Psychedelic-assisted treatment for substance use disorder: A narrative systematic review

Theodore Piper; Francesca Small; Sam Brown; Michael Kelleher; Luke Mitcheson; James Rucker; Allan H. Young; John Marsden

doi:10.1111/add.16762

Psychedelic-assisted treatment for substance use disorder: A narrative systematic review

Theodore Piper, Francesca Small, Sam Brown, Michael Kelleher, Luke Mitcheson, James Rucker, Allan H. Young, John Marsden^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

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Abstract

Background and aims

This is the first systematic review of the extant literature on all major psychedelic-assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic-assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research.

Methods

This was a prospectively registered narrative systematic review of open-label, randomised controlled trials (RCT), and observational studies of d-lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non-randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool.

Findings

37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two-centre, placebo-controlled, phase 2 superiority RCT of psilocybin for AUD, and a two-centre, double-blind, four-arm, placebo-controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open-label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high-RoB and low-GRADE evidence certainty).

Conclusions

Psilocybin-assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic-assisted treatment should report all safety events; screen for person-level characteristics indicating that psychedelic-assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field-specific Core Outcome Set.

Original language	English
Journal	Addiction
Early online date	30 Jan 2025
DOIs	https://doi.org/10.1111/add.16762
Publication status	E-pub ahead of print - 30 Jan 2025

Keywords

alcohol use disorder
cannabis use disorder
cocaine use disorder
psychedelic-assisted treatment
substance use disorder
tobacco use disorder

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Psychedelic‐assisted treatment for substance_PIPER_Publishedonline30January2025_GOLD_VoR (CC BY)Final published version, 1.26 MBLicence: CC BY

Cite this

@article{c84ac10496714969a19fe0dd6186ec29,

title = "Psychedelic-assisted treatment for substance use disorder: A narrative systematic review",

abstract = "Background and aimsThis is the first systematic review of the extant literature on all major psychedelic-assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic-assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research.MethodsThis was a prospectively registered narrative systematic review of open-label, randomised controlled trials (RCT), and observational studies of d-lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non-randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool.Findings37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two-centre, placebo-controlled, phase 2 superiority RCT of psilocybin for AUD, and a two-centre, double-blind, four-arm, placebo-controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open-label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high-RoB and low-GRADE evidence certainty).ConclusionsPsilocybin-assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic-assisted treatment should report all safety events; screen for person-level characteristics indicating that psychedelic-assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field-specific Core Outcome Set.",

keywords = "alcohol use disorder, cannabis use disorder, cocaine use disorder, psychedelic-assisted treatment, substance use disorder, tobacco use disorder",

author = "Theodore Piper and Francesca Small and Sam Brown and Michael Kelleher and Luke Mitcheson and James Rucker and Young, {Allan H.} and John Marsden",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.",

year = "2025",

month = jan,

day = "30",

doi = "10.1111/add.16762",

language = "English",

journal = "Addiction",

issn = "0965-2140",

publisher = "Wiley-Blackwell Publishing Ltd",

}

TY - JOUR

T1 - Psychedelic-assisted treatment for substance use disorder

T2 - A narrative systematic review

AU - Piper, Theodore

AU - Small, Francesca

AU - Brown, Sam

AU - Kelleher, Michael

AU - Mitcheson, Luke

AU - Rucker, James

AU - Young, Allan H.

AU - Marsden, John

PY - 2025/1/30

Y1 - 2025/1/30

N2 - Background and aimsThis is the first systematic review of the extant literature on all major psychedelic-assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic-assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research.MethodsThis was a prospectively registered narrative systematic review of open-label, randomised controlled trials (RCT), and observational studies of d-lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non-randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool.Findings37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two-centre, placebo-controlled, phase 2 superiority RCT of psilocybin for AUD, and a two-centre, double-blind, four-arm, placebo-controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open-label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high-RoB and low-GRADE evidence certainty).ConclusionsPsilocybin-assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic-assisted treatment should report all safety events; screen for person-level characteristics indicating that psychedelic-assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field-specific Core Outcome Set.

AB - Background and aimsThis is the first systematic review of the extant literature on all major psychedelic-assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic-assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research.MethodsThis was a prospectively registered narrative systematic review of open-label, randomised controlled trials (RCT), and observational studies of d-lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non-randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool.Findings37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two-centre, placebo-controlled, phase 2 superiority RCT of psilocybin for AUD, and a two-centre, double-blind, four-arm, placebo-controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open-label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high-RoB and low-GRADE evidence certainty).ConclusionsPsilocybin-assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic-assisted treatment should report all safety events; screen for person-level characteristics indicating that psychedelic-assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field-specific Core Outcome Set.

KW - alcohol use disorder

KW - cannabis use disorder

KW - cocaine use disorder

KW - psychedelic-assisted treatment

KW - substance use disorder

KW - tobacco use disorder

UR - http://www.scopus.com/inward/record.url?scp=85216375060&partnerID=8YFLogxK

U2 - 10.1111/add.16762

DO - 10.1111/add.16762

M3 - Review article

AN - SCOPUS:85216375060

SN - 0965-2140

JO - Addiction

JF - Addiction

ER -

Psychedelic-assisted treatment for substance use disorder: A narrative systematic review

Abstract

Keywords

UN SDGs

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