Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review

This review (2022) assesses the presence of adverse events (AEs) during and after the administration of psychedelics including MDMA, psilocybin, LSD and ayahuasca. Across all compounds, commonly reported AEs included nausea, headaches and anxiety, while only one serious AE occurred in a study involving MDMA administration. Results from qualitative studies suggest that psychologically challenging experiences could have therapeutic benefits. Overall, AEs in psychedelic research require more detailed reporting.

Abstract

“Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions.

Objective: To systematically review the presence of AEs during and after the administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies.

Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies.

Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies.

Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

Authors: Joost A. Breeksema, Bouwe W. Kuin, Jeanine Kamphuis, Wim van den Brink, Eric Vermetten & Robert A. Schoevers

Summary

Introduction

Psychedelic research has provided promising positive results for various mental disorders, but sample sizes were generally small and rather selective. However, phase III trials are nearing completion.

Psychedelic drugs are associated with acute adverse events such as anxiety, panic, dysphoria, paranoia, and/or dangerous behaviors. These adverse events may contribute to enduring psychological problems, particularly in vulnerable patients with treatment-resistant mental disorders.

Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders.

A non-systematic review of adverse reactions to psychedelics in different settings found that AEs existed on a continuum, from acute, time-limited panic reactions during administration, through transient psychoses lasting several days, to recurrent flashbacks and chronic undifferentiated psychotic and treatment-resistant cases.

Assessing adverse effects (AEs) is challenging because of the broad range of potential reactions, the lack of pre-specified terminology, and the highly variable and context-dependent subjective effects elicited by psychedelics.

Patients with mental disorders are likely to be treated with psychedelics in the near future. This paper aims to review any adverse events (AEs) occurring during or after psychedelic treatments with classic/serotonergic hallucinogens and entactogens in patients.

Methods

This review takes an exploratory – rather than a confirmatory – approach, and uses a sequential explanatory design to extract, organize, and synthesize findings from both quantitative and qualitative studies. It will use the term AE for any unfavorable or harmful event first occurring during or after the administration of a classic psychedelic.

Selection criteria

We included all studies on the treatment of mental disorders with classic serotonergic psychedelics and entactogenic drugs published since 2000 and excluded systematic reviews, surveys, secondary analyses, and studies with healthy volunteers.

Search methods

We searched the PubMed/Medline, EMBASE, and PSYCinfo databases for studies on psychedelic compounds, excluding animal studies, and checked reference lists.

Quality assessment

This review assessed the quality of studies on adverse events (AEs) using specific quality criteria, and used the Critical Appraisal Skills Programme (CASP) checklist to assess qualitative studies.

Data extraction and synthesis

We extracted quantitative and qualitative information on acute and late adverse events, the timing of assessment, and serious adverse events from published studies.

Results

We found 5640 articles on PubMed, EMBASE, and PsycINFO, and screened 44 articles for eligibility. Of these, 24 completed trials were included, and reported on 521 unique participants, with mean ages ranging from 25 to 59 years.

MDMA

16 studies were selected, including one qualitative study, on MDMA-assisted treatment of PTSD. Active doses ranged from 50 to 125 mg, and one open-label trial focused on alcohol use disorder.

Quality appraisal

Of all MDMA studies, 11 reported AEs only when spontaneously reported by participants, two RCTs systematically assessed AEs, and one study reported AE severity. Six studies did not report whether participants had ever used MDMA or “ecstasy” prior to study participation.

Physiological effects

Nine studies measured blood pressure, body temperature, and heart rate during MDMA sessions. All reported mild elevations, none of which required medical intervention.

Adverse events

There were no dose-AE relations in the two PTSD studies that assessed different active MDMA doses, and the most common acute physical AEs were jaw clenching and/or tight muscles, headaches, nausea, fatigue, and lack of appetite. Anxiety was the most common psychological AE.

Stuart experienced strong emotional reactions and visceral reactions in the MDMA session, and reflected on his experience as follows: “There’s no easy fix.”

Patients reported fatigue, lack of appetite, low mood, insomnia, need for more sleep, increased irritability, headache, difficulty concentrating, and anxiety up to 2 months after the final session.

End-of-life anxiety

In a crossover RCT, jaw clenching, thirst, dry mouth, perspiration, headache, fatigue, need for more sleep, insomnia, anxiety, jaw clenching, and low mood were reported.

Social anxiety

A RCT on social anxiety in adults with autism reported higher rates of acute adverse events in the MDMA group than in the placebo group.

Psilocybin

We included 20 studies describing the use of psilocybin for the treatment of 257 patients, including six (crossover) RCTs, five articles describing four open-label studies, one single-group, pseudo-randomized dose-escalation study, and eight qualitative studies. The studies included three RCTs on EOLA, two RCTs on MDD, one RCT on migraine headaches, and one qualitative study.

Quality appraisal

Two studies did not report on AEs, most other studies relied on spontaneous reporting by patient and therapist observations, and three studies reported on AE severity. One study reported a higher number of distinct AEs than all other studies.

All studies reported on prior psychedelic use, with a group average of 50% of patients having used psilocybin or other psychedelics before the study. Quality of the eight qualitative studies was high.

Physiological data

Elevated blood pressure and heart rate were the most common physiological effects of psilocybin, but none required medical intervention. Self-limiting severe hypertension occurred in 4 of 18 patients in one study, but resolved upon reassurance by therapists.

Adverse events

A small open-label study on psilocybin treatment for TRD reported anxiety, confusion, and nausea as the most prevalent acute AEs, and both MDD RCTs reported headaches. Patients reported moderate to strong emotional and psychological AEs, including feelings of sadness, grief, and isolation.

I worried that I let the music shape my melancholy, and I had a fearful response to everything. There was a lot of sadness, and letting go was a process.

Post-treatment headache was the only reported late AE; 67% of participants rated one of the psilocybin sessions among their top five most psychologically challenging experiences.

End-of-life anxiety

Two studies reported acute and transient AEs in the psilocybin groups, including physical discomfort (headache, nausea) and psychological discomfort (anxiety, transient thought disorders, and suicidal ideation). One patient committed suicide 11 days after a low dose (1 mg) psilocybin session.

It really hit me very strong, and I was completely disoriented. The therapists were right there, and I reached out my hand and just said “I’m so scared”, and I went with it.

Substance use disorders

Two open-label studies investigated psilocybin as a treatment for SUD. One study reported anxiety and feeling trapped as acute AEs, and headache as a late AE.

After receiving a higher dose of medication, the woman experienced chaotic thinking, but was eventually able to surrender control over her thoughts.

Demoralization

The most common acute AEs in the open-label study on demoralization in gay men were anxiety, nausea, and headache. Two unexpected late AEs occurred: one patient experienced a post-traumatic flashback and another relapse in methamphetamine use.

Ayahuasca

We included three studies, describing 48 patients in total, involving ayahuasca. The studies involved social anxiety disorder, treatment-resistant depression, and MDD.

In one study, ayahuasca users experienced nausea, vomiting, diarrhea, and anxiety. Four patients remained hospitalized for seven days, and one participant experienced an intense episode of transient fear of dying and/or going crazy, distress, and dissociation.

Four studies were included, describing 27 patients in total. They used LSD and/or MDMA in group therapy with patients, mostly with PTSD and/or MDD.

Quality appraisal

In the compassionate group therapy, 39% of participants had prior drug (including cannabis) experience; only 8% in the RCT did.

Adverse events

Acute, transient AEs included illusions, feeling cold, feeling abnormal, and anxiety, and were more prevalent in high-dose groups. Mild-to-moderate emotional distress was of equal severity in low- and high-dose groups.

The first trip was a panic trip, the second trip was a little tensed, but eventually led to relaxation. The key experience is when you get from dark to light, from tension to total relaxation.

Discussion

This review summarizes the findings from studies using MDMA and classic serotonergic psychedelics in the treatment of a range of different disorders. However, caution is warranted because the studies used different assessment procedures and had different populations.

Acute AEs

The most common acute AEs across psilocybin studies were moderate to severe anxiety, headache, and nausea. Ayahuasca participants sometimes dissociated, fearing he/she was dying or going crazy, but therapist interventions helped resolve this episode.

Multiple qualitative studies described occasionally terrifying, frightening, and confusing experiences, but no drug-related AEs or SAEs required medical intervention.

Many of the physiological AEs described in this review are well known from the literature on healthy subjects, and most resolve during the session.

Late AEs

MDMA studies have shown that fatigue, headache, anxiety, difficulty concentrating, and low mood are common late AEs. However, some studies do not report post-acute decreases in mood, including the open-label study on MDMA in patients with an AUD.

One ayahuasca study reported hospitalizing four patients for a week, and two studies reported unexpected adverse reactions in three patients that occurred several weeks post-psilocybin administration. Despite the clinical severity of these complaints, they were not reported as SAEs, which carries the risk of underreporting potential negative consequences.

Several cases were reported in which study participants in an MDMA trial stated that they became suicidal after the trial was finished, including one case in which a participant remained attached to a therapist and was subsequently abused.

Suicidality

We found one study in which a suicide was reported as unrelated to study participation. Overall AE rates seem roughly comparable to those summarized in this review, with higher suicidality rates in active dose groups (10 and 25 mg). Suicidal ideation and behavior were reported in three MDMA studies, although incidence was low and rates were lower or similar in MDMA compared to controls. Nevertheless, scrutinous assessment of treatment-related consequences is warranted.

Interpreting adversity

The qualitative studies in this review illustrated how patients considered working through difficult feelings and emotions as therapeutically beneficial, and that users frequently transform challenging experiences into personally, morally, or spiritually meaningful ones.

Treatment designs that reduce positive contextual components may increase the incidence of adverse effects. Some aspects of the definitions of “AE” are ill-suited in the context of psychedelic treatment, since they focus on undesirable and counterproductive elements. Disentangling physical AEs from psychological experiences is crucial to improve our understanding of the mechanisms of action of psychedelic treatments. In the case of anxiety, the severity and length of the difficult episode may predict suboptimal or even negative clinical outcomes. Careful screening, preparation, session monitoring, psychological support, and post-session integration are crucial prerequisites to maintain a low incidence of AEs and to maximize therapeutic efficacy.

Limitations

The current review has both strengths and limitations, including that most studies were small, varied in study design, dose of psychedelic drug, and demographics, and only few studies assessed adverse events consistently or systematically. Five pilot studies did not report any AEs, and there are not enough placebo-controlled trials to warrant strong conclusions about the causal relation between the psychedelic treatment and AEs. Most trials had strict criteria for participation, excluding patients with almost any comorbid mental disorder, including psychotic, bipolar, dissociative identity, eating, and SUDs. Many studies included patients with previous experience with the experimental drug, limiting generalizability to broader patient populations. Moreover, minorities are underrepresented in clinical research with psychedelics.

Previous experience does not necessarily predict the occurrence of AEs in clinical populations or contexts, and qualitative studies are unevenly divided and relatively scarce.

Conclusions

This review of acute and late adverse effects (AEs) in the treatment with serotonergic psychedelics and MDMA shows that all compounds acutely induce transient headaches, nausea, and anxiety. SAEs seem to be largely absent based on the included studies, as were lasting physiological side effects.