Long-term effects of psychedelic drugs : A systematic review, Jacob S.Aday et al., 2020

Long-term effects of psychedelic drugs : A systematic review

Jacob S.Adaya, Cayla M.Mitzkovitz, Emily K.Bloesch, Christopher C.Davoli, Alan K.Davis

Neuroscience and Biobehavioral Reviews, 2020.

Doi : 10.1016/j.neubiorev.2020.03.017



Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances’ lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. Finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.

Keywords : Psychedelics, Psychedelic drugs, Long-term, Review


1. Introduction

Psychedelic drugs have been used by humans for hundreds—if not thousands—of years for recreational, spiritual, and healing purposes (Jay, 2019). These substances have the capacity to induce intense shifts in consciousness and cognition through transient changes in emotions (Roseman et al., 2019), perceptual processing (Kometer and Vollenweider, 2016), one’s sense of self (Lebedev et al., 2015), and feelings of connectedness (Carhart-Harris et al., 2018c). Scientific interest into their effects grew slowly throughout the early 20th century and boomed during the 1950s and 60s (Aday et al., 2019a; Grinspoon and Bakalar, 1997) before a tightening of pharmaceutical regulations restricted research (Oram, 2016; Strassman, 1991). Clinical psychedelic science remained relatively dormant until the early-1990s and has since seen a resurgence (Aday et al., 2019c).

There is emerging evidence that, in carefully screened and monitored volunteers, psychedelic-assisted psychotherapy can be a potent treatment option for depression (Carhart-Harris et al., 2016a), anxiety (Gasser et al., 2014), obsessive-compulsive disorder (OCD; Moreno et al., 2006), substance misuse (Bogenschutz et al., 2018; Johnson et al., 2014), and end-of-life distress (Griffiths et al., 2016). However, one of the most pressing questions from patients, regulatory bodies, the general public, and the broader scientific and psychiatric communities, regards the long-term effects of psychedelic drug administration—specifically, how long do the positive outcomes last? Although several individual studies in recent years monitored sustained effects, findings have yet to be systematically aggregated. To remedy this gap, this review synthesized the contemporary psychedelic experimental studies examining long-term changes in human subjects. Results from earlier research as well as recent correlational and naturalistic studies are first summarized but were excluded from our systematic search in order to narrow our scope and strengthen confidence in our conclusions. We use 1994 as our cutoff year for the new era of psychedelic research because Strassman et al.’s (1994) study was the first to administer classic psychedelic compounds after several decades of prohibition in the US. Although, it should be acknowledged that psychedelic studies began to reemerge in other parts of the world around the same time (Hermle et al., 1992).

1.1. Early research (pre-1994)

To begin, it may be useful to review the long-term experiments conducted during the first era of psychedelic research. However, the utility of historical studies is an area of contention among researchers, primarily because of the primitive methodological standards of the period (e.g., lack of blinding, lack of independent raters, undetailed reporting of methodology). Nevertheless, results have much to offer in terms of generating hypotheses and corroborating contemporary findings (Bonson, 2018). McGlothlin et al. (1967) utilized methodology generally comparable to today when evaluating the effects of 200 ug of d-lysergic acid diethylamide (LSD) against amphetamine or a low-dose of LSD (25 ug) in healthy participants. At the 6-month follow-up, 33% of participants in the high-dose LSD group experienced less anxiety compared to 13% and 9% for the amphetamine and low-dose LSD groups, respectively. Further, 50% in the 200 ug LSD group reported “enhanced understanding of self and others” compared to 11% across the two control groups. Interestingly, the most common changes in the high-dose LSD group at the 6-month follow-up were enhanced appreciation of music (62%) and art (46%). Validating these subjective reports, the researchers found that 6 months post-drug administration, the high-dose group had significantly higher number of records bought, time spent in museums, and number of musical events attended.

Adverse reactions and case reports of symptoms resembling hallucinogen persisting perception disorder (HPPD) began to appear in the literature during this period as well (Sandison and Whitelaw, 1957; Horowitz, 1969; Rosenthal, 1964). There is considerable variability in symptoms experienced by those with HPPD, but the most common effects include afterimages of color, “floaters” in field of vision, difficulty concentrating, and tinnitus, persisting after using a psychoactive drug. Type I HPPD involves transient flashbacks, whereas Type II is more chronic and invasive. To the best of our knowledge, there are no reliable and direct prevalence estimates of Type I nor Type II HPPD from the first era of research, although Cohen (1960) surveyed researchers working with LSD or mescaline and reported no lasting adverse side effects across roughly five thousand participants. Strassman (1984) reviewed the adverse effects attributed to psychedelic drug administration across recreational and early experimental settings, and found that use was occasionally associated with reports of suicide and prolonged psychotic reactions.
Additionally, research suggesting that LSD may cause chromosomal damage generated considerable publicity during the 1960s (Cohen, Hirschhorn, & Frosch, 1967). While these studies were ultimately refuted for methodological confounds (Dishotsky, Loughman, Mogar, & Lipscomb, 1971; Long, 1972), retraction of the findings did not draw the same media attention as the original work. In their evaluation of adverse reactions, McWilliams and Tuttle (1973) concluded there was a low risk of long-lasting negative psychological side effects when LSD is used by healthy individuals in controlled settings compared to those with unstable psychiatric disorders or in crisis situations.

1.2. Contemporary correlational studies (1994–present)

Correlational research assessing differences between psychedelic users and non-users can also provide insight into long-term differences associated with psychedelic use. However, it is important to keep in mind the inherent methodological limitations associated with correlational studies (i.e., inconclusive causality, selection bias, recall bias, etc.). Despite these limitations, this research has documented that lifetime history of psychedelic use—but not other illicit drug taking—was related to reduced past month psychological distress and suicidality (Hendricks et al., 2015), and not linked to mental illness (Johansen and Krebs, 2015). Forstmann and Sagioglou (2017) found that lifetime experience with psychedelics predicted increases in pro-environmental behavior, and these changes were explained through heightened nature relatedness. A neuroimaging study compared ayahuasca users with controls matched for sex, age, years of education, as well as verbal and fluid IQ (Bouso et al., 2015). Users had reduced cortical thickness in the posterior cingulate cortex (PCC), a main hub of the default mode network (DMN), and this was related to greater intensity and duration of ayahuasca use. These results indicate that, in addition to the psychological differences between psychedelic users and nonusers, there may be structural differences in the brain as well. Pisano et al. (2017) found that psychedelic users were at a 40% reduced risk of abusing opiates in the year prior to the study. Psychedelic users also have lower rates of prison recidivism than non-users (Hendricks et al., 2014), and male users are less likely to perpetrate intimate partner violence (Thiessen et al., 2018). Finally, Type II HPPD seems to be relatively rare, with an estimated 1/50,000 psychedelic users meeting criteria (Halpern et al., 2016). Although limited, correlational research supports the notion that there are long-term differences in various aspects of neuropsychological functioning between psychedelic users and non-users.

1.3. Contemporary naturalistic research (1994–present)

The majority of funding for experimental studies administering psychedelics has been limited to private donors and non-profit foundations, and there are immense regulatory hurdles in administering Schedule I drugs to humans, both of which have restricted the number of recent investigations in psychedelic research. Therefore, some researchers have used naturalistic survey study designs to circumvent these hurdles (Mason et al., 2019; Sampedro et al., 2017). For others (e.g., anthropologists), naturalistic designs are preferred to enhance ecological validity. This research has predominantly recruited participants visiting psychedelic retreats in countries where the practice is legal or unregulated. Although this can increase the methodological rigor compared to correlational research, naturalistic studies can also be limited by a number of factors including potentially unstandardized dosages, unknown drug purity, self-selection biases, lack of control groups, and expectancy effects. Yet, they can be a viable low cost option for testing research hypotheses, yielding results that are useful for a still growing field like psychedelic science.