Psychedelics and Safety

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Safety Research

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Papers

In our literature study we came across the following studies of note. Browse the meta, review, commentary articles for an overview. Check out the individual studies for specific experiments and observations.

Safety pharmacology of acute LSD administration in healthy subjects

2021 | Caluori, T. V., Holze, F., Liechti, M. E., Vizeli, P.

This pooled analysis (n=83) finds that LSD (25-200 µg) is physiologically and psychologically safe in healthy subjects when administrated in a controlled research setting.

On Perception and Consciousness in HPPD: A Systematic Review

2021 | Blom, J. D., Goudriaan, A. E., Ter Meulen, B. C., Vis, P. J.

This review (2021; n=97) finds that hallucinogen-persisting perception disorder (HPPD) encompasses more characteristics than currently recognized by the DSM-5. The most common (of the 64 unique) symptoms were 76% Alice in Wonderland syndrome (AIWS) characteristics (distorted perception and disorientation), 50% non-visual symptoms, and 38% perceptual symptoms not liked to earlier states under the influence.

Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens

2017 | Halberstadt, A. L.

This academic book chapter (2017) reviews the pharmacology and toxicology of members of the N-benzylphenethylamines (NBOMe) hallucinogen class. It found that rhabdomyolysis is a fairly common complication of severe NBOMe toxicity, which can be linked to NBOMe-induced hyperthermia, seizures, and vasoconstriction.

Safer Tripping: Serotonergic Psychedelics and Drug Checking. Submission and Detection Rates, Potential Harms, and Challenges for Drug Analysis

2021 | Hirschfeld, T., Majic, T., Reiche, S., Smit-Rigter, L., Stöver, H., van der Gouwe, D.

This multinational harm-reduction study (2021) investigated the presence and proportion of serotonergic psychedelics submitted to drug checking services across the Netherlands, Spain, UK, Italy, Portugal, Belgium, Canada, and Australia. They found that a considerable amount of novel synthetic phenethylamine psychedelics, such as NBOMes that exhibit higher levels of toxicity and sometimes an unpredictably prolonged duration, have been detected in samples sold as LSD or MDMA.

Ketamine Treatment for Depression in Patients With a History of Psychosis or Current Psychotic Symptoms: A Systematic Review

2021 | Kamphuis, J., Schoevers, R. A., Smith-Apeldoorn, S. Y., Spijker, J., Veraart, J. K. E.

This systematic review (2021) examines whether ketamine treatment in patients with a history of psychosis or current psychotic symptoms and found 9 pilot studies (n=41) which indicate that ketamine's side effects are mild and self-limiting even among these patients. While limited in sample size, the available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients.

Psychedelics and hypnosis: Commonalities and therapeutic implications

2021 | Lemercier, C. E., Terhune, D. B.

The review (2018) examines the similarities between psychedelics and hypnosis with respect to their neurophenomenological features and therapeutic applications and highlights the potential for harnessing the power of suggestion to influence the phenomenological response to psychedelics in the context of therapy.

Serotonin toxicity of serotonergic psychedelics

2021 | Malcolm, B., Thomas, K.

This review (2021) evaluates the safety of combining psychedelics and classical serotonin reuptake inhibitors (SSRIs), describes the signs, symptoms, and risk factors of serotonin toxicity, and outlines potential management strategies. They identify the major risk stemming from psychotropics such as ayahuasca that contain monoamine oxidase inhibitors (MAOI) and risk neurotoxicity via the increase intrasynaptic serotonin.

Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review

2021 | Bakker, I. M., Kamphuis, J., Schoevers, R. A., Smith-Apeldoorn, S. Y., Touw, D. J., Veraart, J. K. E., Visser, B. A. E.

This systematic review (2021) examines the pharmacodynamic interactions between ketamine and generally prescribed psychiatric drugs based on published evidence and found that lamotrigine and benzodiazepines attenuate and shorten ketamine’s antidepressant effects. There are also indications for interactions between ketamine and antipsychotic drugs, such as haloperidol, risperidone and clozapine (but not olanzapine), although further research is necessary to understand their side effects.

Registered clinical studies investigating psychedelic drugs for psychiatric disorders

2021 | Gill, H., Lipsitz, O., Lui, L. M. W., McIntyre, R. S., Rosenblat, J. D., Siegel, A. N., Teopiz, K. M.

This review (2021) summarizes the study characteristics of all ongoing registered clinical trials investigating psychedelic drugs for psychiatric disorders and identifies that their majority focuses on investigating MDMA and psilocybin for treating depression or PTSD, while only 30% of their results are published.

Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability

2018 | Kabbaj, M., Wright, K. N.

This review (2018) examines gender-related differences related to antidepressant effects and abuse liability of ketamine given that women are twice as likely to develop depression and progress through the stages of addiction faster than men. Preclinical evidence suggests that female rats are indeed more sensitive to ketamine’s effects, but more clinical research is needed to verify these gender-related effects in humans.

Key interindividual determinants in MDMA pharmacodynamics

2018 | Farré, M., Muga, R., Papaseit, E., Pérez-Mañá, C., Torrens, M.

This review (2018) examines the main interindividual determinants in MDMA pharmacodynamics and highlights the influence of factors such as gender-sex (more pronounced in women because of weight difference), race-ethnicity, and genetic traits.

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

2018 | Andrews, A. M., Dunlap, L. E., Olsen, D. E.

This review (2018) examines the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine.

Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT)

2018 | Cameron, L. P., Olsen, D. E.

This review (2018) examines the biosynthesis routes of DMT alongside its pharmacology, metabolism, adverse effects, and potential use in medicine.

Production Options for Psilocybin: Making of the Magic

2018 | Blei, F., Fricke, J., Hoffmeister, D., Lenz, C., Wick, J.

This historic review (2019) examines the biosynthesis and pharmacology of psilocybin, and summarizes the biotechnological routes of its synthesis.

Self-Experiments with Psychoactive Substances: A Historical Perspective

2018 | Brandt, S. D., Passie, T.

This book chapter (2018) presents a historic overview of self-experimentation with psychoactive substances whose scientific documentation began in the mid-1850s and continuously expanded over the next 125 years while stimulating scientific (and therapeutic) advances and becoming increasingly widespread amongst layperson with the rise of New Psychoactive Substances. While psychologists like William James and Sigmund Freud drew significant inspiration from their drug experiences, other examples may serve as cautionary tales, such as John C. Lilly’s account of ketamine dependence that developed out of self-experimentation.

Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives

2018 | Giannantonio, M. D., Lerner, A. G., Lorusso, M., Martinotti, G., Montemitro, C., Pettorruso, M., Santacroce, R., Spano, M. C.

This comprehensive literature review (2018) examines the clinical features and treatment options for psychedelic-induced Hallucinogen Persisting Perception Disorder (HPPD), which entails tracers and trailing phenomena among its most resistant symptoms. Although the prevalence is low and hard to assess reliably, the condition is more often diagnosed in individuals with a history of previous psychological issues or substance misuse, and most reported cases were triggered by LSD.

Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

2016 | Ding, Z., Hashimoto, K., Lu, L., Shi, J., Zhang, Y., Zhu, W.

This review (2016) investigates the risks (safety and toxicity) related to the medical use of ketamine (for depression). The most risk is found at chronic and high doses. R-ketamine is found to have greater antidepressant effects with a smaller risk of adverse events.

Ibogaine: a review

2004 | Alper, K.

This book chapter (2001) reviews the topics of the First International Conference on Ibogaine, and reviews the chemical structure of ibogaine, its biological mechanisms of action, effects in humans and animal models, pharmacokinetics, and safety profile, etc. Case reports in humans and effects in preclinical models of drug dependence suggest the iboga alkaloids may have efficacy in addiction on the basis of mechanisms that are not yet known and which can possibly be dissociated from toxic effects and may present significant promise as a paradigm for the study and development of pharmacotherapy for addiction.

Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases

2014 | Alderliefste, G., Brunt, T. M., Litjens, R. P. W., Westerink, R. H. S.

This review (2014) examines the role of serotonergic transmission in Hallucinogen persisting perception disorder (HPPD), a rare perceptual disorder caused by LSD, and other classical hallucinogens, as well as MDMA. The disorder may be a result of a misbalance of inhibitory-excitatory activity in low-level visual processing caused by interneurons expresses 5-HT2A receptors, whose activity would normally suppress afterimages through inhibitory GABA release.

The need for publicly funded research on therapeutic use of psychedelic drugs

2021 | Hall, W.

This perspective paper (2021) advocates the need for public funding of independent evaluations of the efficacy of psychedelic drugs, given that current research efforts spurred by private philanthropic interests may propel a widespread use of psychedelics and demands to implement them as a first-line treatment, ahead of the evidence on their safety, efficacy, and long-term effects.

Side-effects associated with ketamine use in depression: a systematic review

2017 | Fong, J., Galvez, V., Loo, C., Shelker, W., Short, B.

This systematic review (2017) examined the reported side-effects of ketamine treatment for depression across 288 published reports and identified that headache, dizziness, dissociation, elevated blood pressure, and blurred vision were the most common in response to intravenous infusion. The most common acute psychiatric side-effect was anxiety, but there was no conclusive evidence about long-term side effects from the currently available studies.

MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’ users

2017 | Montgomery, C., Parrott, A. C., Quednow, B. B., Roberts, C. A.

This systematic review (2018) examines the long-term effects of MDMA on neurocognitive performance amongst abstinent ecstasy users and found evidence of hemodynamic and electrophysiological changes in the prefrontal brain regions that is reflective of increased cognitive effort to maintain performance levels during executive functions.

Lysergic acid diethylamide: side effects and complications

1980 | Cohen, S.

This early review (1960) details the prevalence of some possible side effects and complications of LSD from the literature. The discussion includes prolonged psychotic symptoms, (attempted) suicides, and others.

The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation

2015 | Hilber, K., Koenig, X.

This review (2015) examines how the anti-addictive drug ibogaine affects the heart and the cardiovascular system and outlines a sequence of deleterious events that lower heart rate and selectively block cardiac ion channels which pave the way for life-threatening arrhythmias. Due to the longevity of noribogaine—ibogaine’s active metabolite—in human plasma, cardiac adverse events may also occur several days after, which highlights the need for developing less toxic variants of ibogaine such as 18-MC.

MDA, MDMA and other mescaline-like substances in the US military’s search for a truth drug (1940s to 1960s)

2017 | Benzenhöfer, U., Passie, T.

This review (2017) summarizes the history of the US military's attempt to operationalize psychotropic drugs, first scopolamine, and mescaline then later on MDMA and other derivatives, as a truth serum. These attempts were largely futile because scopolamine induced a delirium-like state of mind which raised doubt over the validity of the extracted information, whereas psychedelic substances produced excessive hallucinations, thought disturbance, and confusion, which hindered the interrogation process.

Toxicities Associated With NBOMe Ingestion—A Novel Class of Potent Hallucinogens: A Review of the Literature

2014 | Arbelo Cruz, F. A., Correa, A. M., Dekker, M. A., Poklis, A., Poklis, J. L., Suzuki, J., Valenti, E. S.

This meta-analysis (2015, n=20) examined the toxicity of the synthetic serotonergic hallucinogen NBOMe reported in publications that described adverse effects in response to analytically confirmed human ingestion. Severe adverse effects included agitation (85.0%), tachycardia (85.0%), and hypertension (65.0%), and seizures (40.0%) among patients.

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

2021 | Sanacora, G., Schatzberg, A. F.

This commentary review (2014) highlights the strength of evidence from recent proof-of-concept studies of ketamine which bear promise for the rapid treatment of depression which currently lacks efficient treatment alternatives. However, the authors disagree about the underlying mechanism mediating these effects and doubt whether there is a sufficient degree of preclinical evidence to warrant the initiation of novel treatment approaches or widespread availability of the drug in clinical settings.

Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia

2014 | Chen, D. C., Ding, Y., Fan, N., Gueorguieva, R., He, H., Ke, X., Krystal, J. H., Limoncelli, D., Liu, Y., Ning, Y-P., Petrakis, I. L., Pietrzak, R. H., Wang, D., Wang, Z., Xu, K., Zhang, X.

This meta-analysis (n=998) investigated the subjective effects of ketamine (68,31mg) compared to the symptoms of psychosis among heavy ketamine abusers, and patients with early and late-stage schizophrenia. Common symptoms included blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation, and motor retardation, and chronic ketamine abusers and chronic schizophrenics also exhibited difficulty of abstract thinking.

Developing Guidelines and Competencies for the Training of Psychedelic Therapists

2017 | Phelps, J.

This article (2017) lays out guidelines and core competencies for psychedelic therapists in training, which include empathetic abiding presence; trust enhancement; spiritual intelligence; knowledge of the physical and psychological effects of psychedelics; therapist self-awareness and ethical integrity; and proficiency in complementary techniques. It also highlights 12 domains of curricular training that include knowledge of history, neuropharmacology, best practices in set and setting, as well as therapeutic strategies and boundaries.

Psychedelic drug use in healthy individuals: A review of benefits, costs, and implications for drug policy

2017 | Elsey, J. W. B.

This review (2017) shifts the usual focus from psychedelics as a potential treatment for mental health problems to psychedelics as a potential enhancer of well-being in healthy individuals. The author argues that the relatively low risk and high potential benefit of psychedelic drugs are incongruent with the stringent drug laws seen around the world.

Regulation of human research with LSD in the United States (1949-1987)

2017 | Bonson, K. R.

This article (2017) reviews the history of the regulation of LSD research through the 1962 Kefauver-Harris Amendments (making it harder to do psychedelic research) and their implementation over the course of the ensuing decade.

LSD experiments by the United States Army

2017 | Ross, C. A.

This article (2017) examines the history of LSD experiments within the US army and their frequent short and long-term side effects and complications that have, according to the author, not received enough attention in the recent resurgence of interest in psychedelics.

Neuroimaging in moderate MDMA use: A systematic review

2015 | Borgwardt, S., Dolder, P. C., Lang, U. E., Lenz, C., Liechti, M. E., Mueller, F., Steiner, M., Walter, M.

This systematic review (2015; 19 studies) found no convincing evidence that moderate use of MDMA is associated with significant brain alterations. However, the authors point out that the included studies were very heterogeneous and often of low quality.

Set and Setting in the Santo Daime

2021 | Hartogsohn, I.

This observational review (2021) describes ayahuasca use within the set and setting in the Santo Daime church and outlines complex layers of intentions, expectations, visual, auditory, and symbolic environments, social and cultural systems that form a rich tapestry of contextual factors that foster unique experiences. While also describing how the Santo Daime setting can also go wrong, it highlights the role of contextual factors to mitigate harms and facilitate social and personal benefits.

Making a medicine out of MDMA

2015 | Nutt, D. J., Sessa, B.

This commentary (2015) examines how inappropriate, non-evidence-based, legislative restrictions of MDMA have failed to mitigate the harms of recreational ecstasy use but have effectively halted clinical research for therapeutic use. They urge the regulatory authorities to re-schedule MDMA and promote research for therapeutic uses within psychiatry.

Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

2015 | Monteggia, L. M., Zarate, C. A.

This review (2015) provides an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next-generation treatments, which include better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators.

Amanita muscaria: chemistry, biology, toxicology, and ethnomycology

2003 | Melendez-Howell, L. M., Michelot, D.

This review (2003) examines the chemical, biological, and toxicological properties of the alkaloids contained in Amanita Muscaria (Fly Agaric) alongside the sociocultural context of its etymology. The principal substrates ibotenic acid and muscimol exert their psychotropic effects through stimulation of inhibitory glutamatergic and GABAergic neurotransmission.

Recreational Use, Analysis and Toxicity of Tryptamines

2015 | Mannocchi, G., Pantano, F., Saverio Romolo, F., Tittarelli, R.

This comprehensive review (2015) summarizes the chemical characterization, pharmacology, and toxicity of New Psychoactive Substances from the published literature, as well as information gathered from non-peer-reviewed sources, such as drug forums. They provide an overview of useful information, such as reported death cases, for public health workers.

Ethics and ego dissolution: the case of psilocybin

2020 | Sisti, D., Smith, W. R.

This theoretical paper (2020) argues the case for an updated consent process for people undergoing an experience with psilocybin. The paper touches upon the novel risks, the differences with consent for other psychiatric medications, and that between clinical research and mainstream use in psychiatry.

A Public-Health-Based Vision for the Management and Regulation of Psychedelics

2016 | Emerson, B., Haden, M., Tupper, K. W.

This policy article (2016) assesses the harms and benefits of psychedelics use in light of contemporary research and provides a public-health-based model for their regulation, which includes governance, supervision, set and setting controls, youth access, supply control, demand limitation, and evaluation.

MDMA and the “Ecstasy Paradigm”

2014 | Cole, J. C.

This review (2014) examines the lack of evidence to support the notion that MDMA causes widespread cognitive deficits among its users and critiques a prevalent 'ecstasy paradigm' which exaggerates the negative effects of this substance, sustains publication bias by ignoring methodological shortcomings of their study design, and disregarding its therapeutic potential. Although MDMA poses risks to its users, there is no wide-scale evidence to suggest that its users have been damaged, a matter of fact according to the author, which requires no further empiric investigation but a more critical analysis of the already existing evidence.

Psychedelic science in post-COVID-19 psychiatry

2020 | Alexander, L., Baker, A., Brennan, C., Burke, L., Crockett, M. T., Haran, M., Kelly, J. R., O’Keane, V.

This commentary (2020) examines how the COVID-19 pandemic has affected the trajectory of clinical trials investigating psilocybin-treatment for a wide range of conditions, some of which are likely to become even more prevalent in post-COVID-19 clinical psychiatry. Although many of these clinical trials have been temporarily stagnant due to safety measures, ongoing efforts from large scale clinical studies of psilocybin will provide valuable information on its safety, dose optimization, and its efficacy compared to a conventional selective serotonin reuptake inhibitor (SSRI) and additional studies will elucidate whether it is safe to combine them with psilocybin therapy.

Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Review of the Research Literature and Published Case Studies

2021 | Adams, C., Bradley, E. R., DellaCrosse, M., Gallenstein, M. L., Gard, D. E., Garfinkle, E., Michalak, E. E., Penn, A., Pleet, M. M., Riley, L. S., Woolley, J. D.

This review (2021) finds that in the current literature there are some known, but limited, risks of activating mania with psilocybin for those with bipolar depression (BD). The review describes 17 cases of BD and the use of a range of psychedelics.

Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids

2006 | Gable, R. S.

This relatively early study (2006) combined a literature review with interviews of ceremony participants to establish the effects and toxicity of ayahuasca. The author concludes that risks are relatively low (transient psychological effects, low toxicity, low abuse/addiction potential).

Oral ketamine for the treatment of pain and treatment-resistant depression

2016 | aan Het Rot, R., Balukova, S. M., Chaves, T. V., Kortekaas, R., Schoevers, R. A.

The meta-analysis (2016) examined the antidepressant effects of ketamine in specific regard to its oral administration route. In terms of safety, oral ketamine administration over longer time periods appears to be well-tolerated, but its long-term negative side-effects and the strength of its antidepressant efficacy remain understudied.

Verbal memory impairment in polydrug ecstasy users: a clinical perspective

2016 | de Sousa Fernandes Perna, E. B., Kuypers, K. P. C., Linssen, A., Ramaekers, J. G., Sambeth, A., Schultz, B. G., Theunissen, E. L., van Wel, J. H. P.

This meta-analysis of four placebo-controlled studies (n=130; 2016) investigated the effects of MDMA (75 mg) and history of poly-drug use on verbal memory impairment. Although verbal memory was impaired during acute MDMA intoxication, there was no evidence of memory impairment in relation to either post-acute abstinence or long-term ecstasy use.

Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies

2017 | Bouso, J. C., Dos Santos, R. G., Hallak, J. E.

This study (2017) reviews case reports of psychotic episodes occasioned by ayahuasca and DMT. The authors conclude that theses incidences are very rare, but that individuals with a psychotic personal or family history should avoid these substances.

Safety pharmacology of acute MDMA administration in healthy subjects

2017 | Liechti, M. E., Vizeli, P.

This analysis of data from nine double-blind, placebo-controlled studies (n=166) investigated the short-term psychological and physiological safety profile of MDMA (75-125mg) and found that effects were overall positive and risks were low, although adverse effects were more frequent in women than in men.

Compassionate use of psychedelics

2020 | Greif, A., Šurkala, M.

This paper (2020) reviews the safety and efficacy of psilocybin- and MDMA-assisted therapies and argues that it can be rational for some patients to try compassionate psychedelic therapy, notwithstanding the uncertainty of outcomes, as the expected value of psychotherapy can outweigh the expected value of routine care, palliative care, or no care at all. They also address the epistemic risk carried by the notion that psychedelics are philosophically deceptive given that the subjective effects may often feel more real than normal consciousness, but the authors argue that it is not known how classical psychedelics influence one’s beliefs or whether they make one metaphysically irrational, and assert that metaphysics should be ignored in medicine as much as possible. While acknowledging that there are suboptimal uses of psychedelics, the authors see no ethical barriers for their compassionate use in palliative care.

Efficacy and safety of ketamine in bipolar depression: A systematic review

2017 | Alberich, S., González-Pinto, A., López, P., Martínez-Cengotitabengoa, M., Nuñez, N. A., Vieta, E., Zorrilla, I.

This review (2017) compared the safety and efficacy of ketamine for bipolar depression across scientific studies (1 clinical trial, 4 case studies, 5 cohort studies), which showed that symptoms are reduced swiftly and effectively in response to treatment, but they reappear relatively quickly within 3-14 days depending on the scale used to measure symptoms. Ketamine may be considered safe and effective for treating some cases of bipolar depression, although it has a short duration of action, in the absence of confirming studies designed specifically for bipolar depression.

The effects of ecstasy on neurotransmitter systems: a review on the findings of molecular imaging studies

2016 | Booij, J., Reneman, L., Vegting, Y.

This systematic review (2016) examines the acute and long-term neurotoxicity of MDMA across neuroimaging studies that investigated deleterious effects on neurotransmission. MDMA does significantly not affect dopamine transmission, and its effects on the 5-HT2A system remain unclear. Although heavy long-term use was consistently shown to be associated with reduced serotonin binding affinity that may indicate serotonin depletion due to neurotoxicity, abstinence leads to significant recovery. Some studies showed that the use of MDMA is correlated with deficits in several cognitive functions; however, opinions remain divided on this topic.

Ibogaine for treating drug dependence. What is a safe dose?

2016 | Galea, S., Newcombe, D., Schep, L. J., Slaughter, R. J.

This review (2016) argues that the current doses of ibogaine administered as a treatment for drug dependence are too high and should be reconsidered to avoid toxicity and fatalities.

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

2019 | Hashimoto, K.

This historic review (2019) examines cellular mechanisms underlying the antidepressant effects of the R(-) and S(+) ketamine enantiomers and their norketamine and hydroxynorketamine metabolites. Although S(+) ketamine exhibits greater affinity to the NMDAR, which is believed to be the mediator of its antidepressant effect, preclinical evidence from animal models suggests that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects with less detrimental side‐effects. Given that the phase I clinical studies on R(-)ketamine and hydroxynorketamine are now underway, future studies will be able to perform a direct comparison of their efficacy to treat patients with depression.

Nonanesthetic Effects of Ketamine: A Review Article

2018 | Blaise, G., Eldufani, J., Nekoui, A.

This review (2018) examines (preliminary) evidence of the medical benefits of the non-anesthetic effects of ketamine, as well as supporting evidence of the effectiveness and tolerability of ketamine for improving pain conditions, depression, memory function in Alzheimer's disease, and brain damage after stroke. It also examines underlying mechanisms that exert these effects by stimulating or blocking certain neuroreceptor pathways.

Lysergic acid diethylamide: a drug of ‘use’?

2016 | Barnwal, P., Das, S., Mondal, S., Ramasamy, A., Sen, S.

This review (2016) provides a chronologic history of LSD and examines its safety profile, the potential for abuse, its therapeutic potential to treat alcoholism or terminally ill patients. It also summarizes insights about its receptor pharmacology, mechanism of action, and (adverse) effects, while highlighting some of its potential clinical applications such as an antianxiety agent, a creativity enhancer, a suggestibility enhancer, or a performance enhancer.

Ketamine abuse potential and use disorder

2016 | Lin, D., Liu, Y., Wu, B., Zhou, W.

This review (2016) contrasts the therapeutic potential of ketamine as a fast-acting antidepressant to its potential for substance abuse. It specifically examines the social harms, the psycho-physiological and neurochemical effects, reinforcement mechanisms, and the treatment of ketamine abuse. It concludes that ketamine elicits significant reinforcing and toxic effects, which must be weighed against its antidepressant potential, which needs to be investigated in greater depth.

Meta-analysis of executive functioning in ecstasy/polydrug users

2016 | Jones, A., Montgomery, C., Roberts, C. A.

This meta-analysis (2016) compared cognition between current MDMA (n=1221) users and poly-drug users (n=1224) with regard to executive functions, such as updating, switching, inhibition, and access to long-term memory. Current ecstasy users exhibited significant but small-size deficits in executive functioning, with regard to access to long-term memory, task-switching, and memory updating, which was independent of their accumulated lifetime ecstasy dose.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

2014 | Barnes, G., Baumeister, D., Giaroli, G., Tracy, D.

This review (2014) examines the effects of psychedelic drugs with regard to their pharmacodynamics and molecular biology, their electrophysiological and neuroimaging profile, and summarizes the evidence for potential therapeutic mechanisms of action, including effects on neurogenesis, cortical networks, and the immune system. It also examines the clinical profile of psychedelic substances with regard to risks for healthy individuals, as well as the potential to treat clinical conditions such as depression, notwithstanding the criminalized status of psychedelics, despite negligible risk and a lack of evidence for its alleged adverse effects.

Ketamine Users Have High Rates of Psychosis and/or Depression

2015 | Chan, F., Liang, H. J., Tang, K. L., Tang, W. K., Ungvari, G. S.

This meta-analysis (n=129) evaluated the relation between long-term treatment with ketamine and the frequency of psychotic and mood disorders, amongst patients located in Hong Kong, China. According to standardized diagnostic criteria, psychosis and/or depression were very common amongst these patients, which raises the issue of safety when considering ketamine for long-term treatment of depression.

The hallucinogenic world of tryptamines: an updated review

2015 | Araújo, A. M., Carvalho, F. M., Carvalho, M., de Lourdes, B. M., de Pinho, P. G.

This review (2015) provides a comprehensive overview of a broad class of serotonergic hallucinogens known as tryptamines, concerning their evolution, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics, and their physiological and toxicological effects on animals and humans. Although classical psychedelics are generally considered to be physiologically safe molecules, there is a lack of information on new tryptamine derivatives, regarding their acute and long-term effects, interactions with other substances, toxicological risk, or addictive potential.

Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression

2015 | Andrade, C.

This article (2015) examines the advantages and applications of intranasal drug delivery, with a particular focus on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. The article contrasts intranasal delivery to oral and sublingual delivery methods, which are less effective with regards to their bioavailability, crossing of the blood-brain-barrier, and rapid onset of drug effects.

Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments

2020 | Feduccia, A. A., Garel, N., Greenway, K. T., Jerome, L.

This meta-review (2020) examines the therapeutic frameworks surrounding contemporary practices of psychedelic-assisted psychotherapy, with regard to the historic development of therapeutic models and contemporary insights into extra-pharmacological factors and underlying mechanisms. They highlight that these therapies entail greater environmental sensitivity from the patient's perspective, which requires more meticulous attention for the preparation of the set and setting, a considerably resource-intensive endeavor.

Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

2016 | Bobo, W. V., Croarkin, P. E., Frye, M. A., Leung, J. G., Tye, S. J., Vande Voort, J. L.

This review (2016) examines the clinical efficacy of ketamine as fast-acting pharmacotherapy for major depressive disorder and bipolar disorder (BP), in light of the available evidence. In the authors' view, there is insufficient empirical support for the early adoption of ketamine into routine practice, given the lack of data on the longer-term safety of ketamine as an antidepressant therapy, which will require the development of clinical protocols with standardized screening, clinical phenotyping, and follow-up procedures.

Are Psychedelics Something New in Teaching Psychopharmacology?

2020 | Aggarwal, R., Balon, R., Beresin, E. V., Brenner, A. M., Coverdale, J., Guerrero, A. P. S., Louie, A. K., Morreale, M. K.

This editorial paper aims to inform the attitude of medical health professionals towards psychedelics, with regard to evaluating their therapeutic potential in accordance with a rigorous application of the scientific method, while taking social, historical, political, and cultural factors that have influenced their legal status and the discontinuation of prior research.

Flashbacks and HPPD: A Clinical-oriented Concise Review

2014 | Bor, O., Goodman, C., Lerner, A. G., Rudinski, D.

This review (2014) examines the etiology of flashbacks or Hallucinogen Persisting Perception Disorder (HPPD), which represents a cluster of recurrent visual disturbances which have been reported to persist after the acute phase of psychedelic, such as LSD. The authors delineate HPPD type I. disorder that entails short-term, non-distressing, benign, and reversible state accompanied by a pleasant affect, and type II: disorder which entails long-term, distressing, pervasive, either slowly reversible or irreversible, non-benign state accompanied by an unpleasant affect. Although the prevalence of HPPD remains understudied, the authors review a large variety of medications that may alleviate the symptoms of this condition.

How MDMAs Pharmacology and Pharmacokinetics Drive Desired Effects and Harms

2014 | White, C. M.

This review (2014) looks at the desired effects and the possible harms that MDMA can elicit. One could argue that the review in unjustly harsh and implies negative effects not commonly experienced.

Is LSD toxic?

2018 | Grob, C. S., Nichols, D. E.

This study (2018) re-examined five cases of fatality described by media as related to "LSD toxicity," and found that none of those cases were actually attributable to physiological LSD toxicity.

Safety and Side Effects of Ayahuasca in Humans—An Overview Focusing on Developmental Toxicology

2013 | Dos Santos, R. G.

This review (2013) summarizes studies that investigated the toxicity of ayahuasca with regard to its consumption during pregnancy and long-term consumption and did not find evidence indicative of risk. Preclinical studies on rats provide some evidence that select ayahuasca alkaloids may be toxic for development, but these results require further validation through translational research in order to draw conclusions that generalize over human subjects.

Harm potential of magic mushroom use: A review

2011 | Opperhuizen, A., van Amsterdam, J., van den Brink, W.

This review (2011) summarizes the literature on physical or psychological dependence, acute and chronic toxicity, the risk for public health, and criminal aspects related to the consumption of magic mushrooms. The authors conclude that the use of magic mushrooms is relatively safe as only few and relatively mild adverse effects have been reported.

Consumption of Ayahuasca by Children and Pregnant Women: Medical Controversies and Religious Perspectives

2011 | Labate, B. C.

This review (2011) explores common themes and contradictions found between the biomedical, anthropological, and ayahuasca-users' perspectives on the consumption of ayahuasca by children and pregnant women. It raises central issues regarding the limits of freedom of religion and the state's right to interfere in family matters.

Bringing Ayahuasca to the Clinical Research Laboratory

2011 | Barbanoj, M. J., Riba, J.

This commentary article (2005) describes the clinical trials involving the administration of ayahuasca to healthy volunteers at the Autonomous University of Barcelona.

Can MDMA Play a Role in the Treatment of Substance Abuse?

2013 | Jerome, L., Schuster, S., Yazar-Klosinski, B.

This review (2013) evaluates the potential of MDMA to treat substance abuse and dependence. The authors provide evidence that MDMA may have potential as a treatment for these morbidities, but also highlight that classical psychedelics have a better risk:benefit ratio.

Potential Therapeutic Effects of Psilocybin

2017 | Griffiths, R. R., Johnson, M. W.

This review (2017) evaluates the therapeutic research into psilocybin as a treatment for addiction, treatment-resistant depression, and mood and anxiety disorders. The authors also analyse the safety data from these clinical trials.

Hallucinogen persisting perception disorder: what do we know after 50 years?

2003 | Halpern, J. H., Pope Jr, H. G.

This meta-analysis (2003) reviews the findings of 20 studies concerning the diagnosis of Hallucinogen Persisting Perception Disorder (HPPD, or flashbacks) and discusses the difficulty of applying its diagnostic criteria reliably, in light of the ambiguous definition of a 'flashback' and its similarity to other symptoms that are indicative of PTSD. Results conclude that the prevalence of strict HPPD might be very low, while its treatment and etiology remain widely understudied.

Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions

2010 | Ai-Ming, Y., Jiang, X. L., Shen, H. W., Winter, J. C.

This review (2010) summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT, with particular regard to hyper-serotonergic effects of 5-MeO-DMT and bufotenine in response to inhibition of the monoamine oxidase (MAO) metabolic pathway via harmaline (together often found in ayahuasca brews).

Revisiting Wasson’s Soma: Exploring the Effects of Preparation on the Chemistry of Amanita Muscaria

2011 | Feeney, K.

This meta-analysis (n=525) analyzed the effects of Amanita Muscaria (or fly agaric) with regards to inebriation, nausea, and vomiting, sampled across various sources of self-reported ingestion. The dried mushroom caused less nausea and vomiting than when it was consumed fresh, which supports the notion that the preparation methods described for Soma in the Rig Veda may have been a means of reducing the toxicity of Amanita Muscaria, in accordance with Wasson's theory over the identity of Soma.

Health status of ayahuasca users

2012 | Barbosa, P., Bogenschutz, M. P., Mizumoto, S., Strassman, R. J.

This meta-analysis (2012) reviewed the health status of ayahuasca users reported across 10 independent studies, using both quantitative and qualitative analyses. Ayahuasca subjects had similar or better scores than controls and/or the general population on measures of psychiatric morbidity, and psychosocial status, well-being, and consistently less alcohol-related problems, and various subjective (e.g. religious, existential, emotional) benefits.

Do hallucinogens cause residual neuropsychological toxicity?

1999 | Halpern, J. H., Pope Jr, H. G.

This review study (1999) finds few, to none, long-term neuropsychological deficits/toxicity that can be attributed to psychedelic (mainly LSD) use.

A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses

2020 | Chi, T., Gold, J. A.

This review (2020) presents modern human studies into psychedelic drugs, including psilocybin, LSD, MDMA, and ayahuasca in the treatment of various psychiatric illnesses, including treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. Safety and efficacy data are also presented, from both human and animal studies.

Psychedelic mushrooms in the USA: Knowledge, patterns of use and association with health outcomes

2021| Lerer, B., Lerer, L. B., Matzopoulos, R., Morlock, A., Morlock, R.

This preprint survey study (n=7139) assessed the use of psychedelic mushrooms amongst adults in the US. The survey found that people generally self medicate with psychedelic mushrooms for reasons related to mental health, with users reporting significantly higher levels of anxiety and depression. The study concludes with a call for a use-related harm reduction strategy for psychedelic mushrooms in the US.

“Meeting the Medicine Halfway”: Ayahuasca Ceremony Leaders’ Perspectives on Preparation and Integration Practices for Participants

2021| Callon, C., Lafrance, A., Williams, M.

This interview study (n=15) explores the perspectives of ayahuasca ceremony leaders regarding preparation and integration. Four categories are identified, 1) preparation (honesty, respect, willingness, resources), 2) preparation and integration (therapy, spiritual practice, creative expression), 3) integration (sharing experiences, working with insights), and 4) ineffective integration.

Psychedelic Knowledge and Opinions in Psychiatrists at Two Professional Conferences: An Exploratory Survey

2021| Barnett, B. S., Beaussant, Y., Doblin, R., King, K.

This survey study (n=106) asked psychiatrists at two conferences about their knowledge (many aware of the promise) and opinions/concerns (lack of training, logistics, patients with contraindications) regarding psychedelic therapy. Those who worked more in research, know more about psychedelics, or were less concerned about the addictive potential scored higher in their beliefs on the effectiveness of psychedelic-assisted therapy.

The adverse events of ibogaine in humans: an updated systematic review of the literature (2015-2020)

2021| Borràs, T., Bouso, J. C., Colomina, M. T., Dos Santos, R. G., Hallak, J. E., Ona, G., Rocha, J. M.

This review (s=18) did a qualitative analysis of studies with ibogaine and describes the acute adverse events (cardiac, gastrointestinal, neurological) and long-lasting effects (persistent cardiac, psychiatric, neurological). The authors note that phase I studies with standardized products are necessary as the products quantity and mix was widely varied.

Cancer Healthcare Workers' Perceptions toward Psychedelic-Assisted Therapy: A Preliminary Investigation

2021| Akroyd, A., Evans, W. J., Muthukumaraswamy, S., Reynolds, L. M, Stack, A., Sundram, F.

This qualitative interview study (n=12) examined the perspectives and attitudes of cancer healthcare workers towards psychedelic-assisted therapy. In general, they were open to the concept, viewed it as an innovative approach, and acknowledged their responsibility towards alleviating suffering in advanced cancer patients. However, this view was also met with caution and highlights the need for further research to ensure efficacy and safety.

Two Models of Legalization of Psychedelic Substances: Reasons for Concern

2021| Appelbaum, P. S., Smith, W. R.

This opinion paper (2021) raises concerns over the two concurrent models of legalizing the possession, personal use, and noncommercial sharing of psychedelics in California and clinical use in Oregon. In light of cautionary precedents involving the commercialisation of ketamine and cannabis, their chief concern is that non–evidence-based marketing strategies founded on one-sided enthusiasm for the benefits of psychedelics may supplant evidence-based practices, thereby putting vulnerable populations at risk of their potential side effects that have not been studied outside of the clinical population.

Moral Psychopharmacology Needs Moral Inquiry: The Case of Psychedelics

2021| Dyck, E., Langlitz, N., Repantis, D., Scheidegger, M.

This opinion paper (2021) examines the effects of psychedelics on moral flexibility and argues that the context sensitivity of these substances entails that randomized placebo-controlled trials are insufficient for appreciating the full range of their possible effects. In order to understand its effects on moral behavior, the authors advocate a complementary approach of culture-controlled trials that investigate this moral psychopharmacology under different social and cultural circumstances with the help of anthropological, sociological, and philosophical observers, in order to determine what constitutes a good use of psychedelics beyond clinical trials.

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

2021| Abi-Gerges, N., Ansonoff, M., Bechand, B., Havel, V., Hemby, S. E., Hodges, A., Hunkele, A., Hwu, C., Javitch, J. A., Katritch, V., Kruegel, A. C., Majumdar, S., McIntosh, S., Nelson, M., Pintar, J. E., Sames, D., Stallings, L., Wulf, M. G., Yang, M., Zaidi, S. A.

This preprint (2021) animal in vivo and human in vitro study examines a new class of oxa-iboga alkaloids (10 & 40 mg/kg) with respect to their effects on opioid addiction in rats and their cardiotoxic effects on human heart cells. In contrast to noribogaine, oxa-iboga analogs exhibited no risk of inducing arrhythmia in adult human primary cardiomyocytes, and oxa-noribogaine induced acute and long-lasting suppression of morphine self-administration in rats in response to both single and repeated dosing regimes.

Psychedelics not linked to mental health problems or suicidal behavior: A population study

2015| Johansen, P. Ø., Krebs, T. S.

This 2015 observational survey study (n=135 095) investigated the association between lifetime psychedelic use (LSD, psilocybin, mescaline) and mental health problems, but found no indication of increased likelihood for psychological distress, mental health treatment, suicidal behavior, depression, or anxiety amongst psychedelic users (n=19 299). These results contest the justification for prohibiting psychedelics as a public health measure.

Developmental outcomes of 3,4-methylenedioxymethamphetamine (ecstasy)-exposed infants in the UK

2013| Fulton, S., Goodwin, J., Min, M. O., Moore, D. G., Parrott, A. C., Singer, L. T., Turner, J. J. D.

This longitudinal, between-subjects cohort study (n=96) investigated whether use of recreational MDMA during pregnancy is damaging to the development of newborn children and found that prenatal MDMA exposure was related to higher ratio of male gender, lower cognitive development scores at 12 months of age, and persistently poorer motor quality and milestone achievement over the first 2 years of life. Prenatal MDMA exposure correlated with fine and gross motor delays in a dose dependent manner.

MDMA, cannabis, and cocaine produce acute dissociative symptoms

2015| Bosker, W. M., Giesbrecht, T., Kuypers, K. P. C., Merckelbach, H., Ramaekers, J. G., Spronk, D. B., Theunissen, E. L., van Heugten-Van der Kloet, D., van Wel, J. H. P., Verkes, R. J.

This randomized, double-blind, placebo-controlled, four-way, cross-over study (n=37) investigated the acute dissociative effects of MDMA (25, 50, and 100 mg), cannabis (THC 21mg/70kg), and cocaine (300 mg) and compared them to data of schizophrenia patients, Special Forces soldiers, and ketamine users. Results indicate that MDMA, cannabis, and (to a lesser extent) cocaine can produce dissociative symptoms that are similar to dissociative pathology.

Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects

2020| Davis, A. K., Lancelotta, R.

This observational survey study (n = 515) examines the prevalence of benefit enhancement (BE) strategies using secondary data from a survey of 5-MeO-DMT users and its associations with "mystical", challenging, and enduring effects. It concluded that the BE strategies were common in use and BE strategies were linked to increases in positive mystical-type and enduring effects.

Associations between lifetime classic psychedelic use and cardiometabolic diseases

2021| Carhart-Harris, R. L., Hendricks, P. S., Osika, W., Simonsson, O.

This observational survey study (n=752.374) investigated the relationship between lifetime classic psychedelic use and cardiometabolic diseases and found that lifetime classic psychedelic use was associated with a 23% lower odds of heart disease and a 12% lower odds of diabetes in the past year.

Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

2017| Borgwardt, S., Dolder, P. C., Müller, F., Schmid, Y.

This placebo-controlled, double-blind, cross-over study (n=24) compared the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg) in healthy subjects using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI). It found that while all active drugs induced comparable hemodynamic and adverse effects, MDMA induced subjective, emotional, sexual, and endocrine effects that were distinctive from those of methylphenidate and modafinil with the doses used.

Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects

2019| Borgwardt, S., Duerig, R., Eckert, A., Holze, F., Ley, L., Liechti, M. E., Müller, F., Varghese, N., Vizeli, P.

This placebo-controlled, randomized, double-blind, cross-over study (n=28) investigated distinct acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg) in healthy subjects. The results show that LSD, MDMA and D-amphetamine had different ratings on the 5 Dimensions of Altered States of Consciousness scale (5DASC) and Mystical Experience Questionnaire (MEQ). It also clearly indicates the distinct neurological and behavioral profiles of LSD, MDMA and D-amphetamine.

Self-reported negative outcomes of psilocybin users: A quantitative textual analysis

2020| Bienemann, B., Campos, M. L., Mograbi, D. C., Negreiros, M. A., Ruschel, N. S.

This text-mining study (n=346) analyzed the semantic structure of negative experiences in response to using psilocybin reported on the Erowid database and found that states of paranoia, fear, and anxiety were typically associated with thought distortions. Bad trips were also more prevalent among female users, medical emergencies were linked with using high doses, and long-term negative outcomes were linked to concurrent use with other substances.

In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation

2020| Berquist, M. D., Fantegrossi, W. E., Kristensen, J. L., Leth-Petersen, S.

This animal study (n=41) compared the hyperthermic side effects of MDMA ( and a deuterium-substituted analog d2-MDMA in rats and found that d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA.

Greater empathy in MDMA users

2019| Carlyle, M., Fawaz, L., Kosmider, S., Marsh, B., Morgan, C. J. A., Stevens, T.

This observational cohort study (n=67) compared the long-term effects of repeated MDMA use on empathy and the experience of social pain between MDMA, alcohol, and poly-drug users. MDMA users exhibited greater cognitive and emotional empathy compared with non-MDMA poly-drug users.

LSD, madness and healing: Mystical experiences as possible link between psychosis model and therapy model

2021| Falchi, M., Feilding, A., Palhano-Fontes, F., Ribeiro, S., Tófoli, L.F., Wießner, I.

This randomized, double-blind, placebo-controlled, crossover study (n=24) investigated the subjective effects of LSD and found significant overlap in the phenomenology of psychotic, mystical, and ego-dissolving experiences. The authors highlight the importance of meaning attribution to psychotic experiences in explaining how these different constructs converge in mystical experiences.

Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

2020| Brandt, S. D., Chatha, M., Halberstadt, A. L., Klein, A. K., Wallach, J. V.

This study investigates the correlation between the hallucinogens potency in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species such as rats and humans. It used dose-response studies with psychedelics in mice and found a very strong correlation (r=0.95) with earlier human data (n=36).

LSD-associated “Alice in Wonderland Syndrome”(AIWS): A Hallucinogen Persisting Perception Disorder (HPPD) Case Report

2015| Lerner, A. G., Lev Ran, S.

This case study discusses the LSD-linked “Alice in Wonderland Syndrome”(AIWS) or Todd’s syndrome in a patient with a history of sporadic and recreational cannabis, alcohol, and LSD use. The observation suggests that AIWS only manifested during LSD use and continued post LSD suspension, namely, Hallucinogen Persisting Perception Disorder (HPPD). While this did not result in a major functional impairment, it induced considerable worry and concern because of its persistent continuation.

A Survey of American Psychiatrists’ Attitudes Toward Classic Hallucinogens

2018| Barnett, B. S., Pope Jr, H. G., Siu, W. O.

This 2018 survey (n=324) explores the perception of American Psychiatrists regarding classic hallucinogens in the treatment of psychiatric disorders. The study noted that respondents viewed hallucinogens as "appropriately illegal for recreational purposes" as well as "potentially hazardous". However, a sizeable minority, including male and trainee and younger psychiatrists, showed a positive response to the therapeutic potential of hallucinogens in psychiatric treatment; this survey opined was due to more exposure to recent positive publications about hallucinogens.

Interaction of Sex and Age on the Dissociative Effects of Ketamine Action in Young Healthy Participants

2019| Colic, L., Derntl, B., Hornung, J., Li, M., Sen, Z. D., Walter, M.

This placebo-controlled, double-blind study (n=69) investigated the dissociated effects of ketamine in young healthy individuals (aged 18-30) and found that men had greater depersonalization and amnestic symptoms than women. The study also found that age was a factor in the overall effect of ketamine on dissociative symptoms with men with rising age being less affected than women. This conclusion links gender and age to the effects of drugs and recommends including them as factors so that psychiatric treatments could be more effective.

Anxiety, panic, and hopelessness during and after ritual ayahuasca intake in a woman with generalized anxiety disorder: A case report

2017| Crippa, J. A., Dos Santos, R. G., Hallak, J. E., Osório, F. L.

This case report (n=1) describes a woman with generalized anxiety disorder who experienced extreme anxiety, panic, and hopelessness during and up to three days after taking ayahuasca. This is the first description of a prolonged 'bad' trip in the literature.

Hallucinogen Persisting Perception Disorder After Ibogaine Treatment for Opioid Dependence

2018| Belgers, M., Knuijver, T., Markus, W., Schellekens, A., van Oosteren, T., Verkes, R. J.

This case study (n=1) describes one participant who took ibogaine in a study to treat their opioid use disorder (SUD) and subsequently suffered from hallucinogen persisting perception disorder (HPPD).

Collective self-experimentation in patient-led research: How online health communities foster innovation

2019| Bailey, J., Kempner, J.

This digital ethnographic study investigates how online health communities use self-experimentation to determine their treatment protocols by examining the case study of clusterbusters, a platform that came into being when a self-experimenter reported that LSD had prevented his usual cluster headache cycles on an internet forum. This example typifies how a rare disease being responded to with an even rarer form of intervention is cultivated through the collective experimentation of patient communities embedded in social networks who engage in collective forms of knowledge production.

Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action

2019| Coffeen, U., Pellicer, F.

This review (2019) examines the analgesic, anti-inflammatory, and psychoactive properties of the hallucinogenic plant Salvia Divinorum and its bioactive (analog) constituents.

‘Never drop without your significant other, cause that way lies ruin’: The boundary work of couples who use MDMA together

2019| Anderson, K., Boden, Z., Reavey, P.

This qualitative interview and diary study (n=14) investigated the context in which romantic couples use MDMA and found that it occasioned shared experiences which could modulate and enhance existing feelings of closeness in the process of being subsumed into things that couples enjoyed doing together, to the effect that it refreshed and revitalized their relationship.

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

2017| Brown, R., Cooper, K., Cozzi, N. V., Gassman, M. C., Henriquez, K. M., Hetzel, S. J., Hutson, P. R., Muller, D., Nicholas, C. R., Ribaudo, A. S., Thomas, C. D.

This open-label study (n=12) gave healthy participants increasing doses of psilocybin (21-42mg/70kg). The study found the half-life to be about 3 hours, this was not predicted by body weight, and no adverse effects were observed.

Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial

2018| Alonzo, A., Glue, P., Huggins, C., Loo, C., Martin, D., Mitchell, P. B., Rodgers, A., Somogyi, A. A.

This randomized, double-blind, placebo-controlled, safety study (n=5) found that intranasal (IN) ketamine was not well tolerated at dosages leading up to 100mg. The absorption between patients varied up to two-fold.

Effect of Ritualistic Consumption of Ayahuasca on Hepatic Function in Chronic Users

2018| Corrêa-Neto, N. F., Costa, J. L., Lanaro, R., Linardi, A., Mello, S. M., Silveira, G., Soubhia, P. C.

This safety study (n=22) investigated alterations to the liver of those who consumed ayahuasca at least twice a month, for at least a year and found none. They concluded that ayahuasca doesn't affect liver (hepatic) function.

N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain

2021| Bari, F., Berkecz, R., Cozzi, N. V., Dvorácskó, S., Farkas, A. E., Farkas, E., Frank. R., Frecska, E., Hantosi, D., Kecskés, S., Kömöczi, T., Krizbai, I. A., Menyhárt, À., Szabó, Ì., Tömmböly, C., Varga, V. È.

This animal study (n=69) examined whether DMT (1mg/kg/h) administration achieves neuroprotection via Sig-1R activation during an experimentally induced forebrain ischemia in rats and found that DMT attenuated the electrophysiological signature neurodegeneration even when 5-HTR binding was inhibited with a serotonergic antagonist, which confirmed the neuroprotective role of Sig-1R activation in their hypothesis.

Subjective effects of MDMA ('Ecstasy') on human sexual function

2000| Aizenberg, D., Weizman, A., Zemishlany, Z.

This observational qualitative survey study (n=35) investigated the acute effects of ecstasy/MDMA on sexuality in a real-world setting and found that it enhanced sexual desire, satisfaction, female arousal, and orgasmic intensity, but also delayed orgasm and decreased erectile ability in 40% of the males.

MDMA and Human Sexual Function

1986|

This retrospective survey study (n=26) examined self-reported sexuality under the influence of MDMA (≈125mg) compared to sober state and found that it increased emotional closeness, enhanced receptivity to being sexual, and was often chosen as a sexual enhancer by the participants, but it did not stimulate the desire to initiate sex and decreased erectile ability in 46% of the male participants.

MDMA and Sexual Behavior: Ecstasy Users' Perceptions About Sexuality and Sexual Risk

2021|

This retrospective interview study (n=98) examined the sexual behavior of ecstasy users and found that the majority of male and female respondents reported that Ecstasy increased feelings of sensuality and produced strong feelings of empathy and emotional closeness, but often without the need or culmination of sexual activity. A second distinct group of users reported that ecstasy increased sexual desire and sexual fulfillment, and this subpopulation also exhibited more sexual risk-taking behaviors.

Day trip to hell: A mixed methods study of challenging psychedelic experiences

2021| Johnstad, P. G.

This interview (n=38) and survey (n=319) study identified new themes as part of negative or challenging psychedelic experiences. Specifically, it identified fear (69%) and confusion (62%) to be a larger component than previously recognized, and ego dissolution as less central and sometimes even protective.

Visitors of the Dutch drug checking services: Profile and drug use experience

2021| Benschop, A., Koning, R., Noijen, J., Wijffels, C.

This survey study (n=1530) examined the demographic profiles of people who made use of drug checking services in the Netherlands in 2018 and found that most participants who acquired this service had longstanding experience and a higher lifetime prevalence of using ecstasy/MDMA than the average Dutch citizen.

Are Ecstasy Induced Serotonergic Alterations Overestimated For The Majority Of Users?

2018| Erritzoe, D., Maier, L. J., Szigeti, B., Winstock, A. R.

This study compared survey data (Global Drug Survey, >11.000 participants who used ecstasy) to that of those included in brain imaging studies and found that the latter group fell within the top 5-10% of users of ecstasy, possibly overestimating use and serotonergic (transporter levels) effects/disturbance for the average user.

Rapid antidepressant effect of S-ketamine in schizophrenia

2018| Bartova, L., Dold, M., Kasper, S., Milenkovic, I., Papageorgiou, K., Weidenauer, A., Willeit, M., Winkler, D.

This open-label case study (n=1) describes a patient with schizophrenia whose treatment regimen was augmented with a ketamine (25mg) infusion to alleviate her symptoms of depression and suicidal ideation (SI). Her symptoms underwent a robust and sustained remission after the infusion, without any accompanying psychotic or dissociative phenomena.

Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

2018| Dunlop, B. W., Edwards, J. A., Galendez, G. C., Garlow, S. J., Job, G. P., McDonald, W., Reiff, C. M., Riva-Posse, P., Saah, T. C.

This retrospective open-label study (n=66) assessed the blood pressure safety profile of subanesthetic ketamine (35mg/70kg) infusion for patients with depression. Although hypertensive patients had higher blood pressure peaks during the infusions, the overall changes in blood pressure were small, well-tolerated, and clinically insignificant.

Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions

2015| Farré, M., González, D., Torrens, M.

This open-label observational study (n=20) assessed the emotional, subjective, and cardiovascular effects of 2C-B (20mg) and found that it increased reactivity to negative stimuli, enabled emotional expression through speech, and heightened feelings of well-being with oneself and others, which reflect the entactogenic activity of the substance.

Acute pharmacological effects of 2C-B in humans: An observational study

2021| de la Torre, R., Farré, M., González, D., Papaseit, E., Pujadas, M., Pérez-Mañá, C., Torrens, M., Ventura, M.

This open-label observational study (n=16) assessed the acute subjective, physiological, and pharmacokinetic effects of 2C-B (10, 15, or 20 mg), and found that it produces a constellation of psychedelic-psychostimulant like effects. Mood changes were more prominent than perceptual changes, and the profile of physiological effects entailed a moderate increase of blood pressure and heart rate parameters that were lower than that of MDMA by comparison.

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine

2018| Barsuglia, J. P., Malcolm, B., Polanco, M.

This retrospective cohort study (n=50) investigated the efficacy of ibogaine (1.26 – 1.4g/70kg) to treat withdrawal symptoms amongst patients with opioid use disorder and found that ibogaine reduced effectively facilitated opioid detoxification, reduced cravings, and reduced withdrawal.

LSD treatment in Scandinavia: emphasizing indications and short-term treatment outcomes of 151 patients in Denmark

2017| Larsen, J. K.

This retrospective follow-up study (n=151) assessed the case material of 151 patients who applied for financial compensation for harms elicited by psychedelic treatments administered between 1959 to 1973 and re-evaluated in 1986. It found that one-third of the patients experienced a transient improvement in their mental state independent of the diagnosis, while the mental state of another third of the patients deteriorated with treatment.

Ascending-dose study of noribogaine in healthy volunteers: Pharmacokinetics, pharmacodynamics, safety, and tolerability

2014| Friedhoff, L., Glue, P., Hung, C. T., Hung, N., Lam, F., Lockhart, M.

This ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study (n=36) investigated the safety and pharmacokinetic profile of orally ingested noribogaine (3, 10, 30, or 60mg), and found that it was rapidly absorbed and slowly eliminated, and generally safe and well-tolerated in healthy male volunteers.

Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers: results of an experimental double-blind placebo-controlled study

1999| Gouzoulis-Mayfrank, E., Habermeyer, E., Hermle, L., Kovar, K., Kunert, H. J., Lindenblatt, H., Sass, H., Spitzer, M., Thelen, B.

This randomized, double-blind, placebo-controlled, between-subjects study (n=32) investigated the effects of MDE (140mg/70kg), psilocybin (14mg/70kg), and methamphetamine (14mg/70kg) on the mental state and the neuroendocrine and autonomic nervous system of healthy participants. The entactogen MDE took an intermediate position between the stimulant methamphetamine and the hallucinogen psilocybin and elicited highly characteristic emotional effects, that were qualitatively different from the effects of the other two drugs, which supports the hypothesis that entactogens constitute a distinct psychoactive substance class.

Migraine prevalence in visual snow with prior illicit drug use (Hallucinogen Persisting Perception Disorder) versus without

2021| Alderliefste, G., Ferrari, M. D., Onderwater, G. L. J., Terwindt, G. M., van Dongen, R. M.

This between-subjects cohort study (n=48) compared the prevalence of migraine in individuals with visual snow (continuously flickering dot hallucination) in a cohort diagnosed with Hallucinogen Persisting Perception Disorder (HPPD) versus visual snow cohort without prior use of illicit drugs. HPPD-related visual disturbances were primarily caused by ecstasy but weren't accompanied by migraines, whereas visual snow disturbances were accompanied by migraines in over half of the control cohort.

Investigation of the Structure−Activity Relationships of Psilocybin Analogues

2020| Anderson, E. I., Brandt, S. D., Chapman, S. J., Chatha, M., Halberstadt, A. L., Klein, A. K., Laskowski, L. J., McCorvy, J. D.

This animal study investigated the pharmacology and behavioral effects of psilocybin-analogs, with a substituted hydroxy or acetoxy group at the 4-position, and found they all consistently elicited psychedelic-like effects via the 5-HT2A receptor.

Discriminative Stimulus Effects of Substituted Tryptamines in Rats

2020| Carbonaro, T. M., Gatch, M. B., Hoch, A.

This animal study (n=64) evaluated the hallucinogen-like effects of eight novel substituted tryptamines in rats and characterized their potency and abuse liability according to their substituted side chains. All compounds fully substituted for the discriminative stimulus effects of 0.5 mg/kg DOM without any adverse effects, unlike other tryptamine analogs.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

2014| Brallier, J., Burdick, K. E., Chang, L. C., Charney, D. S., Foulkes, A., Iosifescu, D. V., Levitch, C. F., Mathew, S. J., Murrough, J. W., Perez, A. M.

This randomized, double-blind, active placebo-controlled study (n=62) investigated the neurocognitive and antidepressant effects of ketamine (35 mg/70kg) or midazolam (3.15mg/70kg) compared to the benzodiazepine anesthetic midazolam in patients with depression. Neurocognitive performance improved independently of treatment condition or change in depression severity due to learning, which indicates an absence of adverse effects of ketamine on neurocognitive functioning in contrast to electroconvulsive therapy which impacts memory.

Ketamine Use for Suicidal Ideation in the General Hospital: Case Report and Short Review

2018| Baup, E., Lefebvre, D., Lemogne, C., Limosin, F., Passeron, A., Rieutord, M., Seigneurie, A. S., Thauvin, I., Vulser, C., Vulser, H.

This case report (n=1) describes an anorexic patient who was treated with repeated dose ketamine (0.5mg/kg, 20mg) following a suicide attempt and persevering suicidal ideation (SI). Although the first dose had little effect, the second dose administered 2 weeks after led to a dramatic decrease in depression, hopelessness, and suicidal ideation.

Crisis Intervention Related to the Use of Psychoactive Substances in Recreational Settings – Evaluating the Kosmicare Project at Boom Festival

2014| Carvalho, J., Carvalho, M., de Sousa, M. P., Dias, P., Frango, P., Rodrigues, M., Rodrigues, T.

This observational field study (n=176) evaluated the efficacy of a natural setting-based crisis intervention program aimed at festival attendees who encountered challenging experiences while using psychoactive substances. While many of the care-seekers resolved their crises in response to onsite interventions, unresolved crises were more often related to outbursts of mental health episodes that were either brought on by psychoactive substance use or not.

Psychedelic pleasures: An affective understanding of the joys of tripping

2017| Bøhling, F.

This qualitative study (n=100) examined the pleasurable aspects of recreational psychedelics (LSD, psilocybin mushrooms) use reported on the Erowid trip database. The author argues that although pleasurable experiences are regarded as irrelevant within therapeutic contexts, it is a key reason why most people use psychedelics, to facilitate a mode of ‘purposeless play’ that transgresses rules, meanings, and boundaries of the normalized everyday.

First Time View on Human Metabolome Changes after a Single Intake of 3,4-Methylenedioxymethamphetamine in Healthy Placebo-Controlled Subjects

2017| Boxler, M. I., Kraemer, T., Liechti, M. E., Schmid, Y., Steuer, A. E.

This randomized, double-blind, placebo-controlled crossover study (n=15) investigated changes in endogenous plasma metabolites following a single intake of MDMA (125 mg) and found an overall increase in oxidative stress indicated by the metabolic ratio of methionine-sulfoxide over methionine.

Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

2017| Curry, D. W., Daoud, G. E., Howell, L. L., Tran, A. N., Young, M. B.

This vehicle-controlled, between-subjects, animal study (n=52) compared the two enantiomers R-MDMA of S-MDMA, and their racemic mixture (5.6 - 7.8 mg/kg) with respect to their prosocial therapeutic effects and adverse neurotoxicity, in mice. Due to a lower potency to release dopamine, R-MDMA exerted fewer adverse effects than SR/S-MDMA, but increased prosocial behavior to a similar magnitude.

Acute and subacute psychoactive effects of Kambô, the secretion of the Amazonian Giant Maki Frog (Phyllomedusa bicolor): retrospective reports

2020| Bermpohl, F., Hage, L. T., Majic, T., Reiche, S., Schmidt, T. T.

This retrospective survey study (n=22) investigated the (sub)acute effects of Kambô, the secretion of the Amazonian Giant Leaf Frog (Phyllomedusa bicolor), using the Altered States of Consciousness Rating Scale (5D/11D-ASC), the Phenomenology of Consciousness Inventory (PCI), the Mystical Experience Questionnaire (MEQ), the Challenging Experience Questionnaire (CEQ), and the Persisting Effects Questionnaire (PEQ). While persistent effects were described as pleasant and bared personal and spiritual significance, the acute effects exhibited no resemblance to psychedelic-type distortions in perception and thinking.

Psychological and cognitive effects of long-term peyote use among Native Americans

2005| Halpern, J. H., Hudson, J. I., Pope Jr, H. G., Sherwood, A. R., Yurgelun-Todd, D.

This correlational study (n=176) investigated the long-term residual psychological and cognitive effects of peyote use amongst native American Church members, compared between regular users (n=61), minimal users (n=79), and members with a history of alcohol dependence (n=36). Only members with prior alcohol dependence showed neuropsychological deficits, but there was no link between psychological or cognitive deficits linked to peyote use.

Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark

2016| Larsen, J. K.

This historic archive case study assessed the reports of 151 patients out of a 400 patient cohort who received treatment with LSD between 1960-73 (without psychotherapy) and who received financial compensation for LSD-inflicted harm in accordance with Danish law. The applicants reported an immediate deterioration of their condition and severe long-term effects.

Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers

2015| Garbe, K., Glue, P., Hung, C. T., Jakobi, H., Lenagh‐Glue, Z., Lyudin, A., Winter, H.

This open-label study (n=21) investigated the pharmacokinetics of a single dose of ibogaine (20mg) in response to inhibiting its metabolism via pretreatment with the antidepressant paroxetine in a placebo-controlled manner. Results indicate that the dose was safe and well-tolerated in all subjects, although paroxetine greatly increased the half-life of ibogaine to detectable levels at 72 hours post-infusion.

Pyretogenic effect of lysergic acid diethylamide

1985| Dille, J. M., Horita, A.

This early (1954) animal study (n=9) investigated the pyrogenic (fever-inducing) properties of LSD (50μg/kg), which produced a rise in body temperature of normal rabbits, cats, and dogs. This rise in temperature which lasted up to 9 hours is antagonized by the administration of sodium pentobarbital but not by antipyrine or adrenergic blocking agents.

Ayahuasca Beyond the Amazon: the Benefits and Risks of a Spreading Tradition

2010| Trichter, S.

This commentary (2010) examines how to integrate these spiritual healing rituals into contemporary Western concepts of psychological health and ethical conduct, and calls for an enforcement mechanism of accountability for monitoring the reputations of different ritual leaders to protect the community from predatory practices.

Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes

2020| Eloff, J. N., Nkadimeng, S. M., Steinmann, C. M. L.

This cell-based study showed that extracts of magic mushrooms (containing psilocybin) didn't induce cell injury and possibly could even have a protective effect. This study provides some evidence for their safety in use for those with cardiovascular disease conditions.

Clinical Studies of Lysergic Acid Diethylamide

1986| Anderson, E. W., Rawnsley, K.

This early clinical study (1954) investigated the dose-range effects of LSD (10-600μg) administered to patients and clinical staff (n=23) across 54 different research sessions and found that its effects entail highly potent perceptual alterations that are sensitive to the environment and variable across different individuals. They also note the emergence of phenomena such as enhanced sexual arousal and ego-dissolution and highlight its utility at illuminating basic personality structures but remain inconclusive as to whether it has therapeutic benefit in response to continued administration.

Effects of mescaline and lysergic acid (d-LSD-25)

1987| Cattell, J. P., Hoch, P. H., Pennes, H. H.

This early clinical study (1952) investigated the effects of mescaline (0.4 - 0.6g) and LSD (10-120μg) in patients with schizophrenia (n=59 & 21) and found that it aggravated their symptoms and made their psychic integration even more disorganized compared to healthy individuals.

Mental changes experimentally produced by d-lysergic acid diethylamide tartrate

1988| Deshon, H. J., Rinkel. M., Solomon, H. C.

This early open-label investigation (1952) reports observations of mental changes in normal adults (n=15) produced by LSD (70μg/70kg) across 17 repeated experiments. Alterations were observed in the areas of thinking and speech, emotion, mood and affect, sensory and time perception, behavior, morbid ideas, and sensory experiences, and neurological signs, which were taken to reflect a schizophrenic-like state.

Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

2020| Barbui, C., Gastaldon, C., Kane, J. M., Raschi, E., Schoretsanitis, G.

This study (n=962) investigated adverse events after administration of nasal esketamine (Spravato) for treatment-resistant depression (TRD). The study found increased suicidal ideation (versus antidepressants) but not suicide attempts or completions.

Ayahuasca and Spiritual Crisis: Liminality as Space for Personal Growth

2008| Lewis, S. E.

This anthropological analysis of phenomenological case reports examines how ayahuasca ceremonies occasion liminal spaces, wherein participants undergo a period of transformation characterized by the process of stripping away one's prior beliefs, identity, and social status, which can also lead to the emergence of spiritual crises. On the basis of a case study within the context of ayahuasca tourism, the authors highlight the need for clinical support to integrate challenging experiences through the exploration of their spiritual and psychological meaning.

Cardiac arrest after ibogaine intoxication

2018| Deyell, M. W., Steinberg, C.

This case study (n=1) documents the cardiotoxicity of the highest survived dose of ibogaine (4.55‐4.9g/70kg) ingested by a 61-year-old man in the context of seeking alternative treatment to overcome a long-standing opioid dependency related to chronic pain. Ibogaine increased heart rate and prolonged the time to recharge heart muscles between beats, and it took 7 days for the patient's heart rhythm to normalize due to the long plasma half-life of the substance. Ibogaine intoxication is therefore a potentially life-threatening scenario due to the cardiotoxic risk of ventricular arrhythmia and requires prolonged cardiac monitoring within a critical care unit.

Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients

2016| Cape, G., Crockett, R. S., Darpo, B., Devane, J., Friedhoff, L., Glue, P., Harland, S., Howes, J. F., Hung, N., Hung, C. T., Lam, F., Lockhart, M., Tunnicliff, D., Weis, H., Zhou, M.

This randomized, double-blind, placebo-controlled study (n=27) evaluated the safety, tolerability, and pharmacokinetics of noribogaine (60, 120, or 180mg/70kg) administered to opioid-dependent patients withdrawing from methadone. Noribogaine was well tolerated across the entire dose range and a statistically nonsignificant trend toward decreased total score in opioid withdrawal ratings. The ascending noribogaine dose was correlated to prolongation of heart contractions (longer QT intervals) to a degree that would be concerning in a clinical setting, which indicates the need for ECG monitoring to enable dose adjustment or discontinuation to mitigate cardiovascular risk in future studies.

Treatment of acute opioid withdrawal with ibogaine

2009| Alper, K. R., Bastiaans, J., Frenken, G. M. N., Lotsof, H. S., Luciano, D. J.

This series of open-label case studies (n=33) investigated the efficacy of ibogaine (0.42 to 2,03g/70kg) to treat acute withdrawal in patients with opioid dependence. Based on the diagnostic observations of two principal investigators, seventy-six percent of the patients in this series were reportedly free of opioid withdrawal signs and symptoms at 24 hours and did not seek drugs over the period of observation of 72 hours. Observations warrant future investigations to assess the efficacy of ibogaine to treat opioid withdrawal more reliably in controlled clinical studies.

Effects of low dose ibogaine on subjective mood state and psychological performance

2016| Forsyth, B., Garbe, K., Glue, P., Jakobi, H., Jowett, T., Machado, L., Winter, H.

This open-label study investigated the effects of low-dose ibogaine 20mg on subjective mood states and a range of cognitive functions. There was no effect on subjective mood states or cognitive performance related to basic visuomotor function, inhibitory function, memory function, task switching, or selective attention. Future studies would require a wider dose range, placebo-controls, and larger sample sizes to determine whether ibogaine affects these faculties.

Human pharmacology of mephedrone in comparison with MDMA

2016| de la Torre, R., Farré, M., Fonseca, F., Mateus, J., Olesti, E., Papaseit, E., Pujadas, M., Pérez-Mañá, C., Torrens, M.

This randomized, double-blind, crossover, placebo-controlled study (n=12) compared the effects of MDMA (100mg/70kg) and mephedrone (200mg/70kg) with respect to the physiological, subjective, psychomotor, and pharmacokinetic parameters amongst healthy male volunteers. Mephedrone induced stimulant-like effects, which included enhanced euphoria, well-being, feelings of pleasure, and mild changes in perceptions, as well as sympathomimetic effects (hypertension, tachycardia, and mydriasis), but with a faster, less intense, and shorter duration compared to MDMA.

Acute effects of lysergic acid diethylamide on circulating steroid levels in healthy subjects

2016| Dolder, P. C., Kratschmar, D. V., Liechti, M. E., Odermatt, A., Rentsch, K. M., Schmid, Y., Strajhar, P.

This randomized, double‐blind, placebo‐controlled, cross‐over study (n=16) investigated the effects of LSD (200μg) on the plasma concentration-time profiles of steroid levels. LSD induced significant effects on plasma glucocorticoids, including cortisol and particularly corticosterone, which was also closely related to the subjective effects of LSD. The glucocorticoid response to LSD showed no acute pharmacological tolerance, in contrast to the glucocorticoid response to MDMA.

Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects

2017| Dolder, P. C., Hammann, F., Kraemer, T., Liechti, M. E., Rentsch, K. M., Schmid, Y., Steuer, A. E.

This analysis of data from two double-blind, placebo-controlled studies (n=40) on the pharmacokinetics of LSD (100 and 200µg) found dose-proportional effects. The effects lasted on average 8.2 and 11.6 hours, there was a strong correlation between the blood-plasma level of LSD and subjective effects, but this was only found within-subjects (over time), not between subjects.

Pharmacology of MDMA in humans

2006| Cami, J., de la Torre, R., Farré, M., Lopez, C. H., Mas, M., Menoyo, E., Ortuno, J., Pizarro, N., Roset, P. N., Segura, J.

This paper (2006, n=27) details the physiological effects of MDMA (50-150mg) in humans. There was a slight impairment of psychomotor (e.g. hand eye coordination) performance, higher plasma cortisol and prolactin (both hormones) levels, and (after a decrease in the first hour) an increase in oral/body temperature.

Acute Psychological Adverse Reactions in First-Time Ritual Ayahuasca Users

2021| Alcázar, M. A., Bouso, J. C., Dos Santos, R. G., Gómez-Sousa, M., Hallak, J. E., Jiménez-Garrido, D. F., Ona, G.

This case studies analysis (n=7 of 40 in an earlier study) of data from first-time ayahuasca users still found positive effects after (or even because of) challenging experiences on mental health six months later. An inappropriate setting/context contributed to the challenging experiences.

Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice

2021| Bannerman, D., Blanco-Duque, C., Breant, B., Goodwin, G. M., Sharp, T., Thomas, C. W., Vyazovskiy, V. V.

This within-subjects animal study (n=8) investigated the effects of psilocin (2 mg/kg; 56mg/28g mouse weight) on the normal sleep-wake cycle and in combination with sleep deprivation. Results indicated that psilocin acutely disrupts sleep, suppressing the maintenance of both NREM and REM sleep, resulting in a pattern of fragmented sleep attempts and frequent brief awakenings which lasted up to 3 hours. No enduring effects of psilocin were observed on sleep-wake quantities, sleep duration, or the recovery from sleep deprivation.

LSD and ketanserin and their impact on the human autonomic nervous system

2021| Olbrich, S., Preller, K. H., Vollenweider, F. X.

This placebo-controlled randomized, crossover study (n=17) investigated the impact of LSD (100 μg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg) on the autonomic nervous system within healthy subjects. LSD predominantly increased the sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely. The magnitude of subjective experiences during the interventions was positively correlated with the sympathetic activity and negatively correlated with the parasympathetic activity, independent of the intervention.

The psychological and physiological effects of MDMA on normal volunteers

1986| Downing, J.

This early study (1986) of the effects of MDMA suggests that MDMA exerts predictable transient psychological effects and shows no major toxicity. However, the author cautiously concludes that the evidence is insufficient to make definitive judgments.

Using the Theory of Planned Behavior to predict implementation of harm reduction strategies among MDMA/ecstasy users

2016| Davis, A. K., Rosenberg, H.

This study (n = 100) used a number of personality variables to predict intention and implementation of harm reduction strategies in MDMA use. The authors found that different variables predicted different strategies.

Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice

2021| Cassidy, K., Gorman, I., Molinar, A., Nielson, E. M., Sabbagh, J.

This paper (2021) introduces the Psychedelic Harm Reduction and Integration approach to working with patients in regards to psychedelics.

Associations between lifetime classic psychedelic use and markers of physical health

2021| Hendricks, P. S., Sexton, J. D., Simonsson, O.

This survey study (2021, n=171,766) aimed to investigate the association between physical health and psychedelic use and found that lifetime psychedelic use was associated with positive physical health markers such as a lower likelihood of obesity. Of course, causality cannot be inferred from these data.

Psilocybin – Summary of knowledge and new perspectives

2013| Horacek, J., Páleníček, T., Tylš, F.

This review (2014) provides a history of psilocybin and a summary of its pharmacology within humans and animals, its psychedelic effects as measured via neuroimaging and psychometric assessments, whilst highlighting its potential for both therapy and abuse.

Dose–response relationships of psilocybin-induced subjective experiences in humans

2021| Hirschfeld, T., Schmidt, T. T.

This meta-analysis (n=349) found that the dose of psilocybin (3-27mg/70kg) correlated positively with positive changes in perception (e.g. ego dissolution). Negative experiences were barely modulated by dose.

Ayahuasca: pharmacology, neuroscience and therapeutic potential

2016| Álvarez, E., de la Fuente Revenga, M., Domínguez-Clavé, E., Elices, M., Feilding, A., Friedlander, P., Pascual, J. C., Riba, J., Soler, J.

This review (2016) examines the pharmacology and neuroscience of ayahuasca, and preliminary findings which indicate the psychological mechanisms associated with its therapeutic benefits are similar to those of mindfulness-based therapy. Ayahuasca appears to enhance self-acceptance and decentering, which converges on evidence from neuroimaging studies that show activation in areas associated with emotional processing and memory formation, thereby enabling individuals to review emotional events with increased vividness and a heightened sense of “reality”. This suggests potential to treat trauma-related conditions and other disorders like borderline personality disorder.

A systematic review of the effects of novel psychoactive substances ‘legal highs’ on people with severe mental illness

2016| Bressington, D., Gray, R., Hughes, E., Ivanecka, A.

This systematic review (2016) examined the available literature on novel psychoactive substances with regard to their effects on people with severe mental illness. Analyses yielded mixed results, given that the people used various different types of substances, or even manifested different types of reactions in response to the same substance in one case with four patients who all had schizophrenia. The review highlights a lack of sufficient empiric evidence on the interaction between psychosis, brain dysfunction, prescribed medication, and novel psychoactive substances to establish adverse effects that are specific to mental illnesses.

A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

2020| Albott, C. S., Erbes, C., Lim, K. O., Shiroma, P. R., Thuras, P., Tye, S., Wels, J.

This randomized active placebo-controlled between-subjects study (n=54) compared the antidepressant efficacy of administering six consecutive ketamine infusions (35 mg/70kg) versus consecutive five midazolam infusions (3.15 mg/70kg) followed by a single ketamine infusion, over twelve days. While acute repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions, there was no significant difference in depression scores after the control grouped had received a single ketamine infusion.

Safety of ibogaine administration in detoxification of opioid dependent individuals: a descriptive open-label observational study

2021| Belgers, M., Donders, R., Knuijver, T., Kramers, C., Schellekens, A., van Oosteren, T., Verkes, R. J.

This open-label observational study (n=14) investigated the safety profile of ibogaine (700mg/70kg) for patients with opioid use disorder who were undergoing acute opioid withdrawal. Although patients experienced mild withdrawal symptoms and transient well-tolerated psychomimetic effects, they exhibited abnormal patterns in heart rhythm that constituted an adverse level of cardiovascular risk. This study indicates that even a low-dose administration of ibogaine requires strict cardiac monitoring, and should be restricted to well-controlled settings.

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports

2021| Barrett, F. S., Erowid, E., Erowid, F., Griffiths, R. R., Gukasyan, N., Nayak, S.

This analysis of online reports (n=96) found that the use of psychedelics in combination with lithium led to seizures (47%), bad trips (64%), and emergency medical treatment (39%). The authors express the caution people should take when self-medicating/combining psychedelics with antidepressants (with lithium being commonly used for bipolar disorder).

Mania following use of ibogaine: A case series

2015| Koek, R. J., Kopelowicz, A., Marta, C. J., Ryan, W. C.

This case report (n=3) examines patients who developed manic symptoms and diagnosed with Bipolar-I disorder in response to ibogaine use. None of the patients had a prior diagnosis or family history of bipolar disorder, but all of them were poly-drug users or recovering from addiction. Manic symptoms which often included grand delusions that lasted up to two weeks after using ibogaine.

Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches

2021| Barrett, F. S., Carbonaro, T. M., Garcia-Romeu, A., Griffiths, R. R., Johnson, M. W.

This analysis of psilocybin dosages given in 10 previous studies (n=288) found no effect of weight, nor gender, on the effects (acute or long-term) of the dosage (20-30mg) of psilocybin used. The authors recommend a fixed dosing approach going forward to simplify dosing regimes.

A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamine

2020| Acosta, P., Palamar, J. J.

This qualitative interview study (n=39) found that within this group about 2/3rds had used 2C drugs (38,5% 2C-B) and compared 2C-B to LSD and MDMA effects, it also compared favorably to other 2C drugs. 4-Aco-DMT was described as mimicking psilocybin.

Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report

2015| Smith, J. M., Szmulewicz, A. G., Valerio, M. P.

This case report describes the clinical profile of a man from Argentina with a family history of bipolar disorder who participated in a four-day Ayahuasca ceremony that led to the eruption of a hypomanic episode two days after, consisting of mystical and paranoid delusional ideas, auditory hallucinations, racing thoughts, disorganized behavior, elevated energy, and manic euphoria. Given that the remission of psychotic symptoms was immediately followed by an onset of depressive symptoms, the authors theorize that antidepressant effects of harmine may have occasioned the manic shift of his bipolar disorder.

The Potential Dangers of Using MDMA for Psychotherapy

2014| Parrott, A. C.

This review (2014) examines both the negative and positive aspects of using MDMA for psychotherapy, with specific regard to its neurohormonal profile, the effects of serotonergic depletion, and neurotoxicity of repeated usage. The most critical issues are related to the release of difficult feelings and memories and the lack of control thereof due to heightened environmental sensitivity, as well as the risk that negative mood states predominating the phase of neurochemical recovery amongst certain individuals.

Self-Experimentations with Psychedelics Among Mental Health Professionals: LSD in the Former Czechoslovakia

2014| Csémy, L., Winkler, P.

This qualitative study (n=22) conducted a structured interview assessing the attitudes towards psychedelic self-experimentation amongst mental health professionals who took LSD (25-1000μg/70kg) legally between the years 1952–1974 in former Czechoslovakia. Most of the respondents reported positive effects in the domain of self-awareness and/or in their didactic ability to comprehend the world of mentally ill patients. None of the respondents reported any long-term negative effect of their self-experimentation.

Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers

2012| Griffiths, R. R., Johnson, M. W., Sewell, R. A.

This study (n=18) found that psilocybin frequently caused mild to moderate delayed and transient headaches in healthy volunteers in a dose-dependent manner.

Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects

2012| Griffiths, R. R., Johnson, M. W., MacLean, K. A., Prisinzano, T. E., Reissig, C. J.

This study (n=8) assessed the subjective effects of salvinorin A (0.026-1.470mg/70kg) and found that they only partially overlap with classic hallucinogens.

Experienced drug users assess the relative harms and benefits of drugs: a web-based survey

2013| Carhart-Harris, R. L., Nutt, D. J.

This survey study (n=93) investigated the subjective harms and benefits of eleven drugs as reported by experienced drug users. Alcohol and tobacco were ranked as the most harmful, MDMA, LSD, and psilocybin as some of the least harmful drugs.

Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs

2011| Gruber, S., Halpern, J. H., Hudson, J. I., Kozin, D., Pope Jr, H. G., Sherwood, A. R.

This field study (n=111) investigated the potential cognitive effects of ecstasy use, improving on previous studies by excluding the use of alcohol or other recreational drugs. The authors found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic-self-regulation, possibly reflecting increased impulsivity. It was unclear if this was a result of ecstasy use or predisposition in ecstasy users.

In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin 2A Receptor Binding in MDMA and Hallucinogen Users

2011| Christoffersen, M., Erritzoe, D., Frokjaer, V. G., Holst, K. K., Jernigan, T. L., Johansen, S. S., Knudsen, G. M., Madsen, M. K., Ramsøy, T., Rasmussen, P. M., Svarer, C.

This positron emission tomography (PET) study (n=45) assessed the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin 2A receptor binding. The authors found evidence that MDMA, but not hallucinogen, use is associated with changes in the cerebral presynaptic serotonergic transmitter system.

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability

2010| Carhart-Harris, R. L., Feilding, A., Nutt, D. J., Rich, A. S., Sessa, B., Tyacke, R. J., Williams, T. M.

This study (n=9) tested the tolerability of psilocybin in an fMRI environment, and found high levels of tolerability. It found that full-dose psychedelic studies with fMRI equipment are viable.

Does getting high hurt? Characterization of cases of LSD and psilocybin-containing mushroom exposures to national poison centers between 2000 and 2016

2018| Klein-Schwartz, W., Leonard, J. B.

This study (2018) analyzed reports from United States poison centers of individuals presenting with LSD or psilocybin consumption and found that serious adverse effects are rare but possible.

Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report

2020| Hassan, A. N., Le Foll, B., Rubin-Kahana, D. S.

This study (2020) presents a case report of a man who developed PTSD after an experience with LSD and DMT.

Cannabinoids is a “No-Go” While a Cancer Patient is on Immunotherapy; but is It Safe to Use Psychedelics During Cancer Immunotherapy?

2021| Brami, M., Lamensdorf, I., Moran, O., Nachliely, M., Romach, E. A.

This in vivo/vitro (cells and mice) study finds that psilocybin and LSD may promote cancer cell growth and lessen the positive effects of immune checkpoint inhibitors (ICIs).

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

2006| Kuypers, K. P. C., Ramaekers, J. G.

This double-blind, placebo-controlled, three-way crossover study (n=18) compared the effects of MDMA (75mg) and Ritalin (20mg) with regard to spatial memory performance. Results indicated that a single dose of MDMA caused subjects to perform worse on a simple spatial memory task only during the acute intoxication, and it did not affect their ability to detect rapid contextual changes in visuospatial information that is relevant for traffic safety.

User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study

2010| Carhart-Harris, R. L., Nutt, D. J.

This survey study (n=626) investigated user perceptions of the benefits and harms of using LSD, psilocybin, MDMA, cannabis, ketamine, and alcohol. Overall, LSD and psilocybin were regarded as having the most positive impact on wellbeing, and the least harms in terms of physical and mental health.

Ayahuasca in adolescence: a neuropsychological assessment

2011| Alonso, J. N., Bertolucci, P. H., da Silveira, D. X., de Rios, M. D., Doering-Silveira, E., Grob, C. S., Lopez, E., Shirakawa, I., Tacla, C.

This study (n=80) evaluated the neuropsychology of adolescents who used ayahuasca in a religious context, compared to a matched control group of adolescents who did not use ayahuasca. There was no significant difference between the two groups on neuropsychological measures.

Ayahuasca in adolescence: Qualitative results

2011| Alonso, J. N., da Silveira, D. X., de Rios, M. D., Doering-Silveira, E., Grob, C. S., Lopez, E.

This retrospective survey (n=54) investigated the impact of religious Ayahuasca use on adolescents. The qualitative data shows that the teens using Ayahuasca religiously appeared not to differ from their non-ayahuasca-using peers. They were reported to be healthy, thoughtful, considerate, and bonded to their families and religious peers.

Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans

1996| Berg, L. M., Qualls, C .R., Strassman, R. J.

This randomized, double-blind study (n=13) investigated tolerance of repeated doses of 21mg/70kg DMT fumarate in hallucinogen-experienced users. Tolerance to “psychedelic” subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores.

Ayahuasca in adolescence: a preliminary psychiatric assessment

2011| Alonso, J. N., da Silveira, D. X., de Rios, M. D., Doering-Silveira, E., Grob, C. S., Lopez, E., Tacla, C.

This study (n=80) evaluated the psychiatric health of adolescents who used ayahuasca in a religious context, compared to a matched control group of adolescents who did not use ayahuasca. The authors found that, compared to controls, considerable lower frequencies of positive scoring for anxiety, body dysmorphism, and attentional problems were detected among ayahuasca-using adolescents despite overall similar psychopathological profiles.

Daytime ayahuasca administration modulates REM and slow-wave sleep in healthy volunteers

2007| Barbanoj, M. J., Clos, S., Giménez, S., Grasa, E., Riba, J., Romero, S.

This randomized, double-blind, active placebo-controlled, cross-over study (n=22) investigated the effects of daytime ayahuasca (DMT 70mg/70kg) consumption on sleep parameters, compared with active placebo (20mg d-amphetamine). Results showed that daytime serotonergic psychedelic drug administration leads to measurable changes in PSG and sleep power spectrum and suggest an interaction between these drugs and brain circuits modulating REM- and SWS- sleep.

Dose-response study of N,N-dimethyltryptamine in humans: subjective effects and preliminary results of a new rating scale

1994| Kellner, R., Qualls, C .R., Strassman, R. J., Uhlenhuth, E. H.

This randomized, double-blind, placebo-controlled study (n=12) investigated the subjective effects of graded doses of DMT in hallucinogen-experienced users. Effects began almost immediately after DMT administration, peaking at 90 to 120 seconds, and were almost completely resolved by 30 minutes. Hallucinogenic effects were seen after 14 and 21 mg/70kg of DMT, while lower doses, 70 and 35 mg/70kg, were primarily affective and somaesthetic (body + sensory perception).

Acute effects of lysergic acid diethylamide in healthy subjects

2014| Borgwardt, S., Brenneisen, R., Enzler, F., Gasser, P., Grouzmann, E., Liechti, M. E., Mueller, F., Preller, K. H., Schmid, Y., Vollenweider, F. X.

This double-blind, placebo-controlled study (n=16) described the effects of LSD (200 μg) in healthy subjects. It inhibited prepulse inhibition (startle reflex), increased blood pressure, elicited a positive mood, and had no adverse effect after 72 hours.

Severe Neurological Sequelae after a Recreational Dose of LSD

2020| Aakerøy, R., Ader, T., Andreassen, T. N., Brede, W. R., Frost, J., Krabseth, H. M., Michelsen, L. S., Slettom, G., Slørdal, L., Steihaug, O. M., Stølen, S. B.

This case report highlights that LSD can be dangerous, leading to seizure and brain damage, but this should be read in the context of millions of dosages (of LSD) being taken each year.

Compared

This section compares the research with psychedelics to other therapies, medicines, or treatments.

Measured

This section highlights the various measures used and their use in research.

Researchers

Who are the top researches in this area, the ones who have done the groundbreaking research.

Gaps

What do we not know at this time? Where are the gaps in our knowledge and are we closing it?

Companies

The companies that are actively engaged in researching this topic or (planning to) provide therapy focussed on this topic.

Outside Academia

This section highlights everything done outside of academia, from popular press to books and non academic research.