Psychedelics: From Cave Art to 21st-Century Medicine for Addiction

Abstract

Background

Psychedelic substance use in ritualistic and ceremonial settings dates back as early as 8,500 BCE. Only in recent years, from the mid-20th century, we have seen the re-emergence of psychedelics in a therapeutic setting and more specifically for the treatment of addiction. This article aims to review research over the past 40 years using classic (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], mescaline) and atypical (ketamine, ibogaine, 5-MeO-DMT, 3,4-methylenedioxymethamphetamine) psychedelics for the treatment of addiction.

Summary

We will start with an overview of the pharmacology and physiological and psychological properties of psychedelic substances from pre-clinical and clinical research. We will then provide an overview of evidence gathered by studies conducted in controlled research environments and naturalistic and ceremonial settings, while we identify the proposed therapeutic mechanisms of each psychedelic substance.

Key Messages

Classic and atypical psychedelics show promise as therapeutic alternatives for the treatment of addiction, through the improvement of psychological and physiological symptoms of dependence. A more comprehensive understanding of the ancient and present-day knowledge of the therapeutic potential of psychedelics can facilitate hope for psychedelic therapeutics in the treatment of addiction, especially for individuals who have failed other conventional treatment methods.

Introduction

It will never be known when our ancestors started to intentionally consume psychoactive substances for consciousness changing, but we can be certain that they encountered psilocybin-containing mushrooms in different regions around the globe [1]. What we can only presume were psilocybin mushrooms, have been depicted in cave art, petroglyphs, and stone sculptures, long before human writing [1]. Archaeological investigations provide evidence of psychedelic use in ritualistic settings, spiritual practices, and therapeutic purposes dating back to 8,500 BCE [1–3].

Psychedelic substances became of scientific interest during the late 19th century with the synthesis of mescaline by Arthur Heffter [4, 5]. In the 1950s through to the early 1970s, there was an explosion of research using psychedelics with a great focus on their therapeutic potential for alcohol and drug addiction. Bill Wilson, founder of Alcoholics Anonymous, was the first person to bring psychedelics on the map for the treatment of addiction [6].

Despite this work and centuries of use within indigenous communities around the world, we have for the past 50 years seen a prohibition and stigmatisation of these substances, driven by the War on Drugs initiated by Nixon, that significantly restrained research on their effects and therapeutic properties [7]. Only in recent years have we seen the overturning of this prohibition with research using psychedelics, entering what has been called the “Psychedelic Renaissance”. For the purpose of this review, we use the term “classic psychedelics” to refer to psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT; ayahuasca), and mescaline that act as agonists at the 5HT2A receptor system and the term “atypical” psychedelics for ketamine, ibogaine, O-methyl-bufotenin (5-MeO-DMT), and 3,4-methyl​enedioxy​methamphetamine (MDMA).

Pharmacology and Receptors

Psychedelics are naturally occurring substances, but they can also be synthesised. A large amount of knowledge about psychedelic pharmacology and mechanisms has been derived from animal models. The head twitch response (HTR; paroxysmal rotational movement of the head) is one of the most common animal models for psychedelic activity [8, 9]. Recent pharmacological research using the HTR has pointed to the importance of the 5HT2A receptor in the action of classical psychedelics [8], with 5HT2A knock-out mice showing the absence of HTR following the administration of classic psychedelics [10]. In humans, the 5HT2A action of psychedelics contributes to their hallucinogenic effects [11, 12]. Aside from the 5HT2A receptor, other serotonin subtypes are involved, including the 5HT2B/C, 5HT1A, and also serotonin transporter [13]. Dopamine and noradrenaline receptors and transporters are also involved in the wider action of psychedelics [13].

The atypical psychedelic ketamine exerts its actions mainly via glutamatergic NMDA channel-blocking [14–17] and ibogaine through the kappa and mu-opioid receptor partial agonism [15, 16]. MDMA is a serotonin, dopamine, and oxytocin releaser, with the release of oxytocin possibly explaining MDMA’s prosocial effects [13, 18]. 5-MeO-DMT probably has a similar action to classic psychedelics [13, 19].

Physiological and Psychological Effects

Common physiological effects include increased heart rate, blood pressure, and body temperature which can remain high for several hours [20]. Nausea and vomiting, especially in high doses have also been observed [20].

The effects of psychedelics can be subjective and vary between individuals. Overall psychedelics can induce psychological alterations including changes in emotions, thoughts, mood, and perception (visual, auditory, tactile, olfactory, time, space) in the form of visual hallucinations and synaesthesia (stimulation of one sense causing the production of another sense), depersonalisation, and tactile sensation [12, 21, 22]. According to Pahnke, there are several characteristics of a psychedelic experience peak including, a “sense of unity, deeply felt positive mood, sense of sacredness, ineffability, and persisting positive changes in domains like attitudes and behaviour towards the self, others, life, and the experience itself” [23, 24].

Psychedelics for Addiction

Classic Psychedelics

Since the mid-late 20th century, a plethora of studies have been published on the use of classic psychedelics for the treatment of addiction [25]. Following the discovery of LSD in the 40s by Albert Hofmann, a spike in the interest of alcoholism treatment with LSD was seen [26]. In 2012, Krebs and Johansen published a meta-analysis of six randomised controlled trials, with a total of 536 treatment-seeking individuals, using a single dose of LSD to assist treatment programs of individual or group psychotherapy for alcoholism. Despite the varied LSD doses, differences in clinical interventions, and variations in the control conditions (low-dose LSD, d-amphetamine, ephedrine sulphate, or non-drug control) between the studies, the meta-analysis reported significant beneficial treatment effects on alcohol misuse following LSD at 3- and 6-month follow-up when compared with placebo (Table 1) [27]. The therapeutic potential of LSD paired with psychotherapy has also been researched for the treatment of heroin dependence (Table 2). Savage and McCabe found that the group assigned to LSD-assisted psychotherapy had significantly higher abstinence rates, with 33% abstinence at 12 months relative to the 5% seen in the control group [28]. Although 6 weeks of inpatient care provided only to the LSD groups could be a confounding factor in the results of this study, the outcomes are astounding for their time.

Table 1.

Summary of studies using classic and atypical psychedelics in non-ceremonial and ceremonial settings for alcohol use disorder

Substance	Author(s)	Year	Study characteristics	Drug and dose	Main findings
a. Classic psychedelics (psilocybin, LSD)	Krebs et al. [27]	2012	Meta-analysis of randomised controlled trials	LSD	Significantly beneficial short-term (2–3-month post-treatment) and medium-term (6-month post-treatment) effects of LSD on alcohol misuse
			Six eligible trials	Single dose	3/6 trials reported maintained abstinence from alcohol at short-term follow-up
			Total of 536 treatment-seeking participants (LSD, n = 325; placebo, n = 211)	Doses range from 3 μg/kg (∼210 μg) to 800 μg
			Trials included treatment programs varying from individual or group psychotherapy, interpersonal skills training, and counselling on alcohol misuse and withdrawal
	Bogenschutz et al. [29]	2015	Single-group within-subject proof-of-concept study	Psilocybin	PHDD and percent of drinking days decreased post psilocybin (weeks 5–12) relative to baseline and weeks 1–4 (therapy only)
			Ten volunteers with alcohol dependence (DSM-IV) with at least two heavy drinking days in the past 30 days	Session 1: 0.3 mg/kg	Abstinence increased significantly following psilocybin administration relative to weeks 1–4 (therapy only)
			12-week MET with two psilocybin sessions (at 4 and 8 weeks)	Session 2: 0.4 mg/kg	Gains were largely maintained at follow-up to 36 weeks
					Intensity of acute effects in the first psilocybin session (week 4) strongly predicted change in
					1. Drinking during weeks 5–8
					2. Increases in abstinence
					3. Decreases in craving
					4. Changes in self-efficacy during week 5
	Garcia-Romeu et al. [30]	2019	Retrospective cross-sectional online survey study	Psilocybin	Following the reference psychedelic experience
			343 individuals fulfilling DSM-V criteria for past or current AUD	LSD	1. 83% no longer met AUD criteria
				DMT/Ayahuasca	2. 28% endorsed psychedelic-associated changes in life priorities/values facilitating reduced alcohol misuse
				Moderate to high doses	3. 69% reported less severe withdrawal symptoms, particularly craving
	Bogenschutz et al. [31]	2022	Double-blind randomised clinical trial	Psilocybin versus diphenhydramine (placebo)	PHDD during the 32-week double-blind period was 9.7% (robust and sustained decreases in drinking) for the psilocybin group and 23.6% for the diphenhydramine group
			Ninety-five adults aged 25–65 years with a diagnosis of alcohol dependence (DSM-IV) and at least 4 heavy drinking days during the 30 days prior to screening	Session 1: 25 mg/70 kg versus 50 mg	Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group
			12 weeks of manualised psychotherapy (MET and cognitive behavioural therapy) and were randomly assigned to receive psilocybin or diphenhydramine twice (at 4 and 8 weeks)	Session 2: 25–40 mg/70 kg versus 100 mg	There were no serious adverse events among participants who received psilocybin
					Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy
					Participants who were treated with psilocybin were more likely than those receiving diphenhydramine to have no heavy drinking days
b. Atypical psychedelics (ketamine, ibogaine, 5-MeO-DMT, MDMA)	Krupitsky et al. [32] (no access to full paper)	1992	Non-randomised transpersonal therapy approaches with elements of aversive therapy in combination with one ketamine session	Ketamine	Ketamine-assisted therapy promoted higher levels of abstinence compared to the control group
			One hundred eighty-six alcohol-dependent individuals who either underwent ketamine assisted therapy or underwent traditional methods of therapy	2.5 mg/kg (im)
	Krupitsky and Grinenko [33] (no access to full paper)	1997	Transpersonal assisted therapy in combination with one ketamine session	Ketamine	65.8% abstinence (>1 year) in the ketamine group compared to 24% in the control group
			Two hundred eleven recently detoxified alcohol-dependent individuals who either underwent ketamine-assisted therapy or were treated as usual	2.5 mg/kg (im)
	Barsuglia et al. [34]	2018	Case report of a 31-year-old male military veteran with moderate AUD	Ibogaine	Alcohol cessation and reduced cravings at 5 days post-treatment
			Used ibogaine HCl on day 1 and vaporised 5-MeO-DMT on day 3	5-MeO-DMT	Effects were sustained at 1 month
			Individual received SPECT neuroimaging before and 3 days after completion of the program	Ibogaine HCl: 1,550 mg (17.9 mg/kg)	Partial return to mild alcohol use at 2 months
				5-MeO-DMT: 5–7 mg (from 50 mg bufotoxin)
	Das et al. [35]	2019	Randomised single-blind placebo-controlled trial	Ketamine	In the ketamine administration immediately followed by MRM relative to the ketamine alone and MRM retrieval alone conditions, significant decreases were found in the following:
			Ninety beer-preferring non-treatment-seeking individuals with problematic alcohol use, no formal AUD diagnosis, and scores >8 in the AUDIT were randomised to one of three conditions	Ketamine HCl and placebo concentrations were maintained at 350 ng/mL for 30 min	1. Drinking volume
			1. Ketamine and MRM retrieval with beer		2. Drinking enjoyment
			2. Ketamine alone with orange juice		3. Urge to drink a beer placed in front of them
			3. Placebo and MRM retrieval		4. General alcohol consumption (beer, wine, or spirits)
	Dakwar et al. [36]	2020	Randomised midazolam-controlled pilot study	Ketamine	Ketamine relative to midazolam significantly
			Forty treatment-seeking alcohol-dependent (DSM-IV) individuals	Ketamine HCl: 0.71 mg/kg (iv)	1. Increased the likelihood of abstinence
			5-week MET and were randomly assigned to receive ketamine or active control midazolam during week 2	Midazolam) active control): 0.025 mg/kg	2. Delayed the time to relapse
					3. Reduced the likelihood of heavy drinking days
	Sessa et al. [37]	2021	Open-label safety and tolerability proof-of-concept study	MDMA	MDMA treatment was safe and tolerated by all participant
			Fourteen detoxification-seeking individuals with AUD (DSM-V) completed a community alcohol detoxification and received an 8-week/10-session course of recovery-based therapy with MDMA at sessions 3 and 7	Total of 187.5 mg in each session: 125 mg initial dose and 62.5 mg booster dose on same day	Psychosocial functioning improved across the cohort
					At 9-month post-detox, there was a decrease in average units of alcohol consumption by participants from 130.6 units/week pre-detox to 18.7 units/week post-detox
	Grabski et al. [38]	2022	Double-blind placebo-controlled phase II clinical trial	Ketamine	Significantly greater number of abstinence days from alcohol in the ketamine relative to the placebo group at 3- and 6-month follow-up (pooled across therapy conditions)
			Ninety-six recently detoxified individuals with AUD (DSM-IV/V) were randomised to one of four conditions	Ketamine: 0.8 mg/kg (iv)	No difference in relapse rates between the ketamine and the placebo groups
			1. Three weekly ketamine (active) infusions plus psychological therapy (MBRP) (active)	Placebo: 0.9% saline (iv)
			2. Three ketamine (active) infusions plus alcohol education (control)
			3. Three saline infusions (control) plus psychological therapy (active)
			4. Three saline infusions (control) plus alcohol education (control)
c. Ceremonial psychedelic use (mescaline-containing Peyote cactus, DMT-containing Ayahuasca brew)	Albaugh and Anderson [39]	1974	American Indians from the Cheyenne and Arapaho tribes with alcohol dependence	Peyote cactus	Discussion about alcoholism and emotions during the NAC ceremonies was helpful in overcoming their alcohol dependence
			30-day inpatient programme at the Clinton Indian Hospital in Oklahoma	Peyote buttons (average: 11 buttons, 45 mg mescaline each)	Carry-over effect of 7–10 days post peyote of openness and willingness to communicate
			Therapeutic approach: group meetings, cultural and occupational therapy, and taking part in meetings at the Native American Church (NAC), with and without peyote/mescaline	Average mescaline: 500 mg
	Doering-Silveira et al. [40]	2005	Cross-sectional study	Ayahuasca	Significantly lower alcohol consumption in
			Eighty-four ayahuasca consuming and national normative sample of adolescents (15–19 years; Brazil)	N/A	1. Last-month
			Ayahuasca-consuming adolescents (ritual context; n = 41) were selected from three syncretic churches Uniao do Vegetal (UDV)		2. Last-year
			Focussing on general drug and alcohol consumption (no addiction)
			Drunk ayahuasca within a ritual context at least 24 times during the last 2 years prior to the assessment
			World Health Organisation (WHO) criteria for psychoactive drug use

ASI, Addiction Severity Index; AUD, alcohol use disorder; AUDIT, Alcohol Use Disorders Identification Test; DMT, N, N-dimethyltryptamine; DSM, Diagnostic and Statistical Manual of Mental Disorders; HCl, hydrochloride; LSD, lysergic acid diethylamide; MDMA, 3,4-methyl​enedioxy​methamphetamine; MET, motivational enhancement therapy; MRM, Maladaptive reward memory; NAC, Native American Church; PHDD, percentage of heavy drinking days; UDV, Uniao do Vegetal (churches); WHO, World Health Organisation; 5-MeO-DMT, O-methyl-bufotenin; MBRP, mindfulness-based relapse prevention.

Table 2.

Summary of studies using classic and atypical psychedelics for opioid use disorder

Substance	Author(s)	Year	Study characteristics	Dose	Main findings
a. Ibogaine	Alper et al. [41] (no access to full paper)	1999	Open-label case series	19.3±6.9 mg/kg	Within 24 h and throughout 72 h, 25/33 cases reported
			Thirty-three opioid-dependent individuals (DSM-IV)		1. Resolution of opioid withdrawal
					2. No drug-seeking behaviour
					Other symptom improvements include
					1. Drug-seeking behaviour without withdrawal signs (n = 4)
					2. Drug abstinence with attenuated withdrawal signs (n = 2)
	Mash et al. [42]	2001	Observational study	Ibogaine HCl: 800 mg (10 mg/kg)	At 12 h, 24 h, and 36 h post-ibogaine treatment, significant reduction in withdrawal symptoms assessed by the “Objective Opiate Withdrawal Scale” and “Opiate-Symptom Checklist”
			Thirty-two opioid-dependent (DSM-IV) individuals seeking heroin or methadone detoxification
			The treatment program offered motivational counselling and referral to aftercare programs and community support groups (twelve-step programs)
	Noller et al. [43]	2017	Observational study	Ibogaine HCl: 31.4±7.6 mg	At 12-month follow-up, there was significant
			Fourteen treatment-seeking opioid dependence (DSM-IV) individuals		1. Attenuation of withdrawal symptoms (ASI Lite)
					2. Decrease in drug craving and use (Subjective Opioid Withdrawal Scale)
					3. Decrease in depressive symptoms
	Brown et al. [44]	2018	Observational study	Ibogaine HCl: 1,540±920 mg	Significant reduction in opioid withdrawal between pre- and post-treatment with ibogaine
			Thirty treatment-seeking opioid-dependent individuals (DSM-IV)		Relative to baseline, at 3-, 6-, 9-, 12-month follow-ups, significant improvement in Drug Use, Family/Social Status, and Legal Status (ASI Lite)
	Malcolm et al. [45]	2018	Observational study	Ibogaine HCl: 18–20 mg/kg	At 48 h post-ibogaine treatment, relative to baseline
			Fifty opioid-dependent individuals (DSM-V) with prior ibogaine treatment experience for their opioid dependence	For participants who experience post-acute withdrawal symptoms at 72 h post-ibogaine administration, an additional 1–5 mg/kg ibogaine HCl was administrated	1. 78% of patients did not experience clinical signs of opioid withdrawal
			Three-part treatment program, including coaching, ibogaine administration, a week-long ibogaine detoxification treatment, and optional residential aftercare program or weekly recovery coaching		2. 79% reported minimal cravings for opioids
					3. 68% reported mild subjective withdrawal symptoms
b. Ketamine	Krupitsky et al. [46]	2002	Double-blind active-placebo-controlled randomised clinical trial	Hallucinogenic/high dose: 2.0 mg/kg (im)	High dose of ketamine relative to the low dose showed significantly
			Seventy detoxified heroin dependent patients	Non-hallucinogenic/low dose: 0.2 mg/kg (im)	1. Greater rate of abstinence within the first 2 years of follow-up
			Existentially oriented psychotherapy in combination with one ketamine session (hallucinogenic dose or sub-hallucinogenic dose active placebo)		2. Greater and longer-lasting reduction in heroin craving
					3. Greater positive change in nonverbal unconscious emotional attitudes
					4. Lower relapse rates
c. Classic psychedelics	Savage and McCabe [28]	1973	Seventy-eight heroin dependent inmates randomly assigned to either a single dose of LSD and psychotherapy or to an outpatient program with weekly psychotherapy sessions (control)	LSD, 300–350 μg	Significantly higher abstinent rates in the LSD-assisted psychotherapy group relative to the control group at 6- and 12-month follow-ups
					At 12-month follow-up, the LSD group presented with 33% abstinence rates relative to the 5% rate of the control group
	Pisano et al. [47]	2017	Association study	Psilocybin	Psychedelic drug use is associated with
			44,000 responders with history of illicit opioid user who completed the National Survey on Drug Use and Health (NSDUH) from 2008 to 2013 and met NSDUH’s dependence criteria	LSD	1. 27% reduced risk of past-year opioid dependence
				Mescaline/Peyote/San Pedro	2. 40% reduced risk of past-year opioid abuse
				DMT/Ayahuasca
				Dose N/A
	Argento et al. [48]	2022	Prospective cohort survey study	Classic psychedelics	Significantly reduced odds of subsequent daily opioid use (Adjusted Odds Ratio: 0.45; 95% Confidence Interval: 0.29–0.70)
			Cohorts of community-recruited people who use drugs (PWUD) in Vancouver, Canada	Dose N/A
			Among 3,813 PWUD at baseline, 1,093 (29%) reported daily use of illicit opioids and 229 (6%) reported psychedelic use in the past 6 months

ASI, Addiction Severity Index; DMT, N, N-dimethyltryptamine; DSM, Diagnostic and Statistical Manual of Mental Disorders; HCl, hydrochloride; LSD, lysergic acid diethylamide; NSDUH, National Survey on Drug Use and Health; PWUD, people who use drugs.

Fast forward to the 21st century, psilocybin has been used in addiction treatment research, especially for alcohol and tobacco. Psilocybin is found in several mushroom species, with the most known being Psilocybe cubensis [49]. The indigenous communities of Mexico have a long tradition of psilocybin-containing mushroom ceremonial use. In 1957, the Mazatec Shaman María Sabina through Gordon Wasson brought the traditional ritual knowledge to the West [50], paving the way for its use in modern-day psychiatry. In 2015 and 2022, Bogenschutz and his team conducted a pilot study and a phase II randomised double-blind clinical trial looking into the therapeutic potential of two psilocybin doses in combination with 12 weeks of motivational enhancement therapy for the treatment of alcoholism. They found a significant increase in abstinence and a decrease in the percentage of drinking days and heavy drinking days following psilocybin and psychotherapy relative to the control condition (Table 1, 3) [29, 31]. Limitations of sample size and lack of a control group in the pilot study were overcome in the phase II clinical trial, but challenges with blinding remained, as diphenhydramine, the placebo used in the trial, was ineffective in maintaining the blind.

Table 3.

Number of treatments needed for each psychedelic (classic and atypical) substance

Drug	Number of treatment sessions
aPsilocybin	2
LSD	1
Ketamine	1–3
MDMA	2
bIbogaine	1–2

^aPsilocybin: 3rd dose is optional.

^bIbogaine: up to ×9 times, most common 1–2 times [60].

Johnson et al. [51] and Garcia-Romeu et al. with a similar concept approached tobacco use disorder with two psilocybin doses plus a combination of cognitive behavioural therapy and mindfulness training for smoking cessation. At the 6-month follow-up, 80% were abstinent, with 67% remaining abstinent at the 12-month follow-up and 60% at the 30-month follow-up (Table 4) [52]. They also found that abstinent individuals scored higher in the psilocybin-occasioned mystical experience relative to participants still smoking at 6 months, with a “complete” mystical experience significantly correlating with smoking cessation outcomes (Table 4) [53]. The results of these studies should be interpreted with caution given the small sample size and open-label design. Potential psychological mechanisms for the therapeutic effects of psilocybin and other classic psychedelics may rely on their ability to elicit mystical, transcendent, or peak experiences [30, 51–53]. Other proposed mechanisms attribute their therapeutic potential to their ability to reduce craving and anxiety, which are key components of relapse [53, 54] and to their ability to increase motivation and self-efficacy [53].

Table 4.

Summary of studies using psilocybin for tobacco use disorder

Substance	Author(s)	Year	Study characteristics	Dose	Main findings
a. Psilocybin	Johnson et al. [51]	2014	Open-label pilot study	Moderate: 20 mg/70 kg	80% self-reported quitting smoking (biologically verified smoking abstinence) throughout the weeks of active treatment
			Fifteen nicotine-dependent smokers with previous unsuccessful quit attempts, still desiring to quit	High: 30 mg/70 kg	80% were abstinent at 6-month follow-up
			15-week smoking cessation CBT with three psilocybin sessions (at 5, 7, and 13 optional weeks)		Significant reductions in self-reported daily smoking from first psilocybin session to 6-month follow-up
					Significantly decreased craving
					At 12-month follow-up, 10/12 (67%) returning participants were smoking abstinent (Johnson et al. 2017)
					At long-term follow-up (average 30-months), 9/12 (60%) were smoking abstinent (Johnson et al. 2017)
	Garcia-Romeu et al. [53]	2015	Open-label pilot study	Session 1 (moderate): 20 mg/70 kg	At 6-month follow-up 80% were abstinent
			Fifteen smokers with previous unsuccessful quit attempts, still desiring to quit	Session 2 (high): 30 mg/70 kg	The abstinent individuals scored significantly higher on a measure of psilocybin-occasioned mystical experience relative to participants still smoking at 6 months
			15-week smoking cessation treatment intervention (CBT and mindfulness training) with two psilocybin session at week 5 and 7 and an optional high third dose at week 13		60% met criteria for “complete” mystical experience which was significantly correlated with smoking cessation outcome
	Johnson et al. [52]	2017	Retrospective cross-sectional anonymous online survey	Psilocybin	38% reported continuous smoking cessation after psychedelic use (Quit group)
			358 individuals who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting	LSD	74.5% of the “Quit group” reported >2 years of abstinence
				Mescaline	28% reported a persisting reduction in smoking (Reduce group)
				DMT/Ayahuasca	62% of the “Reduce group” reported >2 years reduction in smoking
				Dose N/A	34% reported temporary reduction in their smoking before returning to baseline smoking level (Relapse group)
					Participants across all groups reported less severe affective withdrawal symptoms (e.g., depression, craving) after psychedelic use compared with previous quit attempts
					Participants in the “Relapse group” rated the reference psychedelic experience as significantly less personally meaningful than those in the “Quit group”

CBT, cognitive behavioural therapy; DMT, N, N-dimethyltryptamine; LSD, lysergic acid diethylamide.

Retrospective and prospective online survey studies focussing on classic psychedelics have reported very similar outcomes across alcohol, tobacco, cannabis, opioids, and stimulant addictions. The most common themes included a decrease in withdrawal symptom severity, abstinence, and reduced odds of daily substance use (Table 1, 4, 5) [30, 48, 55–58]. From association studies, there is evidence that the use of classic psychedelics can reduce the odds of past-year opioid addiction/abuse and cocaine use disorder (Table 2, 6) [47, 59].

Table 5.

Summary of studies using classic and atypical psychedelics in non-ceremonial and ceremonial settings for polydrug use and abuse

Substance	Author(s)	Year	Addiction	Study characteristics	Drug and dose	Main findings
a. Classic psychedelics (psilocybin, LSD, mescaline)	Garcia-Romeu et al. [56]	2020	Cannabis use disorder	Retrospective cross-sectional online survey study	Psilocybin	Following the reference psychedelic experience
			Opioid use disorder	444 individuals (cannabis n = 166); opioid n = 123; stimulants n = 155) who met Drug Use Disorders Identification Test-Consumption (DUDIT-C) and DSM-V criteria for their primary drug/class of interest	LSD	1. 28% reported less severe withdrawal symptoms, particularly craving compared to prior attempts (56% of cannabis users and 75% of opioid users)
			Stimulant use disorder		Moderate to high doses	2. 74.5% greatly reduced or quit using their primary substance (DUDIT-C)
						3. Out of 95.7% substance use disorder (SUD) criteria before the reference psychedelic experience, only 27.3% met SUD criteria in the time since their reference psychedelic experience
	Agin-Liebes et al. [57] and Uthaug et al. [58] (both utilising the same dataset)	2021	Alcohol use disorder	Retrospective naturalistic online survey	Mescaline (San Pedro)	48% reported having the most memorable experience
		2022	Drug use disorder	452 participants	Moderate to high dose (8–13 h)	Participants with previous substance misuse/dependence reported improvement following their most memorable experience
				International epidemiological study	Oral self-administration for spiritual and nature connection	1. Alcohol misuse/use disorder = 76% (n = 48)
						2. Drug misuse/use disorder = 68% (n = 58)
						2–5% of participants with psychiatric conditions reported intentions to address/resolve their condition with mescaline
b. Atypical psychedelics (ibogaine, 5-MeO-DMT)	Schenberg et al. [60]	2014	Polydrug abuse	Retrospective observational study	Ibogaine	One treatment of ibogaine led to median of 5.5 months abstinence
				Data from 75 polydrug (alcohol, cannabis, cocaine, crack cocaine) users (DSM-IV)	Single dose of Ibogaine HCl: 17 mg/kg	Multiple treatments of ibogaine led to median of 8.4 months abstinence
				Combined approach of ibogaine and cognitive behavioural therapy (clinic in Brazil)	If weak response to initial dose, they would increase up to 20 mg/kg	Both single and multiple ibogaine treatments led to statistically significant longer periods of abstinence than before the first ibogaine treatment
					Option for multiple treatment was available if individuals were experiencing intense craving, relapse, difficulty changing old drug-related habits
	Davis et al. [61]	2018	Alcohol use disorder	Retrospective online survey study	5-MeO-DMT	66% reported improvement in AUD symptoms e.g., craving/desire
			Substance use disorder (non-alcohol)	515 responders	Dose N/A	60% reported improvement SUD symptoms e.g., craving/desire
	Mash et al. [42]	2018	Opioid use disorder	Retrospective observational stud of 191 open-label case series	Ibogaine	Significant decrease in craving symptoms post-treatment and at 1-month follow-up
			Cocaine use disorder	Treatment (detoxification) seeking opioid and cocaine dependent (DSM-IV) individuals	Ibogaine HCl: 8–12 mg/kg	Significant decrease in depression symptoms at 1-month follow-up
				Treatment program also included motivational counselling and referral to aftercare programs and community support groups		Decrease in withdrawal symptoms individually (no statistical significance)
c. Ceremonial psychedelic use (DMT-containing ayahuasca brew)	Fábregas et al. [62]	2010	Polydrug abuse	127 ritual jungle- and urban-based ayahuasca users and 115 rural controls (Brazil)	Ayahuasca	Ritual ayahuasca users relative to controls showed significantly
				Addiction severity was assessed using the ASI	Dose N/A	1. Lower ASI Alcohol scores
						2. Lower scores in the Psychiatric Status subscales
						3. Lower drug use (except of cannabis)
	Thomas et al. [63] (no access to full paper)	2013	Polydrug abuse	Observational prospective study	Ayahuasca	Self-reported alcohol, tobacco and cocaine use declined
				“Working with Addiction and Stress” retreat combined 4 days of group counselling with two expert-led ayahuasca ceremonies	Dose N/A	Statistically significant reductions in problematic cocaine use
				Twelve polydrug (alcohol, opioids, cocaine, tobacco, cannabis) rural aboriginal population users (Canada)
	Barbosa et al. [64]	2018	Alcohol use disorder	Cross-sectional study with ayahuasca users and national normative sample (Brazil)	Ayahuasca	Alcohol and tobacco use disorder were lower in ritual ayahuasca using UVD members
			Tobacco use disorder	1,947 Uniao do Vegetal (UDV) church members	Dose N/A	Reduction of alcohol and tobacco use disorder was significantly impacted by
				Alcohol and tobacco use was evaluated through questionnaires first developed by World Health Organisation and the Substance Abuse and Mental Health Services Administration		1. Attendance at ayahuasca ceremonies during the previous 12 months
						2. Years of UDV membership

ASI, Addiction Severity Index; AUD, alcohol use disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; DUDIT-C, Drug Use Disorders Identification Test-Consumption; UDV, Uniao do Vegetal (churches); 5-Meo-DMT, O-methyl-bufotenin.

Table 6.

Summary of studies using classic and atypical psychedelics for cocaine use disorder

Substance	Author(s)	Year	Study characteristics	Drug and dose	Main findings
a. Ketamine	Dakwar et al. [65]	2014	Crossover double-blind randomised trial	K1: 0.41 mg/kg	K1 relative to LZP significantly
			Eight cocaine dependent (DSM-IV) non-treatment and non-abstinence seeking	K2: 0.71 mg/kg	1. increased motivation for changing cocaine use
			Three infusions of sub-anaesthetic psychoactive dose of ketamine (K1, K2) or active control lorazepam (LZP)	LZP: 2 mg	2. Decreased cue-induced cocaine craving
					K2 further reduced cue-induced craving
					Observed trend in craving reduction following K1
	Dakwar et al. [66]	2017	Crossover double-blind randomised trial	Ketamine HCl: 0.71 mg/kg	Ketamine relative to midazolam significantly reduced cocaine self-administration by 67%
			Twenty cocaine dependent (DSM-IV) non-depressed, non-treatment and non-abstinence seeking	Midazolam: 0.025 mg/kg	Ketamine led to significant reductions in cocaine use and cocaine craving initially, but was not sustained after several days
			Cocaine self-administration paradigm
			Two infusions of sub-aesthetic dose of ketamine or of the active control midazolam
	Dakwar et al. [67]	2019	Randomised clinical trial	Ketamine HCl: 0.5 mg/kg (iv)	48.2% abstinence (last 2 weeks of trial) in the ketamine group compared to 10.7% in the midazolam group
			Fifty-five treatment-seeking cocaine dependent (DSM-IV) individuals	Midazolam: 0.025 mg/kg (iv)	In the ketamine group compared to the midazolam group
			5-week course of MBRP and were randomly assigned to receive ketamine or active control midazolam during week 1		1. Was 53% less likely to relapse (use cocaine/drop out)
					2. Craving was 58.1% lower
					44% of the ketamine group reported abstinence at 6-month telephone follow-up relative to none of the participants in the midazolam group
b. Classic psychedelics	Jones et al. [59]	2022	Association study	Psilocybin	Peyote was the only substance associated with lower odds of CUD (decrease by 50%)
			214,505 responders who met CUD criteria and completed the NSDUH from 2015 to 2019	LSD
				Mescaline/peyote
				Dose N/A

CUD, cocaine use disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; HCl, hydrochloride; LSD, lysergic acid diethylamide; LZP, lorazepam; NSDUH, National Survey on Drug Use and Health; MBRP, mindfulness-based relapse prevention.

Currently, there are also five clinical research projects (clinicaltrials.gov) underway investigating the therapeutic potential of psilocybin for the treatment of cocaine addiction (randomised controlled trial, NCT02037126), methamphetamine addiction (randomised trial, NCT04982796; safety/feasibility, NCT05322954), and opioid-dependent individuals maintained with buprenorphine (double-blind, NCT06067737) or buprenorphine-naloxone formulation (open-label safety, NCT04161066).

Atypical Psychedelics

Out of all the atypical psychedelics, ketamine and ibogaine have been the most popular in the treatment of several addictions including alcohol, opioids, and cocaine (Table 1, 2, 6). Ketamine, a non-competitive NMDA receptor antagonist, was developed and is used worldwide as an anaesthetic and analgesic. In recent years ketamine has re-emerged in the psychiatry world in the form of intranasal esketamine (an optimal isomer of ketamine) spray for the treatment of depression [68, 69]. Krupitsky and colleagues in Russia brought the first significant work using ketamine for addiction treatment in the early 90s [32]. In 1997, Krupitsky and Grinenko conducted a non-randomised study with participants having the freedom to choose between transpersonal ketamine-psychedelic therapy (KPT) or traditional therapy. At 1-year follow-up, 65.8% of the ketamine group was abstinent, compared to 24% of the control group [33]. They proposed that some of the psychological mechanisms of KPT lie in ketamine’s ability to harmonise personality traits and emotional attitudes to self and others and to increase insight and spirituality [33]. Although the study’s results were promising for their time, the study could be subject to selection bias in the treatment allocation. Similar findings were observed by Krupitsky et al. [46] in a much stronger research design of a double-blind active-placebo randomised clinical trial for heroin dependence. Compared to the low ketamine dose control, the high-dose KPT showed greater levels of abstinence at a 2-year follow-up and a longer-lasting reduction in heroin craving.

More recently, clinical trials of ketamine for alcohol and cocaine dependence have built on Krupitsky’s early work, while trying to address methodological limitations by randomly assigning treatment, using pharmacological (active/saline) or psychological placebos, and blinding both the participant and the researchers [35, 36, 38, 65, 66]. Recently ketamine has been paired with mindfulness-based relapse prevention, not only in alcohol addiction [38] but also in cocaine [67] and cannabis [70] addiction. Common effects of this approach across studies showed that ketamine and mindfulness-based relapse prevention increased and sustained abstinence and reduced use and craving.

Maintenance of motivation for sobriety seems to be one of the important proposed psychological mechanisms of ketamine [36, 65]. Depression and addiction are highly comorbid and intertwined, with some studies supporting that ketamine may have downstream effects on neural circuits related to common transdiagnostic factors between depression and addiction like reward sensitivity and anhedonia [36, 38]. Evidence suggests that ketamine promotes downstream signalling pathways that induce neuronal plasticity [71]. Due to ketamine’s ability to sustain over time its therapeutic outcomes, a pro-plasticity and modulatory mechanism of action is also proposed [66]. Lastly, Das et al. [35] propose that the interference of ketamine with memory consolidation may allow the “overwriting of maladaptive drinking memories” and thus its therapeutic effects.

Ibogaine is another psychoactive alkaloid commonly used for the treatment of opioid (Table 2) addiction, mainly due to its unique properties of blocking opiate withdrawal, providing an alternative approach to treatment [72]. Ibogaine is found in the roots of the Tabernanthe iboga plant mainly found in Gabon of occidental equatorial Africa and it has been used for centuries in the Biwiti religious ceremonies and spiritual practices [73]. Alper and colleagues conducted in 1999 an open-label case series study with thirty-three opioid-dependent individuals using ibogaine for opioid detoxification. They found that 76% of the sample showed resolution of opioid withdrawal and drug-seeking behaviour up to 72 h post-infusion [41]. Although there is no evidence of randomised clinical trials for ibogaine, observational studies for opioid addiction have seen a significant reduction in withdrawal symptoms and drug craving and seeking behaviour (Table 2) [42–45, 72]. In cocaine addiction and polydrug abuse, similar treatment outcomes have been observed, accompanied by long-term abstinence [42, 60]. Aside from the therapeutic dream-like visions that people encounter under the influence of ibogaine [34], it is proposed that the therapeutic benefits of ibogaine are brought from its ability to “suppress the autonomic changes, objective signs, and subjective distress associated with opiate withdrawal” and possibly through its action on the mu-opioid receptors [72]. Although ibogaine appears to have promising treatment effects, especially for opiate dependence, it should be used under appropriate medical supervision, due to its ability to induce QTc prolongation, bradycardia, and severe ataxia, even if the symptoms are reversible [74]. Thus, patients and participants in research studies should undergo thorough physical screenings to ensure their safety.

In 2018, a combination treatment approach with ibogaine and 5-MeO-DMT was used for the treatment of alcohol addiction in a military veteran. 5-MeO-DMT is found on the skin of the Sonoran Desert Toad (Incilius alvarius) and has been used by the Yoeme (Yaqui) people in Sonora [75]. The case study reported alcohol cessation and reduced craving for up to 1-month, with a return to mild alcohol use after 2 months [34]. The release of negative emotions following 5-MeO-DMT use is thought to play a key role in its therapeutic effects [34]. 5-MeO-DMT has also been used for alcohol and substance use disorder with a retrospective online survey study showing that 5-MeO-DMT improved significantly craving and desire to use [61].

MDMA, an atypical psychedelic or entactogen, has been used once for the treatment of addiction, more specifically alcohol. An open-label safety and tolerability study was conducted in Bristol utilising a ten-session recovery-based therapy course assisted by two MDMA sessions (Table 1). At 9 months, the majority were abstinent and those who were not had an average decrease of alcohol units from 131 to 19 [37]. They propose that MDMA’s ability to access emotionally distressing thoughts, images, or memories of alcohol misuse with reduced avoidance while increasing empathy towards the self and others may explain its therapeutic abilities [37]. It may also address symptoms of other comorbid conditions with addiction, like psychological trauma [37, 76].

Psychedelics in a Ceremonial Setting

Psychedelics have a long history of ceremonial and spiritual use among different cultures of the globe. The mescaline-containing peyote cactus (Lophophora williamsii; [77]) has been used for centuries by natives in Mexico and North America [2]. Since 1920, mescaline has become legal to use in religious ceremonies by the Native American Church (NAC) [3]. Albaugh and Anderson in 1974 examined the effectiveness of a treatment program for American Indians to treat their alcohol addiction, which included peyote meetings in the NAC (Table 1). They found that open discussion (“cathartic expression”) about their alcoholism during the NAC ceremonies played a pivotal role in addressing their addiction. They also found that the carry-over effect post peyote ingestion promoted suggestibility and openness to communicate [39]. The vast supportive network and ritual offered by the NAC in synergy with the psychedelic effects of peyote seem to be key components of peyote’s therapeutic effect [78, 79].

Ayahuasca is the DMT-containing brew native to the indigenous communities of the Amazonian rainforest. The two key components of the brew are the DMT-containing leaves of Psychotria viridis and the β-carboline (monoamine oxidase-A inhibitor) containing bark of Banisteriopsis caapi, which is essential to render DMT orally active [80]. According to Miller and colleagues, there is documentation of a ritual bundle containing harmine (β-carboline) and DMT, the primary ingredients of ayahuasca, in the Andean region, dating back 1,000 years ago [81]. In recent years, research has looked into the therapeutic properties of ayahuasca in ceremonial settings. Three cross-sectional studies were conducted in Brazil and one observational prospective study in Canada investigated the therapeutic potential of ayahuasca in a ceremonial/ritualistic setting for drug and alcohol abuse and dependence (Table 1, 5). They found ayahuasca consumption in a ritualistic setting decreased (problematic) drug and alcohol use and addiction severity scores, partly possibly attributed to being part of the church and community [40, 62–64].

Conclusions

We have a rich history of psychedelic use with Indigenous communities being the gatekeepers of psychedelic plant knowledge, so they should be treated with the uttermost respect. While we move forwards in the 21st century, we should learn from our ancestors’ healing practices and destigmatise the use of psychedelic substances, especially in a therapeutic context. Their consciousness-expanding properties, mystical experiences, and improvement in well-being are some of the therapeutic factors that render psychedelics a promising alternative treatment for addictions, especially for individuals who have failed other conventional treatment approaches. Aside from their psychological effects, they are also able to diminish the physiological responses of addiction recovery, including withdrawal symptoms, craving, and drug-induced responses. Changes in governmental policies and funding across countries like the UK, Canada, and Australia, which recently rescheduled psilocybin and MDMA, making them medically accessible for use in the treatment of treatment-resistant depression and PTSD [82, 83], bring us hope for the future of psychedelic therapeutics for the treatment of addiction and other psychiatric and medical co-occurring disorders.

Conflict of Interest Statement

Ioanna Vamvakopoulou has acted as a paid intern and consultant for Neural Therapeutics with shares. David Nutt’s research group at Imperial College has received research support from the following companies with an interest in the psychedelic space – COMPASS Pathways, Usona, Beckley Psytec, MAPS, and Filament. He also acts as a part-time chief research officer for Awakn Life Sciences a biotech company that is developing novel ketamine and MDMA therapies for addictions and advises Alvarius, Algernon Pharmaceutics, and Neural Therapeutics on their psychedelic research programmes.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Ioanna Vamvakopoulou searched and screened the literature and wrote the manuscript. David Nutt reviewed and provided feedback and corrections for the manuscript. All authors read and approved the final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.