Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans

Ayahuasca is a traditional hallucinogenic decoction prepared from Banisteriopsis caapi (rich in β-carbolines such as harmine, tetrahydroharmine and harmaline) and DMT-containing leaves (for example Psychotria viridis). N,N-dimethyltryptamine (DMT) is orally inactive unless peripheral monoamine oxidase-A (MAO-A) is inhibited; the β-carbolines in B. caapi reversibly inhibit MAO-A and thereby enable systemic and central effects of DMT. Acute ayahuasca produces characteristic perceptual, cognitive and emotional effects and transient autonomic and endocrine changes, while long-term ritual use has not been associated with major cognitive or psychiatric harms in observational work. Nunes and colleagues note growing anecdotal, preclinical and observational reports that ayahuasca and its alkaloids may have anxiolytic, antidepressant and anti-addictive properties, but that existing studies are heterogeneous and often uncontrolled. To address this gap, they performed a systematic review of quantitative studies up to 6 January 2016, seeking animal experiments and human investigations that used statistical analysis to assess effects of ayahuasca or its isolated alkaloids (DMT, harmine, THH, harmaline) on drug-related behaviours, biochemical markers or dependence symptoms.

The review followed PRISMA guidance and searched PubMed from 1 January 1966 to 6 January 2016 using the terms: ayahuasca OR dimethyltryptamine OR harmine OR tetrahydroharmine OR harmaline AND dependence OR addiction. Handsearching of reference lists and inclusion of chapters from specialised books were also performed. Only complete articles published in peer-reviewed journals and book chapters reporting quantitative studies with statistical analysis were eligible; qualitative reports, case studies, letters, abstracts and conference proceedings were excluded. Included study designs were animal models of drug-induced disorders, observational studies of ayahuasca consumers that used validated scales to assess drug-related symptoms, and clinical trials involving patients diagnosed with drug abuse or dependence by DSM criteria. The review accepted studies on invertebrates (planarians), rodents, healthy human volunteers (including experienced ritual users) and patients with drug-use diagnoses. Interventions comprised administration of ayahuasca or isolated alkaloids; comparators included experimental psychoactive drugs such as cocaine, amphetamines, ibogaine and nicotine. Outcomes encompassed behavioural and biochemical parameters in animals and psychometrically assessed symptoms or substance use in humans. Data extraction was performed independently by two reviewers with a third resolving disagreements. Extracted items included author, year, study design, participant characteristics, response criteria, intervention type and dose, and outcome measures. The authors separated results into animal and human study groups for clarity. The search returned 93 references for abstract screening; the extracted text reports eight potentially relevant references identified at that stage and refers to a flow diagram, but the diagram itself is not included in the provided text.

Overall yield and study types: The review identified preclinical (animal and invertebrate) experiments and observational human studies that met the quantitative inclusion criteria. The abstract and discussion indicate five animal studies and five human observational studies, although the methods section reports the initial screening of 93 records and eight potentially relevant references without fully listing the final selection process in the extracted text. Animal studies: Several alkaloids and ayahuasca preparations produced effects on drug-related behaviours. Harmaline administered intraperitoneally to rats (2.5–80 mg/kg) produced significant, dose-dependent acute reductions in morphine and cocaine self-administration that persisted for at least a day after dosing. Harmine reduced naloxone-precipitated morphine withdrawal signs in morphine-dependent rats when given intraperitoneally at 5–10 mg/kg, attenuating almost all measured withdrawal behaviours except jumping. In rat brain-slice preparations, harmine (300 nM) increased dopamine efflux in the nucleus accumbens shell to about 148% of baseline; cocaine increased efflux to about 179%, and combined exposure produced additive effects (~260%). Harmine’s effects on dopamine were reduced by 5-HT2A/2C antagonism and were reportedly independent of MAO inhibition. In a planarian model, harmine (0.01–10 µM) did not itself elicit characteristic stimulant-induced “C-shape” behaviours but significantly inhibited such responses induced by cocaine, amphetamines and nicotine, with greatest efficacy against cocaine; the anti-stimulant effect appeared mediated by glutamatergic mechanisms. Acute administration of ayahuasca in mice (reported intraperitoneal doses 30–500 mg/kg; specific regimen for one study was 100–300 mg/kg during a reinstatement protocol) reduced ethanol-induced acute hyperlocomotion, attenuated locomotor sensitization and decreased reinstatement of ethanol-induced sensitization, without altering spontaneous locomotor activity at the tested doses. Human studies: The extracted text summarises five observational or non-controlled human studies in ritual or therapeutic settings. A retrospective study of adolescents comparing 37 UDV members and 43 controls found no differences in lifetime substance consumption on the Drug Use Screening Inventory, but UDV adolescents reported lower last-year (46.3% v. 74.4%) and last-month (32.5% v. 65.1%) alcohol consumption than controls. A United States study of 32 Santo Daime members (mean lifetime ceremonies 269 ± 314.7; range 20–1300) used the SCID and interviews; many reported prior substance problems (eight with previous alcohol abuse, five with past alcohol dependence, four cannabis abuse, three cannabis dependence and smaller numbers for other substances), and most reported reductions in use or abstinence after group membership, with only isolated partial remissions or continued use. In a Brazilian sample of 83 Santo Daime members, 41 had a history of dependence; reported recovery percentages included tobacco 99%, alcohol 27%, cocaine 24%, crack 8%, and other substances 5% (as reported in the extracted text). A Canadian observational study of a rural First Nations retreat recruited 12 ayahuasca-naïve volunteers who received group counselling and two ceremonies; follow-up assessments up to five months using the 4 Week Substance Use Scale showed mean decreases for tobacco, alcohol, cannabis and cocaine but a statistically significant reduction only for cocaine. That retreat study also reported significant improvements on measures of hope, empowerment, mindfulness and quality of life. Finally, a non-controlled clinical programme in the Brazilian Amazon and a Spanish cohort (13 participants, including nine with heroin or cocaine dependence) that received twice-weekly ayahuasca sessions for up to 3–9 months reported reductions in impulsivity-related personality subscales (TCI-R), increases in self-directedness, reductions in general psychopathology (SCL-90-R), neuropsychological improvements (FrSBe reductions and improved Stroop interference resistance) and gains in purpose in life and spiritual orientation. Aggregate findings: In animal models all included studies reported improvements in biochemical or behavioural parameters related to drug-induced disorders. Among the five human quantitative studies described, four reported significant reductions in dependence symptoms or substance use and/or improvements on related psychometric measures, whereas one did not find significant effects. Reported human effects were most apparent for alcohol and cocaine use. Adverse events and tolerability are not systematically presented in the extracted results, though earlier background text notes common transient effects of ayahuasca such as nausea and vomiting.

Nunes and colleagues interpret the assembled preclinical and observational evidence as suggestive that ayahuasca and its alkaloids possess properties that could assist in treating substance dependence or its sequelae. Animal data show that harmine and harmaline attenuate withdrawal signs and reduce self-administration of morphine and cocaine, while ayahuasca reduced ethanol-related sensitisation in mice. The authors propose that multiple neurochemical systems may underpin these effects, including reversible MAO-A inhibition by β-carbolines and modulation of glutamatergic, dopaminergic and serotonergic neurotransmission. For example, harmine’s increase in nucleus accumbens dopamine efflux appears to be mediated via 5-HT2A/2C receptors and not solely by MAO inhibition, and harmine’s inhibition of stimulant-like behaviours in planarians seems linked to glutamatergic mechanisms. The discussion cautions that preclinical mechanisms may not translate directly to humans. Human neuroimaging cited in the review did not show clear striatal activation after ayahuasca administration, although some clinical work reported increased perfusion in nucleus accumbens and related regions in depressed patients following ayahuasca. The authors also emphasise psychosocial and contextual contributors to observed benefits in human studies: ritual frameworks, religious group membership (for example Santo Daime and UDV), and psychedelic experiences that can be described as mystical or insight-producing may foster abstinence, improved decision-making and psychosocial recovery. Comparative examples such as psilocybin and peyote within ritual contexts are invoked to illustrate how psychedelic-induced subjective experiences and community contexts could bolster recovery from substance misuse. Key limitations are acknowledged. The human literature consists mainly of small, observational, non-randomised studies often sampling experienced ritual users, which may introduce selection bias by excluding individuals who had adverse reactions and discontinued use. The ritual context complicates attribution of effects to pharmacology versus social, cultural or religious factors. The authors therefore conclude that despite promising signals, controlled clinical trials are needed to establish efficacy, elucidate mechanisms and assess safety in clinical populations.