Psychedelic Therapy Research Articles

Psychedelic Therapy as Form of Life

In the historical context of a crisis in biological psychiatry, psychedelic drugs paired with psychotherapy are globally re-emerging in research clinics as a potential transdiagnostic therapy for treating mood disorders, addictions, and other forms of psychological distress. The treatments are poised to soon shift from clinical trials to widespread service delivery in places like Australia, North America, and Europe, which has prompted ethical questions by social scientists and bioethicists. Taking a broader view, we argue that the ethics of psychedelic therapy concerns not simply how psychotherapies are different when paired with psychedelic drugs, but how psychedelic therapies shape and are shaped by different values, norms, and metaphysical commitments. Drawing from the published literature and interviews with seven psychedelic therapists working in clinical trials in the United States, Germany, Switzerland, and Australia, this article opens the black box of the treatments to consider the values and informal debates currently animating the therapies. Considering questions of patient autonomy, mechanisms of therapeutic action, and which therapies are best suited to pair with psychedelic substances, we examine the ethics of psychedelic therapy as an emergent form of life. To bring this form of life out in fuller relief, we conclude by comparing and contrasting it with ayahuasca use in Amazonian shamanism.

Scanning the new frontier of mental health: psychedelic brain imaging

The use of psychoactive substances for ritual, spiritual and medicinal purposes stretches back into prehistory and has been a common feature of many diverse cultures and societies globally. Psychedelics, with their unique ability to amplify feelings of connectedness and openness, may have also served as tools for promoting tribal cohesion and trust in ancient cultures. Psychedelic is a broad term derived from the Greek words ‘psyche’, meaning soul or mind, and ‘deloun’, which means to manifest. Classic psychedelics, such as psilocybin (the active ingredient in magic mushrooms), act directly on the serotonin 5-HT2A receptor, while atypical psychedelics, such as MDMA and ketamine, have different pharmacological modes of action and tend to have less of a hallucinogenic effect. They all produce (as the origin of their name suggests) a profound shift in consciousness, generally positive emotional states and feelings of connectedness and openness. Lysergic acid diethylamide (LSD) is in many ways the prototypical psychedelic and began the first wave of psychedelic research in western medicine after it was first synthesized in the early 1940s. By the 1960s, thousands of patients had received LSD therapy in the USA, the UK, Czech Republic and elsewhere for depression, anxiety, addiction and a number of other disorders. This period concurrently saw the development of other key psychiatric drugs such as monoamine oxidase inhibitors as antidepressants and dopamine antagonist drugs as antipsychotics. This revolution in psychiatric treatment ushered in a wave of research and entirely new perspectives on the biological mechanisms underpinning psychiatric disorders.

Ukraine MH professionals offered psychedelic therapy training

In response to the psychological trauma inflicted by the ongoing conflict in Ukraine, Fluence, a leader in comprehensive, evidence‐based training in psychedelic therapy announced last week a collaboration with the Ukrainian Psychedelic Research Association (UPRA) and the U.S. nonprofit Health Ukraine Trauma (HUT), to provide free training in psychedelic therapy to Ukrainian psychologists and doctors.

Psychiatric risks for worsened mental health after psychedelic use.

Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. A "bottom margin analysis" approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. We find that 16% of the cohort falls into the "negative responder" subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality disorder subsample (b = 1.425, p < 0.05). We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.

UK medical students’ self-reported knowledge and harm assessment of psychedelics and their application in clinical research: a cross-sectional study

ObjectiveTo capture UK medical students’ self-reported knowledge and harm assessment of psychedelics and to explore the factors associated with support for changing the legal status of psychedelics to facilitate further...

Psychedelic Therapy: A Primer for Primary Care Clinicians-The Strengths, Weaknesses, Opportunities, and Threats of Psychedelic Therapeutics.

The reviews in this special edition have presented a primer on the state of the literature for 7 different psychedelic compounds and their plausible roles in medicine. In a common format underscoring strengths, weakness, opportunities, and threats (SWOT), this article addresses how psychedelic compounds fit into the broader health care landscape for indicated conditions. Historically, psychiatric pathologies have been treated with small-molecule compounds that have limited effect sizes and carry a variety of adverse effect profiles. Psychedelic medicines offer the opportunity to provide more potent and rapidly acting treatments. It is crucial to note that this is an emerging field of medicine, and only one of these compounds (esketamine) is currently Food and Drug Administration-approved for depression. The other compounds discussed are investigational, and this discussion is both imaginative and prospective in nature.

Psychedelic Therapy: A Primer for Primary Care Clinicians-3,4-Methylenedioxy-methamphetamine (MDMA).

After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names "molly" and "ecstasy," has emerged as a powerful treatment for post-traumatic stress disorder (PTSD). There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1-2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings. Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7-0.91, up to 2-3 times higher than the effect sizes of existing antidepressant treatments. 67%-71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions. Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy. Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.

Psychedelic Therapy: A Primer for Primary Care Clinicians-N,N-Dimethyltryptamine and Ayahuasca.

N,N-dimethyltryptamine (DMT) is a naturally occurring serotonergic psychedelic found in natural plants around the globe. As the main psychoactive component in ayahuasca, which also contains monoamine oxidase inhibitors, DMT has been consumed as plant-based brew by indigenous peoples for centuries. Further research is required to delineate the therapeutic utility of DMT. Although previous research has shown that DMT is synthesized endogenously, it may not be produced at physiologically relevant concentrations. Additionally, the phenomenological similarities between the DMT-induced state and near-death experiences led to the popular hypothesis that endogenous DMT is released during the dying process. However, this hypothesis continues to be debated. Generally, DMT and ayahuasca seem to be physiologically and psychiatrically safe, although ayahuasca is known to cause transient vomiting. A double-blind, randomized controlled trial showed that, within 1 week, ayahuasca causes remission in 36% of patients with treatment-resistant depression. According to top-line results from a recent phase IIa trial, 57% of patients with major depressive disorder experienced remission 12 weeks after receiving a single intravenous dose of DMT. There has only been a single published double-blind randomized controlled trial on ayahuasca and 2 on DMT. All clinical trials have had small sample sizes (≤34 participants). DMT requires further research to understand its therapeutic and clinical potential as a psychedelic. Preliminary evidence indicates that ayahuasca and DMT may be more effective than existing antidepressants for treating major depressive disorder and treatment-resistant depression.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

Invited Commentary on Psychedelic Therapy: A Primer for Primary Care Clinicians.

Invited Commentary on Psychedelic Therapy: A Primer for Primary Care Clinicians.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Historical Perspective and Overview.

Psychedelic drugs have recently emerged as plausibly effective pharmacological agents for the management of depression, anxiety, and other neuropsychiatric conditions, including those that are treatment-resistent. The latter half of the 20th century marked a revolution in the treatment of mental illnesses, exemplified by the introduction of selective serotonin reuptake inhibitors and other pharmacological agents. Nevertheless, mental illness remains a major public health crisis, affecting nearly one billion individuals worldwide. Because of the decades-long status of several psychedelics as Schedule I drugs, there have not been very many large, double-blind, randomized controlled trials of psychedelics. Owing to small sample sizes, there may be rare yet serious adverse events that have not been reported in the clinical trials thus far. Esketamine, a dissociative hallucinogen drug, was approved for the management of major depressive disorder by the Food and Drug Administration in 2019. As of January 2024, two Phase III trials of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug that inhibits the serotonin transporter, have been completed; the results indicate that MDMA is superior to existing pharmacological treatments for post-traumatic stress disorder. A phase III trial of psilocybin, a naturally occurring serotonin receptor partial agonist, is currently underway. The following series details the current state of research in psychedelic therapeutics, including lysergic acid diethylamide (LSD), N-N-dimethyltryptamine (DMT) and ayahuasca, psilocybin, ibogaine, MDMA, and ketamine. While initial clinical trials of psychedelics for depression were very promising, trials of psilocybin with larger sample sizes (100+ participants) suggest that its remission rate is 25%-29%. This is about the same as the remission rate of antidepressants, which is roughly 30% according to the landmark STAR*D trial. Psychedelic drugs and structural derivatives offer a great deal of promise for the management of a wide range of psychiatric morbidities. It is imperative that clinicians become familiar with these novel agents and learn how to integrate psychedelic therapy with the rest of their care through open communication and referral.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Lysergic Acid Diethylamide (LSD).

Lysergic acid diethylamide (LSD) is a hallucinogenic agent. In the mid-20th century, it was used to augment psychoanalysis and to treat alcohol use disorder. However, LSD was banned in 1970 in part because of concerns that it could bring about or exacerbate mental illness. Its therapeutic potential remains incompletely understood. While uncontrolled recreational use of LSD can, in rare instances, lead to long-term psychosis, adverse events in clinical trials of LSD, such as anxiety, headache, and nausea, have almost always been mild and transient. Serious adverse events, such as intense panic, suicidal ideation, and psychosis, were reported in either none or very few of the participants. However, patient selection criteria, optimal dosing strategy, and appropriate clinical follow-up guidelines remain to be established. Preliminary data suggest that LSD may be effective for the management of alcohol use disorder, anxiety, and depression. In trials of LSD for treating anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrate durable relief at 1 year post-treatment. Top-line data from a large-scale phase IIb trial (n = 198) indicate that 50% of participants experience remission from generalized anxiety disorder after a single 100 μg dose of LSD. According to a meta-analysis of RCTs on LSD from the mid-20th century, single-dose regimens of LSD significantly improve alcohol use disorder (P < 0.0003) with an odds ratio (OR) of 1.96. Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. Further studies with large sample sizes are needed to explore potential clinical applications. Preliminary data suggest that LSD may be one of the most potent treatments for anxiety in patients both with and without a life-threatening illness. LSD may also be beneficial for treating depression and substance use disorders.

Increases in Aesthetic Experience Following Ayahuasca Use: A Prospective, Naturalistic Study

Psychedelic drugs are currently being investigated for their potential to facilitate a variety of long-lasting psychological changes. One area that has yet to be systematically investigated in psychedelic research, however, regards changes in aesthetic experience (i.e., one’s attitudes, perceptions, and expression of art). This is surprising given the wealth of anecdotes directly noting increased appreciation of aesthetic experiences after psychedelic use and that psychedelics have facilitated their own distinctive aesthetic (i.e., “psychedelic art”). To address this gap in the literature, participants in the current study ( N = 54) completed a validated and multifaceted measure of aesthetic experience 1-week before, 1-week after, and 1-month after attending an ayahuasca retreat. We found that compared with baseline, participants exhibited increased levels of aesthetic experience at both the 1-week and 1-month follow-ups. Contrary to our hypotheses, measures of acute drug effects (e.g., mystical-type experiences, awe, and ego dissolution) did not predict changes in aesthetic experience. Although the study was limited by an open-label design, the results support anecdotal reports noting changes in aesthetic experience after psychedelic use. Further research is needed to address limitations related to the study design as well as to identify predictors and mechanisms of changes in aesthetic experience following psychedelic use.

Psychedelic Research as a Career Path: A Roundtable Discussion with Early Career Researchers in the Field

Psychedelic Research as a Career Path: A Roundtable Discussion with Early Career Researchers in the Field

Aggressive behaviours associated with MDMA and psychedelics: a narrative review.

Monoamine neurotransmitters play a role in aggression, especially when altered by illicit substances. However, some literature suggests that not all illicit substances may lead to aggression, notably psychedelics. This narrative review investigates the associations between serotonergic psychedelics and MDMA on aggressive behaviour. PubMed and PsycINFO were searched for original, peer-reviewed articles evaluating the effects of serotonergic psychedelics and 3,4-methyl enedioxy methamphetamine (MDMA) on violent and aggressive behaviour using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After removing duplicates, a total of 555 articles were screened, with 16 meeting the inclusion criteria. One additional article was obtained through reference screening bringing the total to 17 articles. Of these 17 articles, 14 studies focused on MDMA and three on serotonergic psychedelics. Findings were mixed, with some results demonstrating increased aggression following psychedelics and others suggesting protective effects. Limitations in the current literature include varied definitions of psychedelics, lack of standardised objective outcome measures and failure to control for confounding. As psychedelic research continues to expand, further assessment on the effects of serotonergic psychedelics and MDMA on aggressive behaviour is required.

As Psychedelic Research Advances, Can Youth Benefit?

As Psychedelic Research Advances, Can Youth Benefit?

Psychedelics in Psychiatry, the Nursing Influence, and the Future of Psychedelic Therapies.

Psychedelics and psychedelic-assisted therapies (PATs) are on the cusp of becoming medicalized treatment modalities within the United States, both as potential U.S. Food and Drug Administration (FDA)-approved treatment and therapeutic options outside the medical model, through decriminalization efforts within individual states. Bringing with it a paradigm shift in the delivery of health care for both physical and mental health treatment. A workforce of highly trained facilitators will be needed to meet the anticipated demand for this type of treatment and nurses can play a key role in meeting this demand. This article serves to introduce psychedelic-assisted therapies to psychiatric-mental health nurses as we start to see this new field emerge. Review of published literature and other media. Results based on historical data, modern applications, and future considerations. Nurses have been involved with psychedelic-assisted therapies in the past and are fully capable of providing a wide range of roles upon the anticipated approval as a treatment modality.

Bernard Lerer: Pre-clinical, translational and clinical research focused on the use of psychedelic drugs and their derivatives to treat psychiatric disorders

Professor Bernard Lerer is in the Faculty of Medicine, Hebrew University, Jerusalem, Israel, where he is Director the Center for Psychedelic Research (https://cfpr.brainlabs.org.il/) at Hadassah Medical Center, in Jerusalem. The Center has a growing staff that includes senior scientists, post-docs, Ph.D. and graduate students, technicians, and psychiatrists undergoing research training. Their research is preclinical, translational, and clinical and focuses on the use of psychedelic drugs and their derivatives to treat psychiatric disorders. Previously, he was Head of the Biological Psychiatry Unit at Hadassah Medical Center for 30 years, with research and clinical responsibilities. A conversation with Professor Lerer covered topics on his life and career.

Will psychedelic research and the ‘psychedelic renaissance’ create another generational divide?

Will psychedelic research and the ‘psychedelic renaissance’ create another generational divide? Erika Dyck, Canada Research Chair in History of Health &amp; Social Justice at the University of Saskatchewan, discusses changing attitudes to psychedelics and the challenges in forming a strong evidence base from available psychedelic research. As psychedelics re-emerge in the 21st century, their storied past continues to haunt their future. Tales have circulated of their entanglement in unethical medical research and implication in violent behaviours, including suicides and homicides. Psychedelics have even been blamed for turning an entire generation of young people to question authority and the values of a post-World War culture. Are psychedelics really to blame for these social divisions? I do not think that psychedelics are the problem, but they may be a symptom.

Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression.

To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075). We used data (n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin. Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm. Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.