (FDA) granted
"Breakthrough Therapy" designation in 2017 for PTSD, recognizing its significant therapeutic
potential. In July 2026, Resilient (formerly Lykos Therapeutics) resubmitted its application for approval,
which is currently under FDA review. MAPS, which led the clinical research, is not currently conducting clinical trials.

MDMA has completed Phase 3 clinical trials for the treatment of post-traumatic
stress disorder (PTSD).
The clinical research was led by MAPS (Multidisciplinary Association for Psychedelic
Studies) through its public benefit corporation, originally called MAPS PBC, later renamed
Lykos Therapeutics and now Resilient.

Approval update (US): on August 9, 2024, the FDA issued a Complete Response Letter on Lykos's NDA for MDMA-assisted therapy for PTSD, requesting an additional Phase 3 study to strengthen the safety and efficacy data, also in light of methodological issues that emerged (e.g. functional unblinding). Lykos, now renamed Resilient, resubmitted the New Drug Application (NDA) in July 2026; the application is currently under FDA review.

Related research and bibliography

  1. Effects of MDMA-assisted therapy for PTSD on self-experience. PLoS One, 19(1). van der Kolk, B. A., Wang, J. B., Yehuda, R., Bedrosian, L., Coker, A. R., Harrison, C., Mithoefer, M., Yazar-Klosinki, B., Emerson, A., Doblin, R. (2024)
  2. MDMA‑assisted therapy for moderate to severe PTSD: a randomized, placebo‑controlled phase 3 trial. Nature Medicine, 29(10), 2473–2480. Mitchell, J. M., Ot’alora G., M., van der Kolk, B., Shannon, S., Bogenschutz, M., et al. (2023)
  3. The effects of MDMA‑assisted therapy on alcohol and substance use in a phase 3 trial for treatment of severe PTSD. Drug and Alcohol Dependence, 233, 109356. Nicholas, C. R., Wang, J. B., Coker, A., Mitchell, J. M., Klaire, S. S., Yazar-Klosinski, B., Emerson, A., Brown, R. T., & Doblin, R. (2022)
  4. MDMA‑assisted therapy for severe PTSD: a randomized, double‑blind, placebo‑controlled phase 3 study. Nature Medicine, 27(6), 1025–1033. Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker‑Guilbert, K., Ot’alora G., M., … Mithoefer, M. C. (2021)

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STUDIO AEGLE: MDMA for PTSD

Psilocybin

(4-phosphoryloxy-N,N-dimethyltryptamine)

Chemical formula: C₁₂H₁₇N₂O₄P
Classification: Classic psychedelic (tryptamine)
Onset of action (onset of effects): 20-40 minutes
Peak effects: 2-3 hours

History

Psilocybin is a psychedelic compound found in more than 200 species of mushrooms (the best known is Psilocybe cubensis, a single species), commonly known as “magic mushrooms” or “hallucinogenic mushrooms” (see the Beckley Retreats guide to types of psychedelic mushrooms).

Psilocybin is a psychedelic compound found in more than 200 species of mushrooms belonging to several genera, including Psilocybe, Panaeolus, and Gymnopilus. These mushrooms, commonly known as “magic mushrooms” or “hallucinogenic mushrooms”, have been used for ritual and spiritual purposes by various human cultures.

It is sometimes claimed that these mushrooms were already used in the Pliocene (5.3 million years ago): this is a speculative hypothesis without scientific basis and is not supported by fossil or archaeological evidence. In fact, the genus Homo had not yet appeared at that time.

The oldest archaeological finds suggesting a possible ritual use of psychoactive mushrooms come from sites in Mesoamerica, such as the “mushroom stones” found in Guatemala and Mexico, dating to around 1000 BCE. In addition, modern ethnographic sources confirm the traditional and ceremonial use of psilocybin-containing mushrooms among Indigenous peoples such as the Mazatec, Maya, Mixtec, and Zapotec.

The use of these mushrooms dates back millennia, and evidence of it has been found on several continents, from Africa to Europe to Central America, where they were used in ritual and spiritual contexts among Mexican Indigenous cultures. The task of administering during ceremonies what the Aztecs called the “flesh of the gods” was reserved for the curanderas and curanderos, healer-shamans who acted as connectors between the spirit of the mushrooms and the community.

Learn more

In 1957, banker and mycologist R. Gordon Wasson brought psilocybin to the attention of Westerners after taking part, with his wife, ethnomycologist Valentina Pavlovna, in a Mazatec ceremony in Mexico. The “velada” had been led by the curandera and poet Maria Sabina. Wasson published an article in “Life” magazine titled “Seeking the Magic Mushroom”, complete with photos of the officiating curandera, which aroused great interest.

In 1958, Swiss chemist Albert Hofmann, known for having synthesized LSD, isolated and synthesized psilocybin in the laboratory for the first time, and it is said that even Maria Sabina later confirmed its efficacy.

In the 1960s, psilocybin was the subject of numerous studies for its therapeutic potential in treating mental disorders such as depression. However, because of growing concerns about the recreational use of psychedelics and political pressure, research was halted as restrictive laws came into force between the end of that decade and the early 1970s (in the United States, the Controlled Substances Act of 1970), followed by the “war on drugs” announced by President Nixon on 17 June 1971.

Anthropological
and Cultural Context

Psilocybin-containing mushrooms have a long tradition of use in the spiritual and healing practices of various Indigenous cultures such as the Mazatec, the Mixtec, and the Aztecs. They were used for:

  • religious rituals and shamanic ceremonies
  • physical and spiritual healing
  • divination and communication with the spirit world
Learn more

In the 1960s, psilocybin became a symbol of the exploration of consciousness and of the Western counterculture. After the publication of R. Gordon Wasson’s 1957 article in Life Magazine, titled “Seeking the Magic Mushroom”, interest in natural psychedelics also spread among intellectuals, artists, and celebrities.

Aldous Huxley, Timothy Leary, and Richard Alpert (later Ram Dass) were among the leading promoters of psychedelic use in the West.

In 1960, professors Leary and Alpert launched the Harvard Psilocybin Project, a research project in Harvard’s Department of Psychology aimed at studying the effects of psilocybin on students, volunteers, and artists, often outside a standardized clinical setting.

Timothy Leary became a central figure of American psychedelia, publicly promoting the use of psychedelics as tools for personal and social transformation. His highly media-driven approach contributed both to the initial popularity of psilocybin and to its subsequent stigmatization and prohibition, culminating in its classification as an illegal substance at the end of the 1960s.

In recent years there has been renewed interest in psilocybin as a therapeutic tool, with a growing number of studies exploring its use and efficacy in the treatment of various mental health conditions, particularly treatment-resistant depression and addiction.

Pharmacology

  • Main classification: Classic psychedelic
  • Psychedelic properties: psilocybin induces intense psychedelic effects, characterized by perceptual, emotional, and cognitive alterations. It may facilitate mystical or transcendent experiences, states of deep introspection, and a heightened sense of connection with oneself, with others, and with nature. In some cases, ego dissolution may occur, that is, a temporary loss of the perception of the self as a separate entity.

Psilocybin is a prodrug that, once ingested, is converted by the body into psilocin, the active compound that crosses the blood-brain barrier.

Main effects:

  • Perceptual alterations: changes in visual, auditory, and tactile perception
  • Expansion of emotional and cognitive awareness
  • Mystical or transcendent experiences
  • Sense of connection with oneself, others, and the environment

Risks and Benefits

Benefits:

  • Treatment of treatment-resistant depression: clinical trials have shown significant improvements in patients with drug-resistant depression.
  • Reduction of anxiety associated with terminal illness: it may relieve anxiety and existential distress in patients with serious diagnoses.
  • Help with addiction: preliminary research suggests efficacy in the treatment of alcohol and tobacco addiction.
  • Support for brain activation and neuroplasticity: it may not only promote the patient’s emotional openness, making the psyche more receptive to targeted psychotherapeutic interventions, but also stimulate neuroplasticity.
  • Chronic pain management: used in some painful conditions that are refractory to conventional analgesics.
  • Fibromyalgia: preliminary studies indicate encouraging results for the safety and efficacy of psilocybin in patients with fibromyalgia.

Potential benefits of psilocybin:

  • Treatment of treatment-resistant depression
    → Controlled clinical trials have shown significant improvements in patients with treatment-resistant depression (TRD), including Phase 2 studies conducted by COMPASS Pathways and by the Centre for Psychedelic Research at Imperial College London.
  • Reduction of anxiety associated with terminal illness
    → Clinical trials conducted by Johns Hopkins and NYU have shown that a single dose of psilocybin, in a therapeutic setting, can significantly reduce anxiety and existential distress in patients with advanced cancer.
  • Help with addiction
    → Pilot studies indicate potential benefit in the treatment of alcoholism and tobacco addiction.
  • Support for brain activation and neuroplasticity
    → Preclinical and neuroimaging data suggest that psilocybin may stimulate neuroplasticity (e.g., dendritic spine growth, increased brain connectivity) and promote greater psychological flexibility. However, these effects have not yet been clinically measured or standardized, so they should be described with caution.
  • Chronic pain management
    → Research on psilocybin and chronic pain is still very limited, though promising. Some case reports and exploratory trials suggest benefit in conditions such as cluster headache and refractory neuropathic pain. However, there are not yet any large-scale clinical efficacy studies.
  • Fibromyalgia
    → Preliminary and experimental studies are underway, for example a clinical trial conducted in Canada (MAPS Canada, Phase 2a recruiting in 2024), but no definitive published data so far.

Risks:

Adverse psychological reactions: possibility of intense anxiety, paranoia, or confusion during the experience, known as a “bad trip”.

Exacerbation of preexisting mental disorders: contraindicated for people with schizophrenia, psychosis, or a predisposition to psychotic disorders.

Physical effects: nausea, dizziness, increased blood pressure and heart rate.

Flashbacks or persistent perceptual disorders: in rare cases, persistent symptoms may occur.

High doses: consuming psilocybin at high doses increases the risk of experiencing adverse effects.

Risks and potential adverse effects of psilocybin:

  • Adverse psychological reactions
    → It is possible to experience intense anxiety, confusion, fear, or paranoia, especially in uncontrolled environments or at high doses. These episodes are commonly known as a “bad trip”, and although generally temporary, they can be very destabilizing.
  • Exacerbation of preexisting mental disorders
    → Psilocybin is contraindicated in people with a personal or family history of schizophrenia, psychosis, or psychotic disorders, as it can trigger or worsen latent psychotic symptoms.
  • Physical effects
    → Psilocybin can cause nausea, dizziness, pupil dilation, and a temporary increase in blood pressure and heart rate. These effects are generally mild and transient, but should be monitored in clinical settings.
  • Flashbacks or Hallucinogen Persisting Perception Disorder (HPPD)
    → In very rare cases, some people may experience recurrent visual disturbances or sensations similar to the psychedelic experience days or weeks after taking the substance. This condition is known as HPPD (Hallucinogen Persisting Perception Disorder) and is documented but uncommon.
  • High doses
    → Taking high doses of psilocybin increases the risk of adverse psychological effects, including acute anxiety, disorientation, or loss of contact with reality. It is therefore important that use takes place in safe settings, with preparation and support.

Drug interactions
→ Cases of serotonin syndrome involving psilocybin have rarely been reported, mostly in combination with other drugs that raise serotonin levels, such as SSRI antidepressants or MAOIs. Available studies have not documented this risk with psilocybin alone, but the evidence is still limited: absence of evidence is not evidence of absence of risk.

It is essential that psilocybin be administered in a controlled environment, under the supervision of qualified professionals, to ensure the patient’s safety.

Administration Protocols and Process

The psilocybin therapy protocol combines administration of the substance with psychotherapy sessions, following an integrated approach divided into three phases: preparation, administration, and integration.

Learn more

Treatment Structure:

  • Preparation Sessions:
    • Number of sessions: usually 2–3 meetings before the psilocybin session.
  • Goals:
    • Establish a relationship of trust between patient and therapist
    • Prepare the patient for the psychedelic experience
    • Define therapeutic intentions and expectations
  • Therapeutic Session with Psilocybin
    • Duration: about 6–8 hours
    • Setting: a safe, comfortable, distraction-free setting, often with relaxing music
    • Therapeutic Support: continuous presence of one or two therapists to provide emotional support and guidance
  • Integration Sessions:
    • Number of sessions: at least 1–2 meetings after the session
  • Goals:
    • Process and understand the experiences lived through
    • Integrate insights into daily life
    • Establish strategies to maintain the benefits obtained

Therapist Training

  • Specialized training in psychedelic-assisted therapy
  • Clinical skills in managing altered states of consciousness
  • In-depth knowledge of psilocybin and its effects
  • Adherence to ethical protocols and clinical guidelines

Approval Stage and Organizations Involved

United States:

  • The FDA granted psilocybin "Breakthrough Therapy" designation in 2018 for treatment-resistant depression and in 2019 for major depressive disorder, accelerating the research process
  • Phase 2 and 3 studies are underway with promising results

Europe:

Growing interest in the scientific and medical community

The European Medicines Agency (EMA) is evaluating data from clinical trials

Learn more

Organizations Involved:

Organizations involved in psilocybin research:

  • COMPASS Pathways
    • A biopharmaceutical company focused on clinical research of its patented synthetic psilocybin (COMP360) for treatment-resistant depression (TRD).
    • It conducts multicenter Phase 2 and Phase 3 studies in Europe and the United States, with the goal of obtaining regulatory approval from the FDA and EMA.
  • Usona Institute
    • A US nonprofit organization engaged in clinical research on synthetic psilocybin for major depressive disorder (MDD).
    • After Phase 2 studies, since 2024 it has been running the uAspire Phase 3 trial, in collaboration with public universities and hospitals. It is known for supporting independent research and equitable access to psychedelic treatments.
  • Johns Hopkins Center for Psychedelic and Consciousness Research
    • A leading academic center for psychedelic research worldwide.
    • It has conducted pioneering studies on the use of psilocybin in therapeutic and spiritual contexts.
  • MAPS (Multidisciplinary Association for Psychedelic Studies)
    • Historically focused on MDMA for PTSD, MAPS has supported psychedelic research as a whole, including early support for studies on psilocybin, ibogaine, and ayahuasca.
    • However, it is not currently directly involved in the clinical development of psilocybin.
  • Imperial College London, Centre for Psychedelic Research
    • The first European academic center dedicated to psychedelic research
    • It has conducted major clinical studies with psilocybin

Related research and bibliography

  1. Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384(15), 1402–1411. Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., Nutt, D. J. (2021)
  2. Percentage of Heavy Drinking Days Following Psilocybin‑Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 79(10), 953–962. Bogenschutz, M. P., Ross, S., Bhatt, S., Baron, T., Forcehimes, A. A., Laska, E., Mennenga, S. E., O’Donnell, K., Owens, L. T., Podrebarac, S., Rotrosen, J., Tonigan, J. S., & Worth, L. (2022)
  3. The Potential of Psychedelics for End of Life and Palliative Care. Current Topics in Behavioral Neuroscience, 56, 169–184. Yaden, D. B., Nayak, S. M., Gukasyan, N., Anderson, B. T., Griffiths, R. R. (2022)
  4. Effects of Psilocybin‑Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 78(5), 481–489. Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021; online 2020)
  5. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life‑threatening cancer: A randomized double‑blind trial. Journal of Psychopharmacology, 30(12), 1181–1197. Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016)

Ketamine

(2-(2-chlorophenyl)-2-(methylamino)cyclohexanone)

Chemical formula: C₁₃H₁₆ClNO
Classification: Dissociative anesthetic
Onset of action (onset of effects): 5–10 minutes (intramuscular or intravenous), 2–5 minutes (intranasal)
Peak effects: 30 minutes to 1 hour

History

Ketamine is a dissociative anesthetic first synthesized in 1962 by American chemist Calvin L. Stevens of Wayne State University, who was working as a consultant for the pharmaceutical company Parke-Davis. It was approved by the FDA in 1970 for human and veterinary use as a general anesthetic, an alternative to phencyclidine (PCP) with fewer side effects.

During the Vietnam War, it was used as a battlefield anesthetic. It later became important in pediatrics and emergency medicine.

In the 1970s its psychoactive use emerged, initially explored by psychonauts. In recent decades, it has been studied for the treatment of treatment-resistant depression in adults and adolescents.

Anthropological
and Cultural Context

In addition to its medical use, ketamine has also been used recreationally for its dissociative and psychedelic effects, which led to its regulation.

It is associated with artistic and musical movements, but today the scientific community focuses on its therapeutic use in a safe clinical setting.

Pharmacology

  • Main classification: Dissociative anesthetic
  • Psychedelic properties: these include dissociative effects, perceptual alterations, and out-of-body experiences (K-hole). It differs from classic psychedelics in its mechanism of action.

Ketamine acts as an NMDA receptor antagonist; these receptors are involved in glutamate transmission. It produces dissociative, analgesic, and anesthetic effects.

It stimulates neuroplasticity, particularly in areas such as the prefrontal cortex and the hippocampus. It also interacts with μ-opioid (mu) receptors to a lesser extent.

Main effects:

  • Anesthesia and analgesia
  • Dissociation
  • Mood modulation with rapid and sustained antidepressant effects

Risks and Benefits

Benefits:

  • Treatment of treatment-resistant depression
  • Major depression with lasting effects
  • Reduction of suicidal symptoms
  • Chronic pain management
  • Support for alcohol use disorder
  • Support for neuroplasticity and emotional openness

Risks:

  • Adverse psychological effects: anxiety, agitation, hallucinations
  • Addiction and misuse
  • Physical effects: hypertension, nausea, vomiting
  • Bladder damage with chronic use
  • High doses: risk of delirium, immobility, K-hole

Use in a clinical setting monitored by professionals is essential.

Administration Protocols and Process

The therapeutic use of ketamine for treatment-resistant depression involves specific protocols that combine administration of the substance with psychotherapeutic support.

Learn more

Treatment Structure:

  • Pre-Treatment Assessment:
    • Number of sessions: usually 2-3 meetings before the psilocybin session.
  • Goals:
    • Assess the patient’s suitability for ketamine treatment.
    • Rule out medical or psychiatric contraindications.
    • Establish a baseline for symptoms.

Ketamine administration:

  • Intravenous (IV): this is the most studied and most widely used route in clinical and research settings. The infusion is given slowly over about 40 minutes, at a typical dose of 0.5 mg/kg. It ensures high bioavailability (~100%) and allows precise control of the effects.
  • Intramuscular (IM): used in therapeutic and sometimes emergency settings. It has high bioavailability (~90–95%) and produces a faster and more intense effect than IV infusion, but with less control over the dose. Peak effect generally occurs within 5–10 minutes.
  • Intranasal: used for esketamine (Spravato®), approved by the FDA (March 2019) and the EMA (December 2019) for treatment-resistant depression. Administered in a controlled setting, it has a bioavailability of about 48%.
  • Oral or Sublingual: less common routes in clinical settings, but used in off-label protocols, especially in ketamine-assisted psychotherapy. Oral bioavailability is low (~17–30%), sublingual slightly higher (~25–50%). The effects are less predictable.

Dosage:

  • Subanesthetic doses, generally much lower than those used for anesthesia.

Clinical Setting:

  • A quiet and comfortable setting.
  • Monitoring of vital signs during and after administration.
  • Presence of medical staff to manage any adverse effects.

Therapeutic Support:

  • Integrated sessions to maximize the benefits of treatment.
  • They help the patient process their experiences and integrate the effects into the healing process.

Post-Treatment Follow-up:

  • Monitoring of symptoms and long-term effects.
  • Planning of any additional sessions or maintenance therapies.

Therapist Training:

  • Specialized training in the clinical use of ketamine.
  • Skills in managing dissociative effects and supporting the patient during the experience.
  • Knowledge of safety guidelines and protocols.

Approval Stage and Organizations Involved

United States:

  • In 2013, the FDA (Food and Drug Administration) granted esketamine (not racemic ketamine) “breakthrough therapy” designation for treatment-resistant depression.
  • In 2019, the FDA approved intranasal esketamine (brand name: Spravato®) in combination with an oral antidepressant, for adult patients with treatment-resistant depression (TRD).
  • The indication was later extended to cases of depression with acute suicide risk.

Italy:

  • Intranasal esketamine (Spravato) has been authorized in the EU by the EMA since December 2019 for treatment-resistant depression; in Italy, in 2022, AIFA (Agenzia Italiana del Farmaco, the Italian Medicines Agency) made it reimbursable by the National Health Service in class H, hospital use (AIFA determination no. 334/2022, Gazzetta Ufficiale no. 115 of 18 May 2022).
  • Esketamine is available only through a controlled access program, which requires administration exclusively in authorized healthcare facilities with medical monitoring for at least two hours after each dose, as required by the REMS (Risk Evaluation and Mitigation Strategy) program in the USA and by similar protocols in Europe.
Learn more

Organizations Involved:

Pharmaceutical industry:

  • Johnson & Johnson (Janssen Pharmaceuticals): developed and marketed intranasal esketamine under the name Spravato®, approved by the FDA (March 2019) and the EMA (December 2019) for treatment-resistant depression (TRD); in Italy reimbursed by the National Health Service in class H since 2022.
  • Janssen conducts registration and post-marketing clinical trials and has promoted programs to ensure safe and controlled access, such as the REMS program in the United States.

Specialized clinics:

  • Numerous clinics in the United States, Europe, Canada, and Australia offer treatments with racemic ketamine (IV, IM, oral/sublingual) or esketamine (intranasal) for indications such as:
    • Treatment-resistant depression
    • Post-traumatic stress disorder (PTSD)
    • Severe anxiety and chronic pain
  • They operate according to clinical guidelines, often developed by organizations such as:
    • American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3)
    • Canadian Network for Mood and Anxiety Treatments (CANMAT)
    • Local/national protocols in EU countries

Research organizations:

  • National Institute of Mental Health (NIMH): a US government agency that has funded foundational studies on the use of ketamine for depression, including trials on its rapid mechanisms of action and on applications in people at risk of suicide.
  • Universities and research centers:
    • Yale University
    • Icahn School of Medicine at Mount Sinai (New York)
    • University of Oxford
    • Imperial College London
    • Karolinska Institutet
    • Other European universities engaged in the study of ketamine/esketamine for depression, alcoholism, and pain.

Related research and bibliography

  1. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nature Medicine, 30(7), 2004–2009. Glue, P., Loo, C., Fam, J., Lane, H.-Y., Young, A. H., Surman, P., & BEDROC study investigators. (2024)
  2. Adjunctive Ketamine With Relapse Prevention‑Based Psychological Therapy in the Treatment of Alcohol Use Disorder. American Journal of Psychiatry, 179(2), 152–162. Grabski, M., McAndrew, A., Lawn, W., et al. (2022)
  3. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opinion on Drug Safety, 21(6), 777–787. Nikayin, S., Murphy, E., Krystal, J. H., & Wilkinson, S. T. (2022)
  4. Synthesizing the Evidence for Ketamine and Esketamine in Treatment‑Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. American Journal of Psychiatry, 178(5), 383–399. McIntyre, R. S., Rosenblat, J. D., et al. (2021)

Ibogaine

(10-methoxyibogamine)

Chemical formula: C₂₀H₂₆N₂O
Classification: Psychedelic; dissociative; tryptamine
Onset of action (onset of effects): 30–120 minutes
Peak effects: 4–8 hours, possibly extending up to 12–24 hours.

History

Ibogaine (12-methoxyibogamine) is an indole alkaloid found in the root bark of plants belonging to the Apocynaceae family, in particular the shrub Tabernanthe iboga, native to the rainforests of Central and West Africa, in countries such as Gabon, Cameroon, and the Congo.

The plant is traditionally used in spiritual, initiation, and healing rites by peoples such as the Bwiti of Gabon, who consider it a sacred plant. The earliest documented accounts of its ritual use date back to precolonial times, and archaeobotanical analyses, including traces of charcoal and roots at sacred sites, suggest plausible ritual use for at least 1,000–2,000 years, but there is no definitive archaeological evidence dating its use to a precise period.

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Ibogaine was first isolated in 1901 by French chemist Dybowski, together with Landrin, and its chemical structure was proposed in 1957 by W. I. Taylor (full paper in 1958) and confirmed in 1960 by X-ray crystallography. From the 1960s onward, it attracted attention in the West for its potential in treating addiction, thanks in part to the personal experience of Howard Lotsof, a former heroin user who in 1962 reported that his withdrawal symptoms disappeared after taking ibogaine. His efforts led to the spread of its experimental use and the founding of several movements and unofficial clinics.

Despite its potential, ibogaine has been classified as a controlled substance in many countries because of its psychoactive effects, cardiovascular risks, and the lack of extensive clinical studies. In the United States, ibogaine was placed in Schedule I by the Controlled Substances Act of 1970, along with many other psychedelic substances. Similar bans are in force in much of Europe (e.g., France, Sweden, Belgium).

However, in countries such as South Africa, New Zealand, and the State of São Paulo (Brazil), ibogaine is classified as a prescription medicine, used in therapeutic settings for the treatment of addiction.

In many other countries, including Mexico, Costa Rica, Colombia, and Brazil outside the state of São Paulo, the substance is in a legal gray area: not formally approved as a medicine, but not expressly prohibited either, which allows private clinics to operate.

This situation has contributed to the growth of so-called “ibogaine tourism”, with individuals from the United States, Canada, and Europe traveling to clinics in Latin America or South Africa, often paying high sums for a single therapeutic session, sometimes with little medical supervision or inconsistent clinical standards.

Anthropological
and Cultural Context

Ibogaine is a psychoactive alkaloid found in the root of Tabernanthe iboga, a plant native to the rainforests of Gabon. It has been used for centuries, particularly within the Bwiti spiritual tradition, for rites of initiation, healing, and connection with the ancestors. The experience is characterized by profound visions, introspection, and psychological transformation.

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In the 1980s and 1990s, ibogaine attracted Western interest as a potential treatment for addiction and, more recently, for PTSD. A 2020 study of 51 US veterans treated in Mexico with ibogaine and 5-MeO-DMT showed significant reductions in trauma symptoms, with many participants describing the experience as spiritually transformative.

Currently, much of the ibogaine on the market comes from unsustainable or illegal sources, with plants smuggled out of the forests of Gabon. This has raised serious ecological, cultural, and ethical concerns, prompting the promotion of sustainable cultivation and the inclusion of Indigenous communities in decision-making processes.

Pharmacology

  • Main classification: Dissociative psychedelic, oneirogen (dream inducer)
  • Psychedelic properties: ibogaine induces profound experiences, characterized by intense visions, introspection, and potential processing of past trauma.

Ibogaine is an atypical, oneirogenic psychedelic alkaloid that acts on multiple neurotransmitter systems, including serotonin, dopamine, glutamate, and opioid systems. It induces profound psychedelic experiences, often visionary and introspective, accompanied by a potential resurfacing and processing of trauma. Its possible effect on addiction appears to be multifactorial: observational studies report reduced craving and withdrawal symptoms, sometimes after a single administration, and a role for the brain’s reward pathways and for psychological reprocessing has been hypothesized. Animal studies suggest effects on neuroplasticity, but it has not been shown that ibogaine repairs nerve tissue in people; controlled clinical trials are lacking.

Main effects:

  • Interruption of withdrawal symptoms: reduction of the physical symptoms associated with withdrawal from opioids and other substances.
  • Profound psychedelic experiences: visions and introspection that may help in processing trauma and addictive behaviors.
  • Mood modulation: possible improvement in mood and reduction in cravings for substances.

Risks and Benefits

Benefits:

  • Treatment of addiction
    • Observational studies, mainly in opioid dependence, report that ibogaine can attenuate withdrawal symptoms, sometimes after a single dose; controlled studies are lacking, and data on alcohol, cocaine and other substances are even more limited.
    • In these studies many participants report reduced craving, which could provide a “therapeutic window” that is useful for starting detoxification, rehabilitation, and psychotherapeutic support programs.
  • Introspection and psychological reprocessing
    • It induces visionary and introspective experiences that may facilitate understanding of the inner dynamics related to addiction.
    • It can have a transformative impact on self-perception, motivation to change, and sense of meaning.

Risks:

  • Cardiotoxicity
    • It can cause serious heart rhythm disturbances (e.g., QT prolongation).
    • It requires ECG monitoring and medical screening.
  • Neurotoxicity
    • Possible effects at very high doses in animals. No definitive evidence of clinical neurotoxicity at therapeutic doses.
  • Drug interactions
    • Ibogaine is metabolized by cytochrome P450 (CYP2D6) and may interact with numerous drugs (antidepressants, opioids, alcohol, etc.).
  • Adverse psychological effects
    • Anxiety, paranoia, disorientation, confusion in the absence of preparation or support.
  • Mortality
    • Deaths have been documented in unregulated settings, often due to cardiac complications.
  • High doses
    • They increase the risk of seizures, delirium, or cardiac arrest. A clinical setting, medical screening, and therapeutic support are essential for the safety of the treatment.

Administration Protocols and Process

The therapeutic use of ibogaine for addiction, particularly opiate use disorder, involves specific protocols that combine administration of the substance with psychotherapeutic support.

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Treatment Structure:

  • Pre-Treatment Assessment:
    • Cardiac evaluation (ECG) to rule out abnormalities
    • Blood tests to check liver and kidney function
  • Detailed history:
    • Medical and psychiatric history
    • Current substance and medication use
  • Ibogaine administration (oral):
    • Test dose: a small initial dose to assess individual tolerance
    • Therapeutic dose: administered after the test dose, based on body weight and the patient’s needs
  • Clinical Setting:
    • Safe and comfortable setting
    • Continuous monitoring of vital signs (heart rate, blood pressure, oxygen saturation)
    • Presence of medical staff to manage any emergencies
  • Therapeutic Support:
    • Emotional support and monitoring of psychological effects
  • Integration Sessions:
    • After the experience, to process insights and plan long-term recovery
  • Rehabilitation Plan:
    • Connection with support programs, individual or group therapy
  • Medical expertise:
    • Physicians with experience in toxicology, cardiology, or emergency medicine
  • Ibogaine-specific training:
    • In-depth knowledge of its pharmacological effects and safety protocols
  • Psychotherapeutic support:
    • Therapists trained in managing psychedelic experiences and in caring for patients with addiction

Approval Stage and Organizations Involved

  • Limited Research:
    • Because of its restrictive legal classification in many countries, clinical research on ibogaine is limited.
  • Not approved by the FDA or EMA:
    • Ibogaine is not approved as a medicine for any indication in the United States or the European Union. It is classified as Schedule I (USA) and Tabella I (Italy), limiting medical use and research.
  • Limited but growing research:
    • Because of its restrictive legal classification, official clinical research is limited. However, experimental studies are being conducted by:
      • MAPS
      • ICEERS
      • Universities and centers in North America, South America, Switzerland, Spain, and South Africa
  • Legal status of ibogaine treatment in selected countries:
    • Mexico: ibogaine is neither an approved medicine nor an expressly prohibited substance; private clinics operate in this legal gray area
    • New Zealand: legal by medical prescription
    • South Africa: authorized as a prescription medicine since 2016
    • Brazil (State of São Paulo): clinical use regulated at the state level
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Organizations involved in the use of and research on ibogaine:

  • ICEERS (International Center for Ethnobotanical Education, Research & Service):
    A Spanish NGO that promotes a responsible and culturally respectful approach to the use of traditional psychoactive plants such as iboga. It supports scientific research, public education, and the rights of Indigenous communities.
  • Blessings of the Forest (aka Voice of the Forest):
    An organization based in Gabon, committed to conserving iboga biodiversity and protecting Bwiti spiritual traditions. It works against poaching and promotes sustainable cultivation and respect for the cultural rights of local populations.
  • Americans for Ibogaine (AFI), founded by W. Bryan Hubbard:
    A US organization working to promote regulated medical access to ibogaine for the treatment of addiction, trauma, and mental health conditions. It is engaged in advocacy, public education, awareness raising, and support for clinical research, and is active in promoting legislative initiatives in the USA.
  • Universities and Research Centers:
    Although academic research on ibogaine is limited in the most restrictive jurisdictions, some independent institutions have conducted studies:
    • Department of Psychiatry, University of Amsterdam
    • Stanford Psychedelic Science Group (Stanford University), interested in the neurorestorative and therapeutic effects of ibogaine
    • Other centers in Brazil, Switzerland, South Africa, and Mexico, active in experimental studies

The Stanford study on ibogaine and traumatic brain injury (2024, with a 12-month follow-up in 2026). A Stanford University team followed 30 male US special operations veterans with predominantly mild traumatic brain injury, treated in Mexico with ibogaine combined with magnesium (the MISTIC protocol, designed to reduce cardiac risk) alongside other complementary therapies. One month after treatment, participants reported large improvements in daily functioning and in symptoms of PTSD, depression and anxiety, with no serious or unexpected adverse events (Cherian et al., Nature Medicine, 2024). The 12-month follow-up (Faerman et al., Translational Psychiatry, 2026) suggests that in many cases the improvements lasted: among those who had reached remission, the likelihood of still being in remission at one year was 84% for PTSD, 66% for depression and 61% for anxiety.

Why it matters: these are among the first prospective data on people with traumatic brain injury and PTSD, conditions with few effective treatment options, and they justify controlled trials. What they do not show: the study had no control group, the sample was small and self-selected (only men who had sought the treatment on their own), and it measured symptoms and functioning, not repair or healing of the brain injury; the small changes seen on MRI are preliminary. During the follow-up many participants received other therapies or used other psychedelics, so the one-year results cannot be attributed to the ibogaine treatment alone. Ibogaine remains associated with cases of serious, even fatal, cardiac arrhythmias: magnesium may reduce the risk but does not eliminate it, and treatment requires cardiac screening and monitoring.

Related research and bibliography

  1. Magnesium–ibogaine therapy in veterans with traumatic brain injuries. Nature Medicine, 30(2), 373–381. Cherian, K., Keynan, J. N., Anker, L., Faerman, A., et al. (2024)
  2. Is ibogaine treatment durable? 12-month follow-up of magnesium–ibogaine therapy (MISTIC) in special operations veterans with traumatic brain injuries. Translational Psychiatry. Faerman, A., Lissemore, J., Geoly, A., et al., Williams, N. R. (2026)
  3. One year after taking ibogaine, veterans find continued relief from PTSD. Stanford Medicine News – press release, not peer-reviewed. (2026)
  4. Psychoactive drug ibogaine effectively treats traumatic brain injury in special ops military vets. Stanford Medicine News – press release, not peer-reviewed. Williams, S. (2024)
  5. Psychedelics reopen the social reward learning critical period. Nature, 618, 790–798. Nardou, R., Sawyer, E., Song, Y. J., Wilkinson, M., Padovan‑Hernandez, Y., … Dölen, G. (2023)
  6. Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study. Addiction, 117(1), 118–128. Knuijver, T., Schellekens, A., Belgers, M., Donders, R., van Oosteren, T., Kramers, K., & Verkes, R. (2022)
  7. Psychedelic treatment for trauma-exposed US Special Operations Forces Veterans: A pilot study of ibogaine and 5-MeO-DMT. Chronic Stress, 4, 2470547020939564. Davis, A. K., Averill, L. A., Sepeda, N. D., Barsuglia, J. P., & Amoroso, T. (2020)
  8. Ibogaine treatment outcomes for opioid dependence from a twelve‑month follow‑up observational study. American Journal of Drug and Alcohol Abuse, 44(1), 37–46. Noller, G. E., Frampton, C. M., & Yazar-Klosinski, B. (2018; online 2017)

Ayahuasca

(Banisteriopsis caapi and Psychotria viridis)

Chemical formula: C₁₂H₁₆N₂
Classification: Classic psychedelic (DMT); tryptamine; orally active only in combination with MAOIs.
Plant source: DMT is found in Psychotria viridis or Diplopterys cabrerana.
β-carbolines (from Banisteriopsis caapi): harmine, harmaline, and THH are not classic psychedelics, but oneirogenic psychoactive compounds and MAO-A inhibitors that make DMT orally active
Onset of action (onset of effects): 20–60 minutes.
Peak effects: 1–2 hours

History

Ayahuasca is a traditional psychoactive brew native to the Amazon, used for centuries (and according to some sources even for millennia) in the medicinal, spiritual, and ritual practices of various Indigenous peoples, including the Huni Kuin, Yawanawá, Shipibo-Conibo, and Asháninka, across Brazil, Peru, and Colombia.

The term “ayahuasca” comes from the Quechua language, in which aya means “spirit” and wasca means “vine” or “liana”; it can therefore be translated as “vine of the spirits” or “vine of the soul”, a reference both to its visionary effects and to the plant Banisteriopsis caapi, one of the main ingredients.

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The classic preparation of Ayahuasca combines two plants:

  • Banisteriopsis caapi, a vine containing active β-carbolines (harmine, harmaline, tetrahydroharmine), which inhibit the MAO-A enzyme and make DMT orally active
  • Psychotria viridis, a leaf that contains N,N-dimethyltryptamine (DMT), a potent natural psychedelic

In some regions (e.g., Colombia and Ecuador), Diplopterys cabrerana (chagropanga or chaliponga) is also used; it too contains DMT, often in higher concentrations.

From the 1950s and 1960s onward, Ayahuasca attracted the interest of Western researchers, particularly thanks to the pioneering work of ethnobotanist Richard Evans Schultes, followed by cultural explorers and writers such as William S. Burroughs (in 1953) and Allen Ginsberg (in 1960), who on separate journeys to South America recounted their encounter with this plant in their letters (see The Yage Letters, 1963).

In recent decades, the use of Ayahuasca has expanded globally, with people traveling to Latin America for traditional ceremonies or taking part in rituals organized in Europe, North America, Asia, and Australia as well. This has given rise to a phenomenon known as “Ayahuasca tourism”, accompanied by debates on ethics, cultural appropriation, and environmental sustainability.

Anthropological
and Cultural Context

Ayahuasca is central to the spiritual and healing practices of many Indigenous cultures of the Amazon, including the Shipibo-Conibo, Asháninka, Huni Kuin, Yawanawá, Kichwa, Tukano, Inga, and many others. Depending on the ethnic and linguistic group, the brew is known by various traditional names, including: Uni (Yawanawá), Nixi Pae (Huni Kuin), Yagé (Inga, Cofán, Siona, and other peoples of Colombia and Ecuador), Daime (in the Brazilian syncretic Santo Daime churches), Camarampi, Oasca, Natem (in other local languages).

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It is used in ritual contexts for spiritual and physical healing, divination, communication with spirits, and in rites of passage, such as initiation or conflict-resolution ceremonies. These practices strengthen social cohesion and are considered fundamental to the collective well-being of the community.

Ceremonies are generally led by shamans, curanderos, or vegetalistas, who use icaros (sacred chants) to guide the visionary experience, protect participants, and facilitate the healing work.

Ayahuasca is considered a teacher plant or spiritual ally, able to facilitate access to unseen dimensions and offering profound teachings about life, health, trauma, and balance with nature.

Expansion and new forms of use:

Starting in the 1930s to 1950s, syncretic forms of Ayahuasca use emerged, initially in Brazil:

  • Syncretic churches, such as Santo Daime (founded by Raimundo Irineu Serra in 1930) and the União do Vegetal (UDV) (founded in 1961 by José Gabriel da Costa), which combine elements of Christianity, Afro-Brazilian religions, and Indigenous spirituality.
  • These churches are legally recognized in Brazil and in some other countries.

In recent decades, Ayahuasca has become part of a global phenomenon:

  • Spiritual retreats and therapeutic centers have multiplied in Latin America, Europe, and North America, welcoming people seeking psychological healing, personal transformation, treatment for addiction, or profound spiritual experiences.
  • These settings vary widely in approach, ethics, and preparation.

Pharmacology

  • Main classification: Entheogenic psychedelic
  • Ayahuasca is considered a classic psychedelic because of its DMT content, and is also described as an entheogen in anthropological and spiritual contexts, since it is traditionally used to “generate the experience of the divine”.

Combined mechanism of action:

  • DMT (N,N-dimethyltryptamine): acts as a partial agonist at serotonin 5-HT2A receptors, which are responsible for most of the psychedelic effects. It also interacts with other receptors (5-HT1A, sigma-1, TAARs).
  • Monoamine oxidase inhibitors (MAO-A): the β-carbolines contained in Banisteriopsis caapi (harmine, harmaline, THH) temporarily block the breakdown of DMT, making it orally active.

Note: without β-carbolines, DMT would be inactivated before reaching the brain.

Neuroimaging: shows effects similar to LSD and psilocybin, namely increased functional connectivity, reduced activity of the default mode network (DMN), and greater neurocognitive flexibility.

Main effects:

  • Perceptual alterations: ayahuasca induces complex visions, geometric shapes, intensified colors, and an altered perception of time, space, and self. These effects are attributed mainly to the action of DMT on 5-HT2A receptors, in synergy with the β-carbolines.
  • Deep introspection: many participants report the emergence of deep psychological material, such as repressed memories, unprocessed emotions, and existential reflections. This effect underlies the therapeutic use of ayahuasca for processing trauma, grief, and addiction.
  • Spiritual experiences: commonly described are feelings of unity, connection with nature, the universe, or spiritual entities, and a strong sense of the sacred. Such experiences are often described as transformative and are central to the traditional and syncretic use of the brew.
  • Physical and emotional purification (“la purga”): nausea, vomiting, diarrhea, tremors, or sweating frequently occur, interpreted in many Indigenous cultures as part of a process of “energetic cleansing” or “spiritual liberation”. This process is experienced as an integral part of the healing experience.

Risks and Benefits

Benefits:

  • Depression: randomized clinical trials and observational studies suggest that ayahuasca may rapidly reduce depressive symptoms, even in cases resistant to conventional treatment.
  • Anxiety and PTSD: observational studies and participant accounts suggest a possible benefit for anxiety and trauma processing in structured settings, but there are not yet controlled studies demonstrating efficacy in PTSD or generalized anxiety.
  • Emotional processing: the experiences induced may facilitate access to repressed emotions, the reprocessing of painful memories, and the release of psychological blocks, even in the absence of a formal clinical diagnosis.
  • Personal and spiritual growth:
    • Increased awareness and empathy: participants often report increased inner reflection, a deeper understanding of themselves and others, and greater emotional openness.
    • Sense of connection: ayahuasca is often described as a catalyst for deep feelings of unity, connection with nature, and existential meaning.

Risks:

  • Adverse psychological reactions: possibility of intense or negative reactions, such as acute anxiety, panic, paranoia, emotional disorientation, or the resurfacing of unprocessed trauma. More likely in vulnerable individuals or in unsafe environments.
  • Drug interactions: the MAOIs present in ayahuasca may interact with:
    • Serotonergic antidepressants (SSRIs, SNRIs, MAOIs, TCAs) → risk of serotonin syndrome.
    • Anxiolytics and antipsychotics → unpredictable neurochemical interactions.
    • Stimulants → increased cardiovascular risk.
    • Anesthetics and sympathomimetics.
  • Preexisting health problems: contraindicated in people with heart conditions, epilepsy, or serious mental disorders such as schizophrenia.
  • Uncontrolled setting: increased risk if the ceremony is not led by experienced facilitators or in a safe environment.
  • High doses: they increase the risk of adverse effects.

Note: only take part in ceremonies led by qualified professionals, with a prior medical evaluation.

Administration Protocols and Process

Preparation

  • Diet and Abstinence:
    • A special diet is often recommended before the ceremony, avoiding fatty foods, alcohol, drugs, and certain medications.
    • In some cases, abstinence from sexual activity is suggested, to prepare body and mind.

Ceremony

  • Spiritual Guide:
  • Setting and environment:
    • A safe and comfortable space, often decorated with spiritual symbols.
    • Use of music, chants (icaros), and instruments to guide the experience.
  • Participants:
    • Groups can range from a few people to dozens, depending on the context.
  • Administration:
    • Ayahuasca is drunk in one or more doses during the ceremony.

Integration

  • Medical expertise:
    • Physicians with experience in toxicology, cardiology, or emergency medicine.
  • Specialized training:
    • In Amazonian Indigenous cultures, becoming a shaman requires years of rigorous apprenticeship, with ritual diets (dietas), isolation in the forest, in-depth study of the teacher plants, and oral transmission through sacred chants (icaros).
    • In-depth knowledge of pharmacological effects and safety protocols.
  • Psychotherapeutic support:
    • Therapists trained in managing psychedelic experiences and in caring for patients with addiction.

Approval Stage and Organizations Involved

Legal status

  • Legal gray area:
    • Ayahuasca is not universally regulated. Many countries lack specific legislation on the brew, but it is banned de facto because of the presence of DMT, which is classified as a controlled substance under the 1971 UN Convention.
  • Illegal in some countries:
    • Countries such as France, the United Kingdom, Sweden, and Italy (de facto) consider Ayahuasca illegal because it contains DMT, without distinguishing between chemical synthesis and natural preparations.
    • With the Decree of the Ministry of Health of February 23, 2022 (Gazzetta Ufficiale no. 61 of March 14, 2022), Ayahuasca, the plants Banisteriopsis caapi and Psychotria viridis, as well as the alkaloids harmine, harmaline, and DMT, were added to Tabella I of D.P.R. 309/1990.
  • Religious exceptions:
    • In countries such as Brazil, Peru, and Colombia, Ayahuasca use is legal in traditional religious contexts.
    • In the United States, the Supreme Court (2006) recognized the right of the União do Vegetal (UDV) to the religious use of ayahuasca under the Religious Freedom Restoration Act (RFRA); Santo Daime obtained a similar exemption in 2009, through a ruling by a federal district court in Oregon.
  • Ongoing Studies: over the past two decades, growing scientific interest has developed in the therapeutic potential of Ayahuasca, particularly for:
    • Treatment-resistant depression
    • Post-traumatic stress disorder (PTSD)
    • Substance use disorders (alcohol, tobacco, cocaine)
  • Numerous studies have been conducted or are underway in Brazil, Spain, the United States, the United Kingdom, Switzerland, Germany, and the Netherlands.
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Organizations Involved:

  • ICEERS (International Center for Ethnobotanical Education, Research and Service), Spain:
    • An NGO based in Barcelona.
    • It promotes safe, informed, and ethical use of Ayahuasca and other sacred plants.
    • It publishes observational studies, manuals for facilitators, and legal reports.
    • Academic partner in numerous research projects (e.g., Ayahuasca Treatment Outcome Project).
  • Universities and Research Centers:
    • Universidade Federal do Rio Grande do Norte (UFRN), Brazil:
      • Clinical studies on Ayahuasca for treatment-resistant depression.
    • University of São Paulo (USP), Brazil:
      • Research on neuroimaging and psychopharmacology.
    • Complutense University of Madrid (UCM), Spain:
      • Studies on the neuropsychological effects of Ayahuasca and DMT.
    • Maastricht University, Netherlands:
      • Studies on microdosing and psychoactive pharmacology.
    • University of Girona / ICEERS:
      • Studies on ceremonies and mental well-being.
    • Johns Hopkins University & NYU Langone, USA:
      • Observational studies on spiritual use and long-term impacts.
  • Onaya Science:
    • An NGO founded by researchers, therapists, and Indigenous people.
    • It studies Amazonian healing practices.
    • It promotes the recognition (not the validation) of traditional medicines.

Related research and bibliography

  1. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological Medicine, 49(4), 655–663. Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., Mota-Rolim, S. A., Tófoli, L. F., de Oliveira, L. G., Silva-Junior, A. A., & Araújo, D. B. (2019)
  2. A systematic review on the therapeutic effects of ayahuasca. Plants, 12(13), 2573. MDPI. Gonçalves, J., Luís, Â., Gallardo, E., & Duarte, A. P. (2023)
  3. Human pharmacology of ayahuasca: Subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. Journal of Pharmacology and Experimental Therapeutics, 306(1), 73–83. Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003)
  4. Ayahuasca: pharmacology, safety, and therapeutic effects. CNS Spectrums, 30(1), e2. dos Santos, R. G., & Hallak, J. E. C. (2025; online 2024)
  5. Ceremonial Ayahuasca in Amazonian Retreats – Mental Health and Epigenetic Outcomes From a Six-Month Naturalistic Study. Frontiers in Psychiatry, 12, 687615. Ruffell, S. G. D., Netzband, N., Tsang, W., Davies, M., Inserra, A., Butler, M., Rucker, J. J. H., Tófoli, L. F., Dempster, E. L., Young, A. H., Morgan, C. J. A. (2021)
  6. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Revista Brasileira de Psiquiatria, 37(1), 13–20. Osório, F. L., Sanches, R. F., Macedo, L. R., Maia‑de‑Oliveira, J. P., Wichert‑Ana, L., de Araujo, D. B., Riba, J., Crippa, J. A. S., & Hallak, J. E. C. (2015)
  7. Ayahuasca. La liana degli spiriti. Il sacramento magico-religioso dello sciamanismo amazzonico – Walter Menozzi (2013).

LSD

(Lysergic Acid Diethylamide)

Chemical formula: C₂₀H₂₅N₃O
Classification: Classic psychedelic, ergoline tryptamine
Onset of action (onset of effects): 30–90 minutes
Peak effects: 4–6 hours

History

LSD, or lysergic acid diethylamide, is a potent psychedelic first synthesized in 1938 by Swiss chemist Albert Hofmann at the Sandoz laboratories in Basel. Hofmann was studying derivatives of lysergic acid, isolated from the ergot fungus (Claviceps purpurea), when he synthesized the 25th variant: LSD-25.

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In 1943, Hofmann resynthesized the substance and inadvertently absorbed a small amount through his skin, experiencing unexpected psychoactive effects. On April 19 of the same year he voluntarily took 250 micrograms of LSD, marking the first documented “trip” in history. The episode, known as Bicycle Day, is named after the famous bicycle ride he took home during the experience.

In the 1950s and 1960s, LSD was the subject of more than 1,000 clinical studies on the treatment of psychiatric disorders such as alcoholism, depression, and anxiety. Researchers such as Stanislav Grof, Humphry Osmond, and Sidney Cohen highlighted its therapeutic potential. At the same time, figures such as Timothy Leary and Richard Alpert (Ram Dass) promoted LSD for the transformation of consciousness, profoundly influencing the counterculture.

Because of concerns related to recreational use and its association with the hippie movement, LSD was banned in the United States in 1968, and subsequently placed in Schedule I of the Controlled Substances Act in 1970, with prohibition rapidly extending worldwide. Secret experiments conducted by the CIA under Project MK-Ultra contributed to its controversial reputation.

Anthropological
and Cultural Context

LSD had a significant impact on Western culture in the 20th century. In the 1960s it became a symbol of the counterculture, associated with the hippie movement, the 1967 Summer of Love, and the protests against the Vietnam War. LSD use was often linked to the search for spiritual experiences, personal liberation, and the exploration of consciousness.

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Artists, musicians, and writers were influenced by LSD, contributing to a psychedelic vision in art and music. Bands such as the Beatles, the Grateful Dead, and Pink Floyd, directors and actors such as Federico Fellini and Cary Grant, and poets and writers such as William Burroughs and Allen Ginsberg drew inspiration from psychedelic experiences to create innovative works.

Despite its stigmatization, LSD continued to be used in underground circles until, starting in the 2000s, the scientific community began to take an interest in the substance again, so much so that today LSD is the subject of new clinical trials exploring its use in psychotherapy for various mental health conditions.

Pharmacology

  • Main classification: Classic psychedelic (ergoline)
  • Psychedelic properties: LSD is known for inducing powerful psychedelic effects, including perceptual, emotional, and cognitive alterations. It can cause synesthesia, time distortions, and profound spiritual or mystical experiences.

Mechanism of Action:

  • Mechanism of action: LSD acts mainly as an agonist at serotonin 5-HT2A receptors in the brain. This interaction alters the transmission of serotonin, a key neurotransmitter in the regulation of mood, perception, and cognition. LSD also acts as an agonist at certain dopamine receptors (D1 and D2).

Main effects:

  • Perceptual alterations: changes in visual perception (intensified colors, geometric shapes), auditory perception, and tactile perception.
  • Emotional changes: increased empathy, introspection, and emotional sensitivity.
  • Cognitive experiences: divergent thinking, profound insights, a sense of connection with the universe.
  • Distortion of time and space: a feeling that time is passing more slowly or more quickly, altered perception of distances.

Risks and Benefits

Benefits:

  • Therapeutic potential:
    • Treatment of depression and anxiety: preliminary studies suggest that LSD, in controlled settings, may help reduce symptoms of depression and anxiety, especially in patients with terminal illnesses.
    • Relief of cluster headaches: some research indicates that LSD may reduce the frequency and intensity of these debilitating headaches.
    • Promotion of creativity and personal growth: it may facilitate introspection and help people overcome emotional or creative blocks.

Risks:

  • Adverse psychological reactions:
    • Anxiety and panic: LSD can cause distressing or frightening experiences, known as a “bad trip”.
    • Exacerbation of mental disorders: contraindicated in individuals with schizophrenia, psychosis, or a predisposition to psychotic disorders.
  • Hallucinogen Persisting Perception Disorder (HPPD):
    • In rare cases, flashbacks or persistent perceptual alterations may occur after LSD use.
  • Physical effects:
    • Increased heart rate and blood pressure, pupil dilation, sweating.
  • Drug interactions:
    • It may interact with certain psychiatric medications or other substances, enhancing or altering their effects.
  • High doses: consuming LSD at high doses increases the risk of experiencing adverse effects.

It is essential that LSD, in research or therapeutic contexts, be administered in a controlled environment, under the supervision of qualified professionals, to ensure the participant’s safety.

Administration Protocols and Process

In modern clinical trials, LSD is used in combination with psychotherapy, following rigorous protocols to maximize therapeutic benefits and minimize risks.

Treatment Structure:

  • Preparation Sessions:
    • Number of sessions: generally 2–3 meetings before the LSD session.
    • Goals:
      • Build a relationship of trust between the patient and the therapist.
      • Prepare the patient for the psychedelic experience.
      • Establish therapeutic intentions and goals.
    • Therapeutic Session with LSD:
      • Duration: about 8–10 hours.
      • Setting: a safe, quiet, and comfortable setting, often personalized to put the patient at ease.
      • Therapeutic support: continuous presence of one or two therapists to offer emotional support and guidance during the experience.
    • Integration Sessions:
      • At least 2–3 meetings after the session.
      • Goals:
        • Help the patient process and understand the experiences lived through.
        • Integrate insights into daily life.
        • Develop strategies to maintain the benefits obtained.

Therapist Training:

  • Specialized training in psychedelic-assisted therapy.
  • Clinical skills in managing altered states of consciousness.
  • In-depth knowledge of LSD and its effects.
  • Adherence to ethical protocols and international guidelines for research with psychedelic substances.

Approval Stage and Organizations Involved

  • Ongoing Clinical Research:
    • After decades of restrictions, there is renewed scientific interest in LSD.
    • Phase 1 and 2 clinical trials are exploring its therapeutic potential in various areas.
    • Clinical research on LSD is growing and is exploring its therapeutic potential for treating depression, anxiety (including existential anxiety in terminally ill patients), addiction, and mood disorders.
  • Not yet approved for therapeutic use:
    • LSD remains a controlled substance in most countries and is not approved for medical use.
    • Ongoing studies: in recent years there has been a renewed wave of clinical research on LSD, after decades of restrictions. Studies focus mainly on: treatment-resistant depression, anxiety associated with terminal illness, substance use disorder (including alcohol and tobacco), generalized anxiety disorder, and the potential to stimulate creativity and psychological well-being.
  • Studies are underway in Switzerland, the United Kingdom, the United States, Germany, the Netherlands, and other European countries, promoted by universities, nonprofit organizations, and foundations for psychedelic science.
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Organizations Involved:

  • MAPS (Multidisciplinary Association for Psychedelic Studies):
    • A nonprofit organization that supports clinical research and therapeutic training on the use of psychedelic substances, including LSD.
  • University of Basel (Switzerland):
    • A leading center for clinical studies on LSD, in particular for the treatment of anxiety in terminally ill patients and dose-response studies in healthy volunteers.
  • Imperial College London (United Kingdom):
    • It conducts pioneering studies on the neurobiological effects of LSD in collaboration with the Beckley Foundation.
  • Beckley Foundation:
    • A British organization that promotes scientific research and dialogue on drug policy.
    • It has led groundbreaking studies on LSD, including the first neuroimaging studies in human subjects.

Related research and bibliography

  1. Pharmacological and non‑pharmacological predictors of the LSD experience in healthy participants. Translational Psychiatry, 14(1), Article 357. Vizeli, P., Studerus, E., Holze, F., Schmid, Y., Dolder, P. C., Ley, L., Straumann, I., Becker, A. M., Müller, F., Arikci, D., & Liechti, M. E. (2024)
  2. Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety: Open‑Label Prospective 12‑Month Follow‑Up. The British Journal of Psychiatry, 225(3), 362–370. Holze, F., Gasser, P., Müller, F., Strebel, M., Vizeli, P., Ley, L., Dolder, P., & Liechti, M. E. (2024)
  3. Lysergic acid diethylamide (LSD) for the treatment of anxiety disorders: Preclinical and clinical evidence. CNS Drugs, 37(9), 733–754. Inserra, A., Piot, A., De Gregorio, D., & Gobbi, G. (2023)
  4. Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized‑Controlled Clinical Trials. Frontiers in Psychiatry, 10, Article 943. Fuentes, J. J., Fonseca, F., Elices, M., Farré, M., & Torrens, M. (2020)

5-MeO-DMT

(5-methoxy-N, N-dimethyltryptamine; mebufotenin)

Chemical formula: C₁₃H₁₈N₂O
Classification: classic psychedelic (serotonergic tryptamine)
Duration of action: short (generally 15–45 minutes when inhaled)
Peak effects: very rapid (seconds to minutes, if inhaled)

History

5-MeO-DMT (5-methoxy-N, N-dimethyltryptamine) was first synthesized in 1936 by Japanese chemist Toshio Hoshino together with Kenjiro Shimodaira, as part of studies on substituted tryptamines. At the time there was not yet any psychedelic interest in the modern sense: the substance was initially described in the chemical literature as a new indole derivative (related to perfumery).
In the 1950s the molecule was identified as a natural compound present in some plants (for example species of the genera Anadenanthera and Virola) and later in the skin secretions of certain toads, in particular Incilius alvarius (formerly classified as Bufo alvarius).

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In the 1960s and 1970s, in the context of North American psychedelic research, 5-MeO-DMT began to circulate in experimental and psychonautic circles. Psychonaut and independent researcher Alexander Shulgin described its effects in detail in the book TiHKAL (1997), contributing to its spread in contemporary psychedelic culture.

Since the 2000s, the substance has increasingly attracted scientific and clinical interest, especially because of its rapid onset and very short duration compared with other classic psychedelics. In recent years, biotech companies and academic groups have launched clinical programs for treatment-resistant depression (TRD) and other mood disorders, using standardized synthetic formulations (GMP), distinct from the use of animal secretions. Ethical and environmental note: the rising popularity of so-called “toad medicine” has led to problems of exploitation and ecological stress for Incilius alvarius. In clinical and research settings, only synthetic 5-MeO-DMT is used, avoiding the use of animal secretions.

Pharmacology

5-MeO-DMT is a serotonin receptor agonist, with significant affinity for:

  • 5-HT1A
  • 5-HT2A

The combination of potent serotonergic activity and very rapid pharmacokinetics explains its characteristic profile:

  • almost immediate onset (when inhaled)
  • an intense and brief experience
  • rapid return to baseline

Compared with DMT (N, N-dimethyltryptamine), 5-MeO-DMT tends to produce less structured visual content and a greater likelihood of ego-dissolution experiences or nondual states.

Subjective effects

Effects may include:

  • dissolution of personal identity (“ego dissolution”)
  • profound alteration in the perception of space and time
  • states of consciousness described as mystical or unitive
  • intense emotional activation
  • a sense of “total emptiness”

The experience is often described as extremely intense, even at relatively low doses.

Risks and harm reduction

Psychological risks

  • Acute anxiety or panic
  • Destabilizing experiences
  • Possible exacerbation in people with a history of psychosis or bipolar disorder
  • Physical risks
  • Transient increase in blood pressure and heart rate
  • Nausea and vomiting
  • Loss of motor control or falls in the absence of supervision

Interactions

Particular caution with:

  • MAOIs (monoamine oxidase inhibitors)
  • SSRIs/SNRIs or other serotonergic drugs
  • Other psychoactive substances

Combination with MAOIs can increase intensity, duration, and the risk of serotonergic toxicity.

Therapeutic potential

In recent years, preliminary clinical studies have been published suggesting:

  • Rapid symptom reduction in treatment-resistant depression (TRD)
  • Generally favorable tolerability profile in controlled settings
  • Possible efficacy even after a single administration

    Clinical development programs in late Phase 2 and in preparation for Phase 3 for TRD (Treatment-Resistant Depression) are currently underway.

However:
The samples studied are still relatively small. Long-term follow-up data are limited

Large-scale randomized studies are needed

Stage of clinical development

Standardized synthetic formulations for clinical use are currently in development, mainly for treatment-resistant depression (TRD).
Some programs have received expedited regulatory designations (e.g., Breakthrough Therapy designation in the United States).
The substance is not approved for medical use outside of clinical trials.

Related research and bibliography

  1. Exploring 5-MeO-DMT as a pharmacological model for deconstructed consciousness. Neuroscience of Consciousness. 2025(1):niaf007. Timmermann C, Sanders JW, Reydellet D, Barba T, Luan LX, Angona ÓS, Ona G, Allocca G, Smith CH, Daily ZG, Mason NL, Kloft-Heller L, Kuchar M, Janeckova L, Palenicek T, Erritzoe D, Ramaekers JG, Carhart-Harris RL, Uthaug MV. (2025)
  2. A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression. Front Psychiatry. Jun 20;14:1133414. Reckweg JT, van Leeuwen CJ, Henquet C, van Amelsvoort T, Theunissen EL, Mason NL, Paci R, Terwey TH, Ramaekers JG. (2023)
  3. The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Journal of Neurochemistry, 162(1), 128–146. Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG. (2022)
  4. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety. Am J Drug Alcohol Abuse. 45(2):161-169. Davis AK, So S, Lancelotta R, Barsuglia JP, Griffiths RR. (2019)