Psychedelic Treatments for Substance Use Disorder and Substance Misuse: A Mixed Methods Systematic Review

Figures & data

Figure 1. PRISMA flow diagram.

Table 1. Summary of included studies.

Author (year) Country	Study Design	Sample Size (n=): Female (F), Male (M) Mean age (SD) Ethnicity: %	Substance of Dependence	Duration of Treatment and Intervention	Outcomes (Measures) and Time Points
Bogenschutz et al. (2015)*; Nielson et al. (2018) USA	Before-and-after study	n = 10: 4F, 6 M 40.1 (10.3) Native American/Alaska Native: 20% African American: 10% Hispanic: 40% White: 30%	Alcohol	12-week program Psilocybin orally − 2 sessions 1st dose week 4 (n = 10) = 0.3 mg/kg, 2nd dose week 8 (n = 7) 0.4 mg/kg, and motivational enhancement therapy − 7 sessions	Substance Use (Mean % Drinking Days): Decreased from~42% at baseline to~12% at Weeks 1–4 post first psilocybin session (p = .009), ~17% at Weeks 5–8 post first psilocybin session (p = .015), ~11% at Weeks 9–20 post first psilocybin session (p = .006), and~18% at Weeks 21–32 post first psilocybin session (p = .007). Substance Use (Mean % Heavy Drinking Days): Decreased from~35% at baseline to~9% at Weeks 1–4 post first psilocybin session (p = .007), ~14% at Weeks 5–8 post first psilocybin session (p = .019), ~11% at Weeks 9–20 post first psilocybin session (p = .010), and~13% at Weeks 21–32 post first psilocybin session (p = .004). Self-Efficacy to Abstain from Alcohol Use (Alcohol Abstinence Self-Efficacy): Temptation mean scores decreased from baseline (38.30) to 5-weeks post-psilocybin session (24.56) (p < .05) and 20-weeks post-psilocybin session (26.63) (p < .05). Confidence mean scores increased from baseline (40.10) to 1-week post-psilocybin session (55.56) (p < .05). Consequences of Alcohol Use (Short Inventory of Problems): Interpersonal mean scores decreased from baseline (4.80) to 20-weeks post-psilocybin session (2.56) (p < .01) and 32-weeks post-psilocybin session (2.56) (p < .01). Intrapersonal mean scores decreased from baseline (7.30) to 20-weeks post-psilocybin session (3.89) (p < .05) and 32-weeks post psilocybin session (3.67) (p < .05). Alcohol Craving (Penn Alcohol Craving Scale): Mean scores decreased from baseline (16.00) to 5-weeks post-psilocybin session (10.00) (p < .01), 8-weeks post-psilocybin session (12.11) (p < .05), and 32-weeks post-psilocybin session (8.11) (p < .001). Mood (Profile of Mood Scale): Vigor mean scores increased from baseline (5.60) to 20-weeks post-psilocybin session (9.56) (p < .05). Motivation (Stages of Change Readiness and Treatment Eagerness Scale): Ambivalence mean scores decreased from baseline (15.70) to 20-weeks post-psilocybin session (12.00) (p < .05) and 32-weeks post-psilocybin session (11.56) (p < .05). Taking Steps mean scores increased from baseline (32.30) to 1-week post-psilocybin session (36.33) (p < .05), 4-weeks post-psilocybin session (36.33) (p < .01), 5-weeks post-psilocybin session (37.33) (p < .01), 8-weeks post-psilocybin session (35.78) (p < .05), and 20-weeks post-psilocybin session (36.00) (p < .05). 2nd Report Nielson et al. (2018) Qualitative Content Analysis (Day after each psilocybin session) Ego-dissolution: Fear of completely losing sense of self, and taking comfort in retaining identity Relationship to alcohol: Participants consistently described a change in their relationship to alcohol Motivation for change: Expressions of desire to change and increased confidence in avoiding alcohol Commitment to change: Participants discuss doing things differently and serving a purpose
Brown and Alper (2018) Mexico	Case series	n = 30: 5F, 25 M 29 (9.0) White: 90% Hispanic: 3% Other: 6%	Opioid	3–6-day treatment Ibogaine HCl orally Total average dose 1540 ± 920 mg Test dose: 3 mg/kg Flood dose: 12 mg/kg (2–12 hours posttest dose) Booster dose: 3-5 mg/kg (1–16 hours post-flood dose)	Abstinence (Opioid-free days in previous 30 days): 50% (n = 15) reported no opioid use in past 30 days at 1-month follow-up. 33% (n = 10) reported no opioid use in past 30 days at 3-month follow-up. 20% (n = 6) reported no opioid use in past 30 days at 6-month follow-up. 37% (n = 11) reported no opioid use in past 30 days at 9-month follow-up. 23% (n = 7) reported no opioid use in past 30 days at 12-month follow-up. Withdrawal – Self-rated(SOWS1) (n = 27): Mean scores decreased from pre-treatment baseline (31 points) to post-ibogaine treatment (14 points) (p < .001). Mean time between SOWS administration was 76.5 hours. Composite Drug Use and Functioning Scale (Addiction Severity Index Composite): Drug Use composite scores decreased from baseline (0.40) to 1-month post-ibogaine treatment (0.11) (p < .001), 3-months post-ibogaine treatment (0.15) (p < .001), 6-months post-ibogaine treatment (0.12) (p < .001), 9-months post-ibogaine treatment (0.13) (p < .001), and 12-months post-ibogaine treatment (0.17) (p < .001). Alcohol Use composite scores increased from baseline (0.08) to 1-month post-ibogaine treatment (0.09)^†, decreased from baseline to 3-months post-ibogaine treatment (0.07) ^†, and increased from baseline to 6-months post-ibogaine treatment (0.16) ^†, 9-months post-ibogaine treatment (0.12) ^†, and 12-months. post-ibogaine treatment (0.16) ^†. Family/Social Status composite scores decreased from baseline (0.24) to 1-month post-ibogaine treatment (0.07) (p < .001), 3-months post-ibogaine treatment (0.06) (p < .001), 6-months post-ibogaine treatment (0.08) (p < .01), 9-months post-ibogaine treatment (0.03) (p < .001), and 12-months post-ibogaine treatment (0.04) (p < .001). Employment Status composite scores increased from baseline (0.34) to 1-month post-ibogaine treatment (0.44) (p < .01), decreased from baseline to 3-months post-ibogaine treatment (0.33) ^† and 6-months post-ibogaine treatment (0.26) ^†, increased from baseline to 9-months post-ibogaine treatment (0.37) ^† and decreased from baseline to 12-months post-ibogaine treatment (0.25) ^†. Legal Status composite scores decreased from baseline (0.22) to 1-month post-ibogaine treatment (0.10) (p < .01), 3-months post-ibogaine treatment (0.04) (p < .01), 6-months post-ibogaine treatment (0.14) (p < .05), 9-months post-ibogaine treatment (0.05) (p < .05), and 12-months post-ibogaine treatment (0.10) (p < .01). Medical Status composite scores increased from baseline (0.19) to 1-month post-ibogaine treatment (0.26) ^†, 3-months post-ibogaine treatment (0.27) ^†, and 6-months post-ibogaine treatment (0.25) ^†, decreased from baseline to 9-months post-ibogaine treatment (0.15) ^†, and increased from baseline to 12-months post-ibogaine treatment (0.26). Psychiatric Status composite scores decreased from baseline (0.27) to 1-month post-ibogaine treatment (0.18) ^†, decreased from baseline to 3-months post-ibogaine treatment (0.17) (p < .05), 6-months post-ibogaine treatment (0.16) (p < .01), and decreased from baseline to 9-months post-ibogaine treatment (0.14) ^†, and 12-months post-ibogaine treatment (0.23) ^†.
Glue et al. (2016) New Zealand	RCT	n = 27: 6F, 21 M 41.2 (not specified) White: 74% Maori: 19% Other: 7%	Patients on opioid substitution therapy (25-80 mg/day for at least 30 days prior to screening)	4-day treatment with Noribogaine orally (n = 18) 60 mg/120 mg/240 mg (n = 6 for each dose level) Placebo orally (n = 9) (n = 3 for each dose level)	Withdrawal – Self and clinician rated (SOWS, COWS2, OOWS3): Increases in all scales 1–2 hours prior to resumption of opioid substitution therapy, and decreased within 1–3 hours of opioid substitution therapy. ^†. Withdrawal – Pupil Diameter (mm): Mean pupil diameter increased by 0.47 mm in the 2 hours prior to resumption of opioid substitution therapy across Treatment Arms (Placebo, Noribogaine 60 mg, Noribogaine 120 mg, Noribogaine 180 mg) ^†. Time (hours) to Resumption of Opioid Substitution Therapy (Mean (SD)): - By Treatment Arm: Placebo (n = 9): 13.9 (7.4) 60 mg Noribogaine (n = 6): 8.6 (3.7) ^†. 120 mg Noribogaine (n = 6): 22.5 (10.3) ^†. 180 mg Noribogaine (n = 6): 11.4 (5.0) ^†. - By Cohort: Placebo results for each cohort were similar to those of corresponding active arm (Pearson’s r = 0.993) Cohort 1: Placebo (n = 3): 9.0 (3.1)/60 mg Noribogaine 8.6 (3.7) ^†. Cohort 2: Placebo (n = 3): 20.5 (9.6)/120 mg Noribogaine 22.5 (10.3) ^†. Cohort 3: Placebo (n = 3): 12.1 (3.3)/180 mg Noribogaine 11.4 (5.0) ^†.
Johnson et al. (2014)*; Johnson, Garcia-Romeu, and Griffiths (2017) USA	Before-and-after study	n = 15: 5F, 10 M 51 (10.5) White: 93% Asian: 7%	Nicotine	15-week programme Psilocybin orally (2 doses weeks 5 (20 mg/70 kg), & 7 (30 mg/70 kg), and 1 optional high dose week 13) (n = 3) (30 mg/70 kg) and Cognitive Behavioral Therapy for smoking cessation (weeks 1–4 before psilocybin administration)	Abstinence (Carbon Monoxide Levels, Urine Cotinine, Timeline Follow-back): 80% (n = 12/15) showed 7-day point prevalence abstinence at 6-month follow-up (p < .001). Substance use (Timeline Follow-back): Mean cigarettes per day (CPD) decreased from intake (16.5) to 6-month follow-up (2.7) (p < .001). Biological Markers (Breath Carbon Monoxide Levels and Urine Cotinine): Significant reductions in CO levels (p < .01) and urine cotinine (p = .4) from intake to 6-month follow-up. ^†† Craving (Questionnaire of Smoking Urges): Significantly decreased from intake to 6-month follow-up (p < .001). ^††. Self-efficacy (Smoking Abstinence Self-efficacy Scale): Significant increase in confidence to abstain (p < .001) and significant decrease in temptation to smoke (p < .001) from intake to 6-month follow-up. ^†† Withdrawal (Wisconsin Smoking Withdrawal Scale): Significant decrease from intake to 6-month follow-up (p = .009). ^†† 2nd report: Johnson, Romeu, and Griffiths (2017) Abstinence (Carbon Monoxide Levels, Urine Cotinine, Timeline Follow-back): 67% (n = 10/15) abstinent at 12-month follow-up, 90% abstinent at longer term (>16 months, mean interval of 30 months) follow-up (p < .001). Substance Use (Timeline Follow-back): Significant decrease in Mean CPD from Intake (16.5 CPD) to 12-month follow-up (3.3 CPD) (p < .001) and 30-month follow-up (4.3 CPD) (p < .001). Persisting Effects (Persisting Effects Questionnaire): Higher rates of positive effects than negative in all domains (Attitudes about Life and Self, Mood, Behavior Changes, Mood Changes, Relationships, and Spirituality) at 12-month follow-up. Positive Behavior Change (Mean): Increased from Session 1(52.9) to 12-month follow-up (64.0) ^†. Negative Behavior Change (Mean): Decreased from Session 1 (7.1) to 12-month follow-up (4.0) ^†. Positive Mood Change (Mean): Increased from Session 1 (34.6) to 12-month follow-up (53.0) ^†. Negative Mood Change (Mean): Decreased from Session 1 (14.1) to 12-month follow-up (7.0) ^†.
Malcolm, Polanco, and Barsuglia (2018) Mexico	Case series	n = 40: 15F, 25 M 31.28 (8.38) White: 77.5% Asian: 5% Other: 17.5%	Opioid use disorder	1-week treatment Ibogaine HCl orally 18-20 mg/kg. Test dose: 100 mg Flood dose: Remainder given within 2 hours Booster: 1-5 mg/kg given if post-acute withdrawal symptoms occur at 72-hours post-ibogaine administration 4 days in treatment center, 3 days in residential setting	Withdrawal – Clinician-rated (COWS): Mean group scores decreased from 48-hours pre-ibogaine treatment (8.20) and 24-hours pre-ibogaine treatment (7.64) to 24-hours post-ibogaine treatment (5.26) and 48-hours post-ibogaine treatment (3.30) (p < .01). Withdrawal – Self-rated (SOWS): Mean group scores decreased from 48-hours pre-ibogaine treatment (20.51) and 24-hours pre-ibogaine treatment (17.09) to 24-hours post-ibogaine treatment (12.63) and 48-hours post-ibogaine treatment (10.04) (p < .01). Craving (Brief Self-control Scale): Mean group scores decreased from 48-hours pre-ibogaine treatment (6.58) and 24-hours pre-ibogaine treatment (5.98) to 24-hours post-ibogaine treatment (2.69) and 48-hours post-ibogaine treatment (1.92) (p < .01).
Mash et al. (2018) West Indies	Case series	n = 191: 47F, 144 M n = 102 opioids dependency: 34F, 68 M 35.8 (9.9) White: 95.1% Hispanic: 2.9% Native American: 2.0% n = 89 cocaine dependency: 13F, 76 M 36.1 (9.1) White: 78.7% African American: 2.2% Hispanic: 15.7% Native American: 3.4%	Opioid or Cocaine	12-day inpatient treatment with Ibogaine HCl 8-12 mg/kg orally and motivational counseling during and post ibogaine	Withdrawal – Clinician rated (OOWS): Scores decreased from pre-ibogaine dose (3–13) to~36-hours post-ibogaine dose (0–2) ^†. Craving (Heroin Craving Questionnaire-29) (Opioid Dependent Participants): Emotionality (Negative Mood) mean scores decreased from baseline (3.51) to discharge (2.02) and 30-days follow-up (1.69) (p < .001). Purposefulness (Desire or intent to use drug now) mean scores decreased from baseline (4.10) to discharge (2.21) and 30-days follow-up (2.04) (p < .001). Compulsivity (Lack of confidence in ability to quit using drug) mean scores decreased from baseline (3.23) to discharge (2.04) and 30-days follow-up (1.64) (p < .001). Expectancy (Expected positive benefits of drug use) mean scores decreased from baseline (4.51) to discharge (3.74) and 30-days follow-up (2.90) (p < .001). Craving (Cocaine Craving Questionnaire-45) (Cocaine Dependent Participants): Emotionality (Negative Mood) mean scores decreased from baseline (1.85) to discharge (1.09) and 30-days follow-up (1.19) (p < .001). Purposefulness (Desire or intent to use drug now) mean scores decreased from baseline (2.60) to discharge (1.54) and 30-days follow-up (1.57) (p < .001). Compulsivity (Lack of confidence in ability to quit using drug) mean scores decreased from baseline (4.27) to discharge (2.95) and 30-days follow-up (3.15) (p < .001). Expectancy (Expected positive benefits of drug use) mean scores decreased from baseline (2.51) to discharge (1.93) and 30-days follow-up (1.76) (p < .001). Craving (Minnesota Cocaine Craving Scale): Craving Intensity mean scores decreased from baseline (5.51) to discharge (1.47) and 30-days follow-up (1.96) (p < .001). Craving Frequency mean scores decreased from baseline (2.28) to discharge (0.29) and 30-days follow-up (0.52) (p < .001). Craving Duration mean scores decreased from baseline (2.51) to discharge (1.36) and 30-days follow-up (1.21) (p < .001). Depression (Beck Depression Inventory-II) (Opioid Dependent Participants): Mean scores decreased from baseline (16.5) to discharge (8.9) and 30-days follow-up (4.5) (p < .001). Depression (Beck Depression Inventory-II) (Cocaine Dependent Participants): Mean scores decreased from baseline (14.3) to discharge (4.2) (1.0) and 30-days follow-up (4.5) (p < .001). Mood (Profile of Mood Scale Depression Subscale) (Opioid Dependent Participants): Mean scores decreased from baseline (22.1) to discharge (10.8) and 30 days follow-up (5.8) (p < .01). Mood (Profile of Mood Scale Depression Subscale) (Cocaine Dependent Participants): Mean scores decreased from baseline (19.4) to discharge (7.1) and 30-days follow-up (5.8) (p < .001). Psychological Symptoms (Symptoms Checklist-90 Scale Depression Subscale) (Opioid Dependent Participants): Mean scores decreased from baseline (1.7) to discharge (0.8) and 30-days follow-up (0.4) (p < .001). Psychological Symptoms (Symptoms Checklist-90 Scale Depression Subscale) (Cocaine Dependent Participants): Mean scores decreased total mean score from baseline (1.2) to discharge (0.5) and 30-days follow-up (0.3) (p < .001).
					Qualitative (Subjective interpretations of experience within 3-days post ibogaine) (n = 60): Useful for drug problems = 91.7% Given insight into self-destructive behaviors = 86.7% Mindful of need to become sober/abstinent now = 68.3% Cleansed/healed/reborn = 50.0% Second chance at life = 40.0% Increased self-confidence = 33.3% Impending self-destruction if drug use continued (saw images of their death) = 18.3% Willingness to repeat ibogaine experience = 16.7%
Thomas et al. (2013)^*; Argento et al. (2019)** Canada	Case series	n = 18, n = 12 in first retreat and n = 6 in second; data from n = 12 who attended both retreats and had no missing data 5F, 6 M (1 participant not accounted for) 38 (not specified) First Nations band (indigenous population in Canada)	Problematic substance use	4-day retreat Ayahuasca (tea) and group counseling	Emotional Regulation (Difficulty in Emotional Regulation Scale): Analysis of Variance (ANOVA) scores improved from pre-treatment to 6-month follow-up. Exact values not provided (p = .124). Mindfulness (Philadelphia Mindfulness Scale): ANOVA scores increased from pre-treatment to 6-month follow-up (p = .041) ^††. Empowerment (Empowerment Scale): ANOVA scores significantly increased from pre-treatment to 6-month follow-up (p = .002) ^††. Hope (Hope Scale): ANOVA scores significantly increased from pre-treatment to 6-month follow-up (p = .023) ^††. Quality of Life (McGill Quality of Life Questionnaire): Meaning and Outlook ANOVA scores increased from pre-treatment to 6-month follow-up for Meaning (p = .005) and Outlook (p = .004) scales. Psychological scale ANOVA scores increased from pre-treatment to 6-month follow-up (p = .055) ^††. Substance Use (4-Week Substance Use Scale) (Percentage of participants who had used): Tobacco use decreased from Baseline (81.8%) to 6-month follow-up (63.6%) (n = 11) ^†. Alcohol use decreased from Baseline (50%) to 6-month follow-up (20%) (n = 10) ^†. Cannabis use remained the same from Baseline (45.5%) to 6-month follow-up (45.5%) (n = 11) ^†. Cocaine use significantly decreased from Baseline (60%) to 6-month follow-up (0%) (n = 10) ^†. Sedative use remained the same from Baseline (18.2%) to 6-month follow-up (18.2%) (n = 11) ^†. Hallucinogen use increased from Baseline (0%) to 6-month follow-up (9.1%) (n = 11) ^†. Opioid use remained the same from Baseline (9.1%) to 6-month follow-up (9.1%) (n = 11) ^†. Qualitative (Semi-structured interview at 6-month follow-up): Connection with self: overcoming fears and anger, finding love and respect for self, being given another chance Connection with others: Closer ties to family, enjoying time spent with others Substance use: Retreat helped release the hurt and pain from substance use, ayahuasca helped remove cravings for alcohol/crack cocaine

Key.

*: Denotes main paper of the study.

^†p value for this comparison was not provided in the paper.

^††Exact values for this comparison were not provided in the paper.

1SOWS: Subjective Opiate Withdrawal Scale.

2COWS: Clinical Opiate Withdrawal Scale.

3OOWS: Objective Opiate Withdrawal Scale.

**: Paper used for demographic data extraction only.

Table 2. Quality assessment of includes studies using ICROMS.

Study	Design	Aims & Justification	Sampling	Outcome Measures & Blinding	Follow-up	Other Study Aspects	Analytical Rigor	Other Considerations	ICROMS Minimum Score Required	Global Quality Score
Bogenschutz et al. (2015)	Before-and-after study	5	0	4	2	1	2	8	22	22
Brown and Alper (2018)	Case series	1	0	2	2	0	0	7	22	12
Glue et al. (2016)*	RCT	2	3	5	6	2	2	7	22	27
Johnson et al. (2014)*	Before-and-after study	5	2	2	1	0	1	7	22	18
Malcolm, Polanco, and Barsuglia (2018)	Case series	4	0	2	2	2	0	8	22	18
Mash et al. (2018)	Case series	2	0	2	2	1	2	7	22	16
Nielson et al. (2018)*	Qualitative study	4	2	1	2	1	1	6	16	17
Thomas et al. (2013)	Case series	4	0	2	2	1	2	6	22	17

Bogenschutz, M. P., A. A. Forcehimes, J. A. Pommy, C. E. Wilcox, P. C. R. Barbosa, and R. J. Strassman. 2015. Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. Journal of Psychopharmacology 29 (3):289–99. doi:10.1177/0269881114565144.

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Nielson, E. M., D. G. May, A. A. Forcehimes, and M. P. Bogenschutz. 2018. The psychedelic debriefing in alcohol dependence treatment: Illustrating key change phenomena through qualitative content analysis of clinical sessions. Frontiers in Pharmacology 9 (132):1–13. doi:10.3389/fphar.2018.00132.

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Brown, T. K., and K. Alper. 2018. Treatment of opioid use disorder with ibogaine: Detoxification and drug use outcomes. The American Journal of Drug and Alcohol Abuse 44 (1):24–36. doi:10.1080/00952990.2017.1320802.

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Glue, P., G. Cape, D. Tunnicliff, M. Lockhart, F. Lam, N. Hung, C. T. Hung, S. Harland, J. Devane, R. S. Crockett, et al. 2016. Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients. Clinical Pharmacology in Drug Development 5 (6):460–68. doi:10.1002/cpdd.254.

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Johnson, M. W., A. Garcia-Romeu, M. P. Cosimano, and R. R. Griffiths. 2014. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology 28 (11):983–92. doi:10.1177/0269881114548296.

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Johnson, M. W., A. Garcia-Romeu, and R. R. Griffiths. 2017. Long-term follow-up of psilocybin-facilitated smoking cessation. The American Journal of Drug and Alcohol Abuse 43 (1):55–60. doi:10.3109/00952990.2016.1170135.

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Malcolm, B. J., M. Polanco, and J. Barsuglia. 2018. Changes in withdrawal and craving scores in participants undergoing opioid detoxification utilizing ibogaine. Journal of Psychoactive Drugs 50 (3):256–65. doi:10.1080/02791072.2018.1447175.

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Mash, D. C., L. Duque, B. Page, and K. Allen-Ferdinand. 2018. Ibogaine detoxification transitions opioid and cocaine abusers between dependence and abstinence: Clinical observations and treatment outcomes. Frontiers in Pharmacology 9 (529):1–12. doi:10.3389/fphar.2018.00529.

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Thomas, G., P. Lucas, N. R. Capler, K. W. Tupper, and G. Martin. 2013. Ayahuasca-assisted therapy for addiction: Results from a preliminary observational study in Canada. Current Drug Abuse Reviews 6 (1):30–42. doi:10.2174/15733998113099990003.

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Argento, E., R. Capler, G. Thomas, P. Lucas, and K. W. Tupper. 2019. A qualitative analysis of preliminary findings among an Indigenous community in Canada. Drug and Alcohol Review 38 (7):781–89. doi:10.1111/dar.12985.

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