Long-term effects of psychedelic drugs: A systematic review

This systemic review (2020) presents the results of 34 modern studies into the long-term effects of classical psychedelics in humans beyond the 2-week follow-up. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were correlated with long-term changes in personality, depression, spirituality, anxiety, well-being, substance misuse, meditative practices, and mindfulness. A lack of aversive side effects with properly-executed treatment is also highlighted.

Authors

Aday, J. S.
Bloesch, E. K.
Davis, A. K.

Published

March 16, 2020

Neuroscience and Biobehavioral Reviews

meta Study

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Abstract

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.

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Research Summary of 'Long-term effects of psychedelic drugs: A systematic review'

Introduction

Aday and colleagues frame the review by noting the long human history of psychedelic use and the recent resurgence of clinical research after decades of regulatory restriction. Psychedelic compounds produce transient but profound alterations in perception, emotion, self-experience and connectedness, and contemporary trials have suggested therapeutic promise for conditions such as depression, anxiety, obsessive–compulsive disorder, substance misuse, and end-of-life distress. Despite growing interest, the authors identify a key gap: no systematic synthesis had been conducted on whether beneficial effects observed acutely are sustained over longer follow-ups. This paper therefore set out to synthesise contemporary experimental studies that administered classic psychedelics to human participants and included follow-up assessments of at least two weeks. The review excluded older historical studies and naturalistic or purely correlational work in order to focus on controlled experimental designs conducted in the modern era (post-1994) and to provide a clearer picture of enduring psychological and neural changes following psychedelic administration.

Methods

The investigators conducted a systematic review in accordance with PRISMA-style procedures, searching PubMed and ProQuest with 90 distinct query combinations that paired six psychedelic-related terms (for example, "psilocybin," "LSD," "ayahuasca") with fifteen long-term-related terms (for example, "follow-up," "long-term," "durable"). Searches were filtered for English-language human studies published from 1994 onward, and two of the authors each conducted the searches twice to ensure exhaustiveness; disagreements about inclusion were resolved by team discussion. Selection criteria restricted the review to peer-reviewed experimental studies that administered classic psychedelics (LSD, psilocybin, mescaline, or ayahuasca/DMT), measured psychological or neurological outcomes, and included follow-up latencies of at least two weeks. Naturalistic studies, correlational work, reviews, case reports, and non-experimental designs were excluded. Extracted study characteristics included sample type, drug and dosage, follow-up latency and long-term outcome measures. From 984 PubMed and 892 ProQuest hits the authors screened records and identified 34 unique studies meeting their criteria; the included articles were published between 2006 and 2020. Descriptive synthesis documented study features rather than performing a formal meta-analysis: samples were generally small (range 6–75, mean 16.81, SD 9.80), psilocybin was the most commonly administered drug (28 studies), followed by LSD (5) and ayahuasca (1), and roughly half of studies (15/34) included control conditions. The most frequent follow-up domains assessed were personality/attitudes, depression, spirituality, wellbeing/quality of life, anxiety, affect/mood, and substance use.

Results

Across the 34 included experimental studies, long-term changes were reported in multiple psychological domains. The year range of the studies was 2006–2020, with most published in the last five years and a mean/median publication year of 2016. Clinical samples were dominated by people with depression (10 studies), followed by healthy volunteers (9), individuals with end-of-life distress (7), tobacco use disorder (4), spiritually active participants (2), alcohol use disorder (1) and meditators (1). Depression and anxiety: Twelve study reports examined long-term changes in depression, representing ten unique samples (nine psilocybin, one ayahuasca); nine of the ten distinct samples showed at least short-term reductions in depressive symptoms (two-week-plus follow-up), and five studies with six-month or longer monitoring reported sustained reductions. One small treatment-resistant depression (TRD) sample showed that 19/20 participants had reduced depressive symptoms for at least one week, with over half meeting criteria for complete remission in that short-term window. Seven of eight distinct studies assessing anxiety documented significant long-term reductions. Authors also reported individual variability and some relapses over time, and inconsistent reporting about concurrent antidepressant use across trials. Personality, attitudes and spirituality: Four of seven unique studies measuring openness to experience found sustained increases, and other personality shifts—heightened extraversion, reduced neuroticism, and increases in conscientiousness and absorption—were reported in some studies at one-month follow-up. Ten studies assessed spirituality and nine reported long-term increases; many participants rated their psychedelic session among the most personally meaningful or spiritually significant experiences of their lives (e.g. two-thirds in several samples). Mystical-type experiences, measured with instruments such as the MEQ-30, and constructs like ego dissolution and connectedness were repeatedly associated with durable changes. Wellbeing and quality of life: All nine studies that assessed wellbeing or quality of life reported increases. In healthy or spiritually active samples, 79% of participants in one study reported moderate or large increases in wellbeing at two months, with 64% endorsing the same at 14 months. In trials with patients facing life-threatening cancer, 87% and 82% in two simultaneous trials reported increased life satisfaction or wellbeing at six months. Substance use disorders: One proof-of-concept study of psilocybin for alcohol use disorder reported immediate reductions in percentage of drinking days and heavy drinking days that were sustained for at least 36 weeks. The tobacco cessation literature included three reports from the same pilot sample: verified abstinence was 12/15 (80%) at six months, 10/15 (67%) at 12 months, and 9/15 (60%) at a long-term follow-up averaging 30 months. Measures of mystical experience and session personal meaning predicted abstinence and reduced cravings in these reports. Neuroimaging and mechanisms: Only one included study reported long-term neural measures, finding an increased number of significant resting-state functional connections one month after psilocybin in healthy volunteers. Several studies linked acute neural or task-related changes to later clinical outcomes: for example, some reported that increased amygdala reactivity to emotional stimuli post-treatment predicted symptom improvement, while others reported decreased resting amygdala activity predicting better outcomes; authors suggested these apparent discrepancies could reflect different mechanisms (reduced emotional blunting versus lowered chronic distress). Increased neural entropy, mystical experience, connectedness and emotional breakthrough were commonly hypothesised mechanistic contributors to enduring psychological change. Safety: Long-term adverse effects were infrequently reported in these controlled experimental settings. One summary indicated that as of 2016 no long-term adverse effects had been reported across over 2,000 participants in contemporary trials, though the authors cautioned this does not imply absence of risk. Case reports of hallucinogen persisting perception disorder (HPPD) exist but seem rare; Type II HPPD was estimated elsewhere at about 1/50,000 users. Some trials documented acute psychological challenge—up to almost a third of participants in certain high-dose sessions reported transient anxiety or fear—but most such episodes were managed and resolved. In one trial 1/110 participants required treatment for anxiety and depression in the weeks after psilocybin; other transient emotional instability resolved within a month.

Discussion

Aday and colleagues interpret the collated evidence as indicating that psychedelic experiences, particularly psilocybin administration, can lead to a range of durable psychological changes across clinical and non-clinical populations. They highlight consistent findings of sustained improvements in depression, anxiety, wellbeing, spirituality, and aspects of personality or attitudes, and note that mystical-type experiences, connectedness, emotional breakthrough and increased neural entropy recurrently emerge as candidate mechanisms linking acute sessions to longer-term change. The authors situate these results within the broader literature by noting both concordance with historical and correlational findings and the unique value of contemporary experimental designs. They acknowledge heterogeneity in designs, populations and outcomes but argue the growing number of recent trials strengthens confidence in observed effects. At the same time, several key methodological limitations are emphasised: many studies used small, demographically homogeneous samples (predominantly white, educated, middle-aged), control conditions varied widely (placebos, active comparators, low doses or other psychoactives), and participant selection often excluded people with cardiovascular disease or personal/family histories of psychosis or bipolar disorder—factors that limit generalisability. The potential for expectancy and selection biases, variable dosing regimens, inconsistent reporting of concurrent medication use, and sometimes imprecise operational definitions for psychospiritual constructs are also noted as challenges for interpretation. For future research the authors recommend larger and more diverse samples, stronger blinding and control conditions, standardised dosages, longer longitudinal follow-ups, and more systematic integration of neuroimaging to link acute neural effects with long-term outcomes. They also call for clearer operationalisation of suggestibility, meaning, and placebo enhancement that may interact with psychedelic-assisted interventions, and for further work on drugs beyond psilocybin and on the role of contextual elements such as music and preparatory/integration procedures. High-quality double-blind, placebo-controlled crossover trials for end-of-life distress conducted at major centres are cited as exemplars showing rigorous control is feasible in this field.

Conclusion

This systematic review synthesised 34 experimental human studies from the contemporary era and concludes that, under careful screening, preparation, supervision and integration, classic psychedelics—most notably psilocybin—are associated with generally positive and enduring changes across multiple psychological domains. Sustained effects were documented for depression, anxiety, wellbeing, personality/attitudes, spirituality, and substance use outcomes in several studies, and mystical experiences, connectedness, emotional breakthroughs and neural entropy were frequently proposed as mechanisms. The authors stress that while controlled research suggests a favourable safety profile in research settings, generalisation to recreational contexts remains unclear, and they urge future studies to address current methodological limitations through larger, more diverse samples, refined control conditions and more comprehensive neurobiological assessments.

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INTRODUCTION

Psychedelic drugs have been used by humans for hundreds-if not thousands-of years for recreational, spiritual, and healing purposes. These substances have the capacity to induce intense shifts in consciousness and cognition through transient changes in emotions, perceptual processing), one's sense of self, and feelings of connectedness. Scientific interest into their effects grew slowly throughout the early 20 th century and boomed during the 1950s and 60s) before a tightening of pharmaceutical regulations restricted research. Clinical psychedelic science remained relatively dormant until the early-1990s and has since seen a resurgence. There is emerging evidence that, in carefully screened and monitored volunteers, psychedelic-assisted psychotherapy can be a potent treatment option for depression, anxiety, obsessive-compulsive disorder (OCD;, substance misuse, and end-of-life distress. 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 becausestudy 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. 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.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. 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, althoughsurveyed researchers working with LSD or mescaline and reported no lasting adverse side effects across roughly five thousand participants.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. While these studies were ultimately refuted for methodological confounds, retraction of the findings did not draw the same media attention as the original work. In their evaluation of adverse reactions,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.

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, and not linked to mental illness.found that lifetime experience with psychedelics predicted increases in proenvironmental 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. 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 non-users, there may be structural differences in the brain as well.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, and male users are less likely to perpetrate intimate partner violence. Finally, Type II HPPD seems to be relatively rare, with an estimated 1/50,000 psychedelic users meeting criteria. 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.

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. 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. One such naturalistic study followed-up on first-time ayahuasca users six months after taking the drug in an urban Brazilian religious setting. Participants exhibited decreases in intensity of minor psychiatric symptoms and bodily pain, as well as heightened wellbeing, confidence, optimism, and independence.reported that ayahuasca ceremony attendees exhibited decreased stress and depression four weeks after consumption. Level of "ego dissolution" (i.e., a loss of a sense of self;, experienced during the ceremony seemed to be an important factor as it predicted changes in affect, life satisfaction, and mindfulness. Similarly,examined the long-term effects of a single inhalation of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent hallucinogen secreted by the Sonoran desert toad and produced synthetically. At the one-month follow-up, participants reported increased life satisfaction, mindfulness (non-judgement and awareness), and convergent creativity as well decreased measures of depression, stress, and anxiety; consistent with previous research, ratings of ego dissolution were associated with positive longterm changes in affect. Other naturalistic studies have utilized large-scale survey methods to examine the outcomes of psychedelics used in the natural environment. For example,found that use of 5-MeO-DMT in a naturalistic group setting was associated with improvements in depression and anxiety, and a large survey of 5-MeO-DMT users in the general population found that use of the drug was associated with improvements in substance use problems, post-traumatic stress disorder, depression, and anxiety. Additionally, several studies have documented the effect of psychedelic use on substance use problems, indicating that these drugs could show promise for people with alcohol and other substance use problems. For example, surveys conducted among people with an opioid use disorder who sought ibogaine treatment at a clinic in Mexico have documented the effectiveness of this treatment, wherein approximately 80% of respondents reported that ibogaine eliminated or drastically reduced their withdrawal symptoms in the short-term, and 41% reported sustained abstinence from opioids at the time of the survey. Collectively, these results offer further evidence of long-term psychological changes attributed to experience with psychedelics and preliminary insight into their mechanisms.

THE CURRENT REVIEW

The growing pace of psychedelic research necessitates a review of the field's current understanding of the long-term effects of psychedelic drugs. The limitations associated with historical, correlational, and naturalistic research make them less-ideal candidates for this analysis. Our systematic review filled this crucial gap in the literature by searching for articles which utilized psychedelic drugs, human samples, experimental designs, follow-up measures of at least two weeks latency, and were published within the contemporary era of psychedelic research. This analysis of the literature can coalesce the field's current understanding of the long-term effects of psychedelic drugs-a pressing scientific and public question.

OBJECTIVES AND SEARCH STRATEGY

This review synthesized the contemporary experimental research on the long-lasting effects of psychedelic drugs in human subjects. To this end, we wrote summaries and methodological critiques for each study retrieved from a search conducted in accordance with PRISMA guidelines. Our protocol required searchers to document the sample type, drug, drug dosage, latency of follow-up measures, and type of long-term measures collected. To ensure that our investigation was exhaustive, two of the authors (JSA & CMM) each conducted the search twice using two different search engines, PubMed and ProQuest (Fig.). Discrepancies regarding inclusion were resolved with consultation among the research team.

PUBMED

Established in 1997, PubMed is a premiere search engine for researchers and clinicians and has been utilized in previous systematic reviews of psychedelic science (e.g.,. Six psychedelic-related (e.g., "ayahuasca," "LSD," "lysergic acid diethylamide," "mescaline," "n, n-dimethyltryptamine," and "psilocybin") and fifteen long-term-related (e.g., "chronic," "continuing," "durable," enduring," "follow-up," "lasting," "lingering," "long-lasting," "long-term," "longitudinal," "non-acute," "ongoing," "persisting," "prolonged," and "residual") search terms were systematically cross-referenced into PubMed's search engine for a total of 90 distinct searches (e.g., "ayahuasca chronic," "ayahuasca continuing," etc.). Articles were initially filtered for language (English), species (human), and year . Whilemotivated this cutoff date for the new era of psychedelic research, this study was excluded from our results because no long-term measures were collected.

PROQUEST

ProQuest is an online search engine with an extensive archive of scientific research articles. Our ProQuest search used the same 90 search combinations as the PubMed search and included the same filters.

SELECTION CRITERIA

In addition to our initial filters for year, language, and species, articles returned from our search were examined for those that also met the criteria: they were experimental studies, published in peer-reviewed journals, administered classic psychedelic drugs (e.g., LSD, psilocybin, mescaline, or ayahuasca/DMT), measured psychological or neurological outcomes, and used follow-up latencies that were at least two weeks. Naturalistic studies as well as correlational research, book chapters, reviews, and case reports were excluded. Studies were also required to provide unique datasets, even if they had overlapping samples with other articles. For clarity, we explicitly identify when studies used overlapping samples.

STUDY SELECTION

Our 90 PubMed and ProQuest searches yielded 984 and 892 articles, respectively. From these results, we utilized our selection criteria to reduce the list to 26 articles and added 8 others which were found J.S.TableOur systematic review identified 34 studies examining long-term effects of psychedelics..

DESCRIPTIVES

We begin with a descriptive analysis of our findings to broadly characterize the long-term sequelae examined in contemporary psychedelic studies (Table). First, although our search filters included the years 1994-2019, the year range of the 34 articles was 2006-2020, and the majority of this work was published in the last five years. Indeed, the mean and median year of the included studies was 2016, indicating that this is a growing area of research. The most common sample that was studied and included a long-term assessment was depressed individuals (10 studies), followed by healthy volunteers (9 studies), those with end-of-life distress (7 studies; many of which were also depressed/ anxious), tobacco use disorder (4 studies), spiritually active individuals (2 studies), alcohol use disorder (1 study), and meditators (1 study). Psilocybin was the most common drug administered in these studies (28 studies), followed by LSD (5 studies) and ayahuasca (1 study). Samples were generally small, with a range of 6-75 participants (M = 16.81, SD = 9.80), and roughly half included control conditions (i.e., 15/34 studies). The most prevalent long-term follow-up measures assessed personality/attitudes (14 studies), depression (11 studies), spirituality (10 studies), wellbeing/quality of life (9 studies), anxiety (8 studies), affect/mood (7 studies), qualitative analyses (4 studies), tobacco use (3 studies), alcohol consumption (1 study), mindfulness (1 study), and meditative practices (1 study).

CHANGES BY OUTCOME MEASURE

Next, it may be useful to review how many studies showed change across each individual outcome measure. Our search returned 12 studies examining long-term changes in depression (see Supplementary Material for effect sizes). However, two of these articles used depression datasets overlapping with other studies, leaving ten unique samples. Since these two articles also provided unique long-term data (e.g., personality and neuroimaging measures, respectively), they were still included in the overall review. Of the ten distinct studies which indexed long-term changes in depression (nine psilocybin and one ayahuasca), nine demonstrated short-term reductions in symptoms (i.e., at least two weeks), and the five studies which monitored changes for at least six months demonstrated that these reductions were sustained. Starkly,found that 19/20 participants with treatment-resistant depression showed reduced depressive symptoms for at least one week, with over one-half qualifying for complete remission. Seven of the eight studies examining long-term changes in anxiety found that psychedelic treatment led to significant reductions in symptoms. Of the seven distinct studies examining lasting changes in openness to experience, participants reported increases in four. The increases in openness documented inutilized the same personality dataset as, but this study was still included in the review because it provided additional data as well. All nine studies assessing changes in wellbeing/quality of life showed increases. Of the ten studies assessing long-term changes in spirituality after psychedelic use, nine found increased ratings. All four studies examining psilocybin-assisted psychotherapy for substance use disorders (three tobacco use disorder and one alcohol use disorder) demonstrated positive abstinent effects at the group-level. The only studies assessing changes in meditation frequencyor mindfulnessshowed increases. Finally, only one study collected neuroimaging measures at a long-term follow-up:found that the number of significant resting-state functional connections across the brain increased one month after healthy volunteers received psilocybin.

SAFETY

In addition to examining efficacy, understanding the long-term safety of psychedelic use is a pressing question facing researchers and clinicians. Case reports of HPPD resulting from recreational use have appeared in the literature (e.g.,but are rare. In our search, few subjects reported lasting negative side effects.commented that no long-term adverse effects had been reported across over 2000 participants that had been run through contemporary psychedelic trials as of 2016. This should not, however, be taken as evidence that the drugs are risk-free as they can lead to experiences that are markedly psychologically challenging, particularly when used in the absence of proper preparation, support, and integration. Psychedelics seem to be unique drugs in that their immediate and long-term effects can vary dramatically as a function of the context they are taken in. Even in tightly controlled research settings with robust therapeutic support, some experiments have noted up to almost a third of participants reporting acute anxiety or fear at some point during high dose sessions. Although these episodes have been transient and manageable, it is not hard to imagine how the same situation could escalate or potentially become dangerous in an uncontrolled recreational environment.noted that 1/110 participants who received psilocybin reported experiences of anxiety and depression in the weeks following administration which warranted treatment. Additionally, "a few" noted less severe emotional instability-but all adverse effects were resolved within a month. All in all, limited harm has been reported in the new era of research which utilizes extensive safety protocols (seefor safety guidelines), and the drugs' potential for dependency is low. In subjective accounts, samples with depressionand addictionhave noted the lack of long-term adverse side effects as being a considerable benefit over previous treatments they had attempted (e.g., antidepressants).

DISCUSSION

Our systematic review of the current psychedelic literature revealed that psychedelic experiences can lead to myriad long-lasting psychological changes and research into these effects is a growing area of study. The long-term alterations have been examined across a variety of psychiatric (e.g., depression, anxiety, substance use disorder) and healthy (e.g., meditators, spiritually active) samples. Psilocybin has received the most research interest of the classic psychedelic drugs. In this section, we will explore the long-term findings by outcome measure and provide a critical analysis of the methodological rigor of these studies.

DEPRESSION/ANXIETY

Treatment for depression and anxiety is among the fastest growing areas of psychedelic research. Indeed, in late 2018, psilocybin was designated by the United States Food and Drug Administration as a "breakthrough therapy" for treatment-resistant depression. This designation should streamline future studies and indicated tentative regulatory acknowledgement of the efficacy of psychedelic-assisted psychotherapy. However, it is still important to determine whether these anti-depressive effects are maintained over the long-term given that many current antidepressant options have been shown to have diminishing results over time. Our search documented robust positive and enduring effects of psychedelic treatment on measures of depression across several studies and research groups. An important note is that some studies required patients to abstain from their typical antidepressant treatments, whereas others did not, and many did not report this information. Also, although reductions in depressive symptoms are generally maintained at the group-level, there is evidence that some individuals are prone to relapse and that depression levels may rebound over time-albeit to levels that are still below pre-treatment levels.administered psilocybin to healthy participants and found that depression scores decreased at the one-week follow-up, but returned to baseline when assessed a month after their session. Psychedelic therapy appeared to have similar effects on anxiety, which is unsurprising given the high comorbidity between anxiety and depression as well as the overlap in their treatments and neural mechanisms. The study which did not find changes in anxiety used a healthy sample, suggesting potential floor effects, and no psychotherapy was applied. It is also possible that anxiolytic effects are drug dependent, as this study utilized LSD instead of psilocybin. Given the reliability of these therapeutic effects in recent studies, researchers have begun to elucidate predictors and mechanisms of longterm changes. The degree to which one has a "mystical" experience has emerged as one factor related to a variety of affective changes, including depression. Mystical experiences are characterized by deep feelings of meaning/ sacredness, interconnectedness, transcendence of time and space, ineffability, and a strong positive mood.argued that existential selfnarratives can be "recalibrated" during this period of transcendence and altered perspective.andconcurrently found that the more mystical one's psilocybin session was rated, the greater the reductions in depression at the 6-month followup. When combining psilocybin with a meditation regimen,found that scores on the Mystical Experiences Questionnaire (MEQ-30) were associated with positive outcomes on 18/19 of their measures. Similarly,noted that the degree to which one experienced a unitive, spiritual, and blissful (USB) state during the psychedelic session predicted improvements in depression.conducted structured interviews with depressed patients and identified three main themes for remission. These themes include moving from a state of disconnection to reconnection, confronting painful memories, thoughts, and feelings, and, finally, the treatment promoted acceptance of previously avoided emotions. In another qualitative analysis, depressed individuals suggested that the therapeutic changes stem from a sense of empowerment and acceptance lasting after the session. Researchers have also begun to monitor neural markers accompanying long-term changes in depression.found that decreases in depressive symptoms could be predicted by increased amygdala reactivity to emotional stimuli, with those higher in amygdala activation to fearful stimuli post-psilocybin treatment also showing the greatest clinical improvements. The relationship between psychedelic-assisted psychotherapy-mediated changes in depressive symptoms and amygdala activity appears to be dynamic though, asfound that decreases in amygdala activity at rest the day after psilocybin therapy predicted improvements in symptoms. These apparently discrepant results can perhaps be explained through changes in emotional blunting to affective stimuli. When emotional stimuli are presented post-treatment, increased amygdala activation is consistent with reduced emotional blunting. On the other hand, attenuated amygdala activity at rest may relate to reduced chronic distress-both outcomes would be expected in successful depression treatment. Carhart-Harris and colleagues (2017) also found that increased resting-state functional connectivity (RSFC) between the ventromedial prefrontal cortex (vmPFC) and bilateral inferior-lateral parietal cortex (ilPC) after treatment predicted decreases in depression five weeks later. The authors contended that their results could be representative of a commonality in the antidepressant mechanisms of electroconvulsive therapy (ECT) and psilocybin, where connectivity of the DMN is acutely disintegrated and then normalized post-treatment in a "reset" that facilitates subsequent changes. Finally, researchers have found that, in non-human models, psychedelics can stimulate neuroplasticityand neurogenesis, both of which have been longtheorized to interact with depression; however, these two neural mechanisms remain speculative until further elucidated in humans.

PERSONALITY/ATTITUDES

Changes in personality and attitudes are among the most commonly studied long-term changes related to psychedelic use. In particular, increased openness to experience has been commonly linked to experience with psychedelics. Although 4 of the 7 unique studies assessing openness reported increases, participants in one of the null sampleswere already particularly high in openness prior to the experiment, potentially leading to ceiling effects. It should perhaps be unsurprising that these individuals were high in openness to experience given that they were the first participants administered psilocybin in the modern era of psychedelic research. Predictors of changes in openness include the degree to which one has a mystical experienceas well as increases in global measures of neural entropy. Neural entropy is thought to reflect uncertainty or randomness in neural signaling.argue that psychedelics increase entropy past the point of "criticality", such that there is a wider repertoire of functional connectivity, allowing for individuals to think in new ways. In addition to increased openness, heightened extraversion and decreased neuroticism have been documented, both of which correlated with ratings of insightfulness during the psilocybin session. Measures of conscientiousness and absorption have also been shown to increase one month after administration of psilocybin. Other studies examined broader long-term changes in attitudes about life, one's self, others, and nature. Lasting improvements in mood and positive attitudes were common themes extrapolated from the review, and increased optimism and mindfulness may be driving some of the positive psychological changes.found decreased authoritarianism and strengthened nature relatedness psilocybin, supporting previous correlational findings between psychedelic use and nature ness. These increases in connection seem to be broad and generalizable as studies also noted sustained improvements in social relations and altruism. Psychedelicinduced ego dissolution and declines in DMN activityare consistent with these changes in connection and selflessness, offering speculative underlying mechanisms.

WELLBEING/QUALITY OF LIFE

Long-term changes in wellbeing and quality of life have been studied primarily in healthy, spiritually active (i.e., those with at least intermittent participation in religious or spiritual activities), or end-oflife distress participants. In healthy/spiritually active samples, psilocybinand LSDhave been shown to induce lasting improvements in wellbeing. Notably,found that 79% of participants rated that the experience increased their wellbeing or sense of life satisfaction "moderately" (50%) or "very much" (29%) two months after their psilocybin session. This effect seemed to be generally enduring as 64% responded the same at the 14-month followup. However, further research is needed to identify what factors led to a subset of participants tempering their reaction. In a follow-up psilocybin study, 94% noted improved wellbeing or life satisfaction at the one-month assessment. Improvements in quality of life may be even more important among those approaching death. In their simultaneous trials,andrespectively found that 87% and 82% of patients with life-threatening cancer reported increased life satisfaction or wellbeing six months post-psilocybin treatment. Many indicated that the experience was cathartic, led to a greater appreciation of life, and helped them come to terms with their own mortality. Psychedelic treatment's unique capacity to assuage distress related to dying has been demonstrated in several studies as researchers have found increased sense of continuity after deathand death acceptance, as well as 77% of participants reporting less fear of death in another study. These changes may be contributing to decreases in cancer-related demoralization and hopelessness which have been documented with psilocybin. More direct inquiries into participant accounts have identified several factors which seem to be related to increased wellbeing, particularly in those with end-of-life distress. In their qualitative analysis of participant reports,found that patients with life-threatening diseases consistently reported that their LSD experience was insightful, cathartic, and fundamentally restructuring. They generally felt more relaxed with themselves and others. One representative patient account summarized "Quality of life changed extremely insofar as I became calmer, that I take things easier. It makes a difference if I look upon death with stress or with equanimity. I believe that is an enormous difference in quality of life." Finally,noted there was a strong correlation (r = .72) between memory vividness under psilocybin and long-term increases in wellbeing, suggesting that an assortment of factors can play into these changes.

MEANINGFUL AND SPIRITUAL EXPERIENCES

Given the robustness of the affective changes discussed so far, it should be unsurprising that, long after their sessions, many participants report their psychedelic experiences as being incredibly personally meaningful, and sometimes spiritually significant. In a seminal study,found that two-thirds of participants rated their psilocybin session as being among the top five most meaningful experiences of their entire lives two months after the experiment; 58% responded similarly at the 14-month follow-up. In a subsequent experiment, this research group once again found that two-thirds of a new sample of participants included the experience as being among their five most meaningful experiences five months later. Likewise,evaluated the efficacy of psilocybin treatment for smoking cessation and found that 86% put it in their five most meaningful experiences, and 58% reported similarly in another study one month after their psilocybin session.noted that 71% of healthy participants administered LSD included the session in their ten most meaningful events. The fluctuation across studies likely relates to small sample sizes, but in-general, psychedelic treatment appears to reliably induce meaningful experiences-experiences which have been reported to be comparable in importance to events such as childbirth or losing a parent. In addition to being personally meaningful, in some cases, psychedelic experiences have been described as being spiritually significant and can lead to long-lasting changes in spirituality. These findings are in line with anthropological evidence noting the substances' traditional use in religious ceremonies, which has continued for centuries. In our search, changes in spirituality were shown to be dose-dependentand corroborated by community ratings (i.e., close family members and friends;. The one study which did not find increased spirituality utilized a sample of exclusively spiritually active participants, suggesting potential ceiling effects; however, because these participants reported increased spirituality at an earlier follow-up (i.e., two months;, it is unclear why this effect attenuated at the 14-month follow-up. In addition to lasting trait-level changes in spirituality, some individuals rate their psychedelic session itself as being a spiritually significant experience long after the experiment. For example, 83% of participants in two studies included their psilocybin session as one of their five most spiritually significant experiences at the long-term follow-upand 67% responded similarly in another trial. In this study, the degree to which one had a mystical experience predicted enduring increases in spirituality. It should be noted, however, that it is currently unclear how the extent to which one is primed to explore their spiritual convictions on the drugs, as well as their intention to have a spiritual experience, influences their likelihood of having spiritual insights and/or reinforced spiritual beliefs. This is an important area of study given that psychedelics have been shown to enhance suggestibilityand meaning. That is, while under the influence of the drugs, suggestions and insights can feel more convincing and meaningful than they otherwise would. In the presence of a skilled therapist or shaman, this state can be utilized to positively alter self-narratives and attitudes, or reinforce spiritual convictions. Some, however, have attempted to exploit this state to convince individuals to commit acts they otherwise may not have done, as was seen with Charles Manson. Baseline measures of conscientiousness are one factor which correlate with enhanced suggestibility.

SUBSTANCE USE DISORDER

A reemerging application of psychedelic therapy, which dates back to the first era of research; seefor a meta-analysis), is in their treatment for substance use disorders. Our search returned one proof-of-concept study examining the effects of psilocybin on alcohol use disorder, three studies with tobacco use disorder, and one qualitative analysis of participants' accounts taken several years after the smoking cessation intervention.conducted the only study examining the effects of psilocybin treatment on alcohol use disorder. They found that, relative to baseline, percentage of drinking days and percentage of heavy drinking days immediately decreased, and these changes were sustained at least 36 weeks after treatment. Intensity of acute effects and the degree to which one had a mystical experience predicted long-term changes in abstinence and cravings. Although changes in abstinence and cravings were maintained, measures of mood and motivation were unchanged; currents trials are ongoing to follow-up these preliminary findings. More work has been published examining psilocybin therapy for tobacco use disorder, but all four of the articles we identified used the same sample of participants. The pilot study found that 6 months after psilocybin treatment, 12/15 participants (i.e., 80%) were abstinent and this was verified with nicotine biomarkers; cravings and temptation to smoke were attenuated as well. At the 12month follow-up, 10/15 (67%) remained abstinent as did 9/15 (60%) at the long-term (i.e., avg. 30 months) assessment. Mean ratings of the sessions' personal meaning, spiritual significance, and mystical experience predicted positive changes in cravings, self-reported abstinence, and smoking biomarkers. A long-term qualitative analysis of 12 patient accounts found many reported that the overpowering sense of awe, and subsequent lingering curiosity about life's mysteries, evoked by the session diminished the relative importance of smoking in their lives. Preparatory counselling, secure rapport with the research team, and a sense of momentum once treatment began were additional variables perceived as integral in maintaining abstinence. Decreased intensity and frequency of withdrawal symptoms compared to previous attempts to quit smoking were noted in 11 out of 12 patients. Beyond achieving abstinence, participants subjectively reported various other enduring positive effects including heightened aesthetic appreciation, altruism, prosocial behavior, and interconnectedness-leading some to identify quitting smoking as one of the least important outcomes of the study.

METHODOLOGICAL CRITIQUE

Although the findings reported to-date have been promising and stimulated interest within the recreational and scientific psychedelic communities, it is important to critically assess the methodological rigor of these studies. Doing so can advance future experimental methodology in psychedelic science and, thus, improve subsequent treatment. To begin, although roughly half of the studies in our review included control conditions, there is still much debate within the research community about what constitutes an adequate control for a psychoactive drug. Some experiments have used amphetamines, whereas others have opted to use low doses of hallucinogens, niacin, or Benadryl. This is among the most important methodological concerns in psychedelic research, given the potential self-selection biases inherent to the field. These effects can be magnified in studies which include participants with history of previous psychedelic use. That is, ostensibly only those with positive previous experiences with the drugs would choose to take them again in a study, and those with adverse reactions would want to avoid them and would be less apt to enroll. Another considerable limitation for the field regards the generalizability of the findings; the samples used to date have been largely homogenous: white, educated, and generally middle-aged. There has been a call in recent years to consider individual differences, such as age and race, by incorporating more diverse participants. Screening procedures which commonly exclude those with cardiovascular conditions as well as those with personal or family histories of schizophrenia, Psychotic Disorder, or Bipolar Disorder also limit the generalizability of findings. Typically small sample sizes and, as of yet, variable dosages across studies are additional limitations to the field. Future studies should consistently report if participants used other medications during and after treatment. Researchers should also provide clearer operational definitions for psychospiritual terms and more explicitly detail what changes in spirituality encompass. That being said, some studies have employed a high level of methodological rigor. For example,andsimultaneous dual-site, double-blind, placebo-controlled, crossover psilocybin trials for cancer patients experiencing end-of-life distress conducted at Johns Hopkins University and New York University, respectively, are of particular note, demonstrating that a high level of control is possible in psychedelic research.

FUTURE DIRECTIONS

Several themes emerged from this review that can guide forthcoming studies. First, future researchers should mitigate the previously discussed limitations by including larger and more diverse samples, stronger blinding procedures/control groups, stronger methods to reduce expectancies, and standardized dosages. More direct comparisons between individual psychedelics drugs and further research into the long-lasting effects of psychedelics beyond psilocybin are also important future areas of study. Lengthier longitudinal designs are required to identify the extent to which the aforementioned changes are maintained beyond the long-term latencies studied so far. A notable finding from our review was the paucity of research on how structural and functional neuroimaging measures relate to long-term changes. Four studies related acute neural effects to long-term psychological changes, but only one assessed long-term neural measures. Despite the growing number of psychedelic studies utilizing neuroimaging (see dos Santos et al., 2016 for a review), it seems the drugs' effects on longterm neural measures is an open area of research. Future researchers should also delineate psychedelics' effects on suggestibility, meaning, and enhancement of placebo effects, which could coalesce some of their transdiagnostic applications. Finally, although the role of music in psychedelic therapy sessions is another growing area of research (e.g.,, future studies assessing long-term behavioral outcomes related to interest in music, or art more broadly, are warranted given findings from historical researchand subjective reports.

CONCLUSION

This systematic review filled a critical gap in the literature regarding the long-term outcomes of psychedelic drugs. Our search identified 34 human-sample, long-term studies in the contemporary era of research with classic psychedelics. Most of this work utilized psilocybin and was published in the last five years. Sustained changes in personality/attitudes, depression, spirituality, affect/mood, anxiety, wellbeing, substance use, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were among the most commonly theorized mechanisms leading to long-term change. Psychedelics have been shown to be relatively safe when used with the proper preparation, supervision, and integration, but it is unclear the extent to which this generalizes to recreational use. Future research can improve upon current experimental limitations by utilizing larger and more diverse samples, refining control conditions, and delineating dosage effects. Nonetheless, the weight of the evidence collected to-date suggests that, in carefully screened and monitored individuals, psychedelic treatment can mediate changes in psychological functioning that are generally positive and enduring.