Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis

Simon B. Goldberg, Benjamin Shechet, Christopher R. Nicholas, Chi Wing Ng, Geetanjali Deole, Zhuofan Chen and Charles L. Raison

Psychological Medicine, 2020, 1–12.

doi : 10.1017/S003329172000389X

 

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 lysergic acid diethylamide (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 h post-administration. 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, placebocontrolled randomized trials.

 

Introduction

Humans have intentionally consumed psychoactive substances for thousands of years (Guerra-Doce, 2015). Psychedelic substances, in particular, figure prominently in indigenous medical and religious practices around the world (Samorini, 2019; Schultes, 1969). Scientific interest during the 1950s and 1960s in the therapeutic potential of both plant-based psychedelics (e.g. psilocybin) and synthetic psychedelics [e.g. lysergic acid diethylamide (LSD)] largely ceased following legislative changes during the 1970s and 1980s (Bonson, 2018).

Research has resumed in the past two decades. While early work in this contemporary period focused on pharmacokinetics (e.g. Callaway et al., 1999) or the use of psychedelics as a model for psychiatric conditions (e.g. schizophrenia; Vollenweider, Vollenweider-Scherpenhuyzen, Bäbler, Vogel, and Hell, 1998), a growing number of studies are again evaluating the therapeutic potential of psychedelics (Reiff et al., 2020).

Classical psychedelics are a class of psychoactive substances that share both mode of action (agonism of the 5-HT2A receptor; Carhart-Harris, 2019) and psychoactive effects (marked cognitive, affective, and perceptual changes). Members of this class that have received recent scientific attention include psilocybin, ayahuasca, and LSD (dos Santos, Bouso, Alcázar-Córcoles, & Hallak, 2018). Psilocybin (4 phosphoroyloxy-N,N-dimethyltryptamine) is a naturally occurring plant alkaloid used ritualistically for spiritual and healing purposes by indigenous cultures in Mexico and South America (Guzmán, 2008). Ayahuasca is a plant-based serotonergic psychedelic also used ritualistically by indigenous cultures in South America (McKenna, 2004). The psychoactive effects of ayahuasca are due to N,N dimethyl-tryptamine coupled with reversible monoamine oxidase inhibitors (Ott, 1999). LSD is a synthetic psychedelic first synthesized in 1943 by Hofmann (1980) that is both a serotonin and dopamine receptor agonist (Giacomelli, Palmery, Romanelli, Cheng, & Silvestrini, 1998; Preller et al., 2017).

Numerous studies in the 1960s investigated the therapeutic effects of LSD for the treatment of addiction (Krebs & Johansen, 2012) and other clinical applications (e.g. end-of-life distress; Ross, 2018). Research halted as LSD became associated with the countercultural revolution of the late 1960s coupled with concerns regarding its safety (Nutt, King, & Nichols, 2013).

Studies have begun reexamining the therapeutic potential of classical psychedelics for clinical conditions including depression (Carhart-Harris et al., 2016a, 2018a; Palhano-Fontes et al., 2019), anxiety (Gasser et al., 2014; Ross et al., 2016), and substance use (Bogenschutz et al., 2015; Johnson, Garcia-Romeu, Cosimano, & Griffiths, 2014). Often psychedelics are paired with behavioral interventions intended to maximize benefits by enhancing the mental ‘set’ and physical ‘setting’ (Carhart-Harris et al., 2018b). Other studies have examined effects in non-clinical samples on measures of well-being, personality, and associated constructs (e.g. mindfulness, spirituality; MacLean, Johnson, and Griffiths, 2011; Soler et al., 2018).

Several systematic reviews have examined the safety and efficacy of psychedelics for both clinical and non-clinical populations. These narrative reviews consistently suggest psychedelics can be safely administered (i.e. adverse effects are minimal and transient) and may reduce depression and anxiety symptoms (Muttoni, Ardissino, & John, 2019), provide psychological benefits in the context of life-threatening disease (Reiche et al., 2018), and induce mystical experiences associated with enduring changes in personality and attitudes (Aday, Mitzkovitz, Bloesch, Davoli, & Davis, 2020). Despite several well-conducted systematic reviews, only two quantitative reviews (i.e. meta-analyses) have characterized the efficacy of psychedelics. Krebs and Johansen (2012) meta-analyzed six randomized controlled trials (RCTs) published between 1966 and 1970 testing LSD for alcoholism, finding LSD substantially reduced substance misuse (odds ratio = 1.96). Goldberg, Pace, Nicholas, Raison, and Hutson (2020) found that psilocybin was associated with large reductions in depression and anxiety across four recent studies (Hedges’ gs = 0.82 to 1.47).

The available reviews suggest psychedelics may have therapeutic potential. Yet, a clear quantitative depiction of the breadth of this literature is lacking. A comprehensive meta-analysis would be valuable for characterizing the magnitude and variability (i.e. heterogeneity) of the effect of psychedelics across psychological outcomes, including but not limited to psychiatric symptoms. Such a meta-analysis would be particularly valuable for clarifying effects that have been inconsistent in prior studies (e.g. effects on personality; Barrett, Doss, Sepeda, Pekar, & Griffiths, 2020; MacLean et al., 2011). The small sample size in many primary studies (e.g. mean n = 29.25; Goldberg et al., 2020) also recommends the use of meta-analysis which allows aggregation across studies. Lastly, meta-analysis offers the opportunity to examine whether various study-level features (e.g. psychedelic type, behavioral support) moderate effects.

The current study sought to address this gap in the literature by quantitatively synthesizing psychological effects from experimental studies testing psilocybin, ayahuasca, or LSD. We focus on these three substances due to their shared mechanism of action (5-HT2A receptor agonism) and subjective effects. Other psychoactive compounds that produce partially overlapping effects through partially overlapping mechanisms were not considered [e.g. enactogens such as 3,4-methylenedioxymethamphetamine (MDMA); Reiff et al., 2020]. Given our interest in therapeutic applications, we focus on effects outside of the acute period of intoxication. To provide the most comprehensive depiction, we included studies with either clinical or non-clinical (i.e. healthy) samples. Likewise, we included both between-group (e.g. RCTs) and within-group (e.g. pre-post) designs. Four study-level characteristics (psychedelic type, clinical sample, presence of behavioral support, percentage female) were examined as moderators. We also assess adverse effects and risk of bias within and between studies.

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Goldberg et al-2020-Post-acute psychological effects of classical serotonergic psychedelics- a systematic review and meta-analysis