This review and meta-analysis (2020) of long-term effects of psychedelics finds a large effect (Hedges’ g ≈ 1) on various outcomes, but also notes various biases as issues in current research.
Abstract
“Background: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and LSD on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.
Methods: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ≥24 hours postadministration. Effects were summarized by study design, timepoint, and outcome domain.
Results: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges’ gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.
Conclusions: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.”
Authors: Simon B. Goldberg, Benjamin Shechet, Christopher R. Nicholas, Chi Wing Ng, Geetanjali Deole, Zhuofan Chen & Charles L. Raison
Summary
This study aimed to quantify the psychological effects of psilocybin, ayahuasca, and LSD in the post-acute period, test moderators, and evaluate adverse effects and risk of bias. A systematic review and meta-analysis of experimental studies with psilocybin, ayahuasca, or LSD showed significant within-group pre-post and between-group placebo-controlled effects on a range of psychological outcomes. There was weak evidence of effects on big five personality traits and mindfulness.
Humans have intentionally consumed psychoactive substances for thousands of years. Recent studies have focused on the therapeutic potential of psychedelic substances, and legislative changes have largely ceased research into these substances. Classical psychedelics are a class of psychoactive substances that share both mode of action (agonization of the 5-HT2A receptor) and psychoactive effects (marked cognitive, affective, and perceptual changes). They include psilocybin, ayahuasca, and LSD.
Several studies have examined the therapeutic potential of classical psychedelics for clinical conditions including depression, anxiety, and substance use. These studies have found that psychedelics can be safely administered and may reduce depression and anxiety symptoms, provide psychological benefits in the context of life-threatening disease, and induce mystical experiences. Several systematic reviews have found that psychedelics reduce substance misuse, but only two meta-analyses have found that psilocybin is effective.
A meta-analysis of four studies found that psilocybin, ayahuasca, and LSD were associated with large reductions in depression and anxiety. The meta-analysis also found that various study-level features (e.g., psychedelic type, behavioral support) moderated effects. We included studies with clinical and non-clinical samples and examined four study-level characteristics (psychedelic Running head: Post-acute effects of psychedelics type, clinical sample, presence of behavioral support, percentage female).
We followed the PRISMA guidelines, made several deviations, and aggregated outcomes into conceptually coherent categories based on measures reported across studies. We included studies that administered psilocybin, ayahuasca, or LSD within an experimental setting and reported at least one psychological outcome. We included studies with and without behavioral support, and no restriction was placed on language or publication status.
Studies that were missing data necessary for computing effect sizes were excluded, and principal investigators were contacted regarding available results.
We searched six databases including PubMed, CINAHL, PsycINFO, Web of Science, Scopus, and Cochrane for studies on psychedelics published between 1990 and 2019 and hand searched recent systematic reviews.
Two authors reviewed each title and abstract of potential studies for inclusion. Standardized spreadsheets were developed for study- and effect size-level coding.
We extracted data necessary for computing effect sizes, coding risk of bias, and including adverse events, post-treatment and follow-up timing, behavioral support, and country.
Outcomes were grouped into 14 categories, including adverse effects, targeted symptoms of psychiatric disorders, depression, positive affect-related outcomes, social outcomes, behavior, existential and spiritual outcomes, mindfulness, and the big five personality traits.
We assessed risk of bias in studies using the Cochrane tool, and calculated effect sizes using standard meta-analytic methods. For controlled studies, a between-group effect size was also computed, and when within-group effects were not available, a between-group effect size was computed as the difference between within-group effects.
We computed Cohen’s d for post-acute effects of psychedelics using data from the last available follow-up timepoint. We attempted to represent all outcome measures that were assessed and contacted authors when data remained missing at the time of analysis. Meta-analysis was performed using standard methods and the ‘MAd’ package in R. Effect sizes were computed for each outcome domain and converted from Cohen’s d to Hedges’ g in order to account for small sample bias.
Post-acute effects of psychedelics were studied using 11 studies. Heterogeneity was characterized using I2 and interpreted based on Higgins et al.’s (2003) guidelines.
We assessed publication bias using trim-and-fill analyses in the metafor package. The fail-safe Ns were calculated to determine if there was a significant effect.
We tested four study-level characteristics as moderators: psychedelic type, whether the sample was clinical (i.e., required elevated symptoms of a medical/psychiatric diagnosis for inclusion), whether behavioral support was provided, and percentage female. We also conducted sensitivity analyses with outliers excluded. A total of 34 studies were reviewed, of which 50.0% were single-group pre-post designs, 16.7% were within-group RCTs, and 33.3% were between-group RCTs. The majority of studies tested psilocybin, with 25.0% testing ayahuasca and 16.7% testing LSD.
Sample sizes were generally small, with 51.5% being female and 42.13 years old on average. Approximately half of the studies included participants with clinical conditions, including depression, alcohol dependence, smoking, and AIDS.
Risk of bias varied between studies, and was highest in single-group designs without randomization or blinding. Selective reporting bias was common.
Adverse effects were reported in 79.2% of studies, and none were serious. Commonly reported transient adverse effects included headache, anxiety, nausea, and increased blood pressure.
Post-acute effects of psychedelics were not increased, and within-group effects suggested decreased adverse effects at post-treatment and follow-up. Psychedelics showed significant within-group improvements across several outcome domains at both post-treatment and follow-up, and significant between-group improvements across several outcome domains at longest follow-up. There was no evidence of between-group effects on personality.
There was evidence of funnel plot asymmetry (i.e., publication bias) in eight models, but statistical significance was not impacted by this adjustment. Clinical samples were associated with larger improvements for some comparisons in the domains of negative affect, positive affect, adverse effects, existential/spiritual outcomes, and extraversion.
A meta-analysis of 34 studies found that psychedelics produced significant effects when compared with placebo controls for targeted symptoms. This effect was robust to publication bias and not influenced by outliers. Psychedelics compared favorably with placebo controls on measures of negative and positive affect, social, behavior, and existential/spiritual outcomes, and on depression in samples with depression. The effects were transient and no serious adverse events occurred. We found limited evidence supporting the effects of psychedelics on personality and mindfulness, although some effects may be larger for clinical samples.
Studies testing psilocybin with relatively little behavioral support have achieved moderate to large reductions in psychiatric symptoms. Although the most comprehensive quantitative review to date, the study remained limited in sample size and associated statistical power, and there was a lack of reporting on sample race/ethnicity. This makes it impossible to provide recommendations regarding the specific treatment characteristics most effective.
Although there are several potential limitations to the studies, they generally did not change when accounting for publication bias, trim-and-fill analyses were also likely underpowered, and there are also two potential sources of bias that could be addressed. Selective reporting of study outcomes could be reduced through more consistent pre-registration of study hypotheses. However, the current study joins two previous meta-analyses suggesting that psychedelics are a class of drugs that have potential for post-acute effects.
Future studies should investigate the use of psychedelics for specific clinical conditions and non-clinical applications, including the pairing of psychedelics with behavioral interventions and non-psychotherapeutic approaches to enhance well-being and support flourishing in both clinical and non-clinical samples.
Study details
Participants
549