Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms

Serotoninergic psychedelics (classical hallucinogens) include mescaline, DMT, psilocybin and LSD and act primarily as agonists at serotonin receptors, especially 5-HT2A. The Introduction frames these compounds as producing profound alterations in affect, perception and cognition that vary with dose, set (participant characteristics and preparation) and setting (support and context). The authors note a long history of ritual and therapeutic uses for naturally occurring tryptamines and phenethylamines, interrupted scientific interest in the late 1960s/early 1970s, and a resurgence of controlled human research from the 1990s onwards with a growing body of experimental and clinical studies reporting generally favourable safety profiles in carefully screened samples. Guimar and colleagues set out to synthesise existing reviews and primary studies on the therapeutic effects of serotoninergic hallucinogens for anxiety, mood and substance use disorders, with particular emphasis on clinical and preclinical work carried out by groups at the Universidade de São Paulo (USP) and the Universidade Federal do Rio Grande do Norte (UFRN) concerning ayahuasca/DMT. The paper also aims to discuss proposed biological and psychological mechanisms that might mediate therapeutic effects.

The extracted text does not present a formal methods section describing a systematic search strategy, eligibility criteria, or formal meta-analytic procedures. Instead, the paper is a narrative review that summarises disparate reviews and primary studies across historical, observational, preclinical and clinical domains, and highlights work from the USP and UFRN groups on ayahuasca/DMT. Where relevant, the authors integrate findings from different study types: early clinical trials (1960s–1970s), more recent controlled trials (2000s–2010s), open-label feasibility studies, animal and non-human primate models, observational studies of ritual users, and experimental studies in healthy volunteers. Methodological details of the cited trials and preclinical studies (sample sizes, doses, and designs) are reported within the narrative when available, but the review does not report a standardised risk-of-bias or quality-assessment procedure for the included studies.

Anxiety and depression related to life-threatening illness: Between 1964 and 2016 eleven clinical trials (total n=445) evaluated serotoninergic hallucinogens for anxiety/depression associated with life‑threatening disease. Early open-label work was followed by four randomized, double‑blind, placebo‑controlled crossover trials published between 2000–2017 (sample sizes 12–51). Single doses of LSD (one study at 200 μg) or psilocybin (three studies, 14–30 mg/70 kg) given with psychological support reduced anxiety and depression and improved quality of life, death acceptance and optimism; benefits persisted from weeks up to six months in some reports. Adverse effects were generally transient (anxiety, distress, perceptual changes, headache, nausea, transient cardiovascular effects). The authors note small samples and crossover designs as limitations, while these promising results prompted proposals for Phase III trials. Unipolar depression: A systematic review of 21 studies from 1949–1973 (LSD or mescaline, n=423) reported clinician‑judged improvement rates approaching 80%, but these early trials were largely uncontrolled and heterogeneous. More recent open‑label work in treatment‑resistant major depressive disorder (MDD) reported rapid and sustained symptom reductions after two psilocybin doses (10 mg and 25 mg, 7 days apart) in a 12‑participant feasibility trial, with effects evident at one week and three months. The FDA granted psilocybin Breakthrough Therapy designation for treatment‑resistant MDD in October 2018; larger multicentre controlled trials were planned at the time of writing. Substance use disorders: Historical controlled trials (six trials, 1966–1970) examined single high‑dose LSD sessions (210–800 μg) in 536 alcoholic patients and reported reductions in alcohol misuse and increased abstinence from one to 12 months post‑treatment, though methodological limitations were common. More recent open‑label psilocybin trials for alcohol and nicotine dependence (doses 20–30 mg/70 kg; n≈10–15) reported significant reductions in use and craving that persisted to six months, but these were uncontrolled and small. No controlled trials of ayahuasca for addiction had been completed at the time of the review. Ayahuasca/DMT and other indications: The trajectory of ayahuasca research is distinct; ritual use persisted in Amazonian and Brazilian religious contexts and scientific study began later, with observational work from 1996 onward. Preclinical rodent studies reported anxiolytic and antidepressant effects of β‑carbolines (harmine, harmaline, THH) and of DMT (including microdosing in rodents). A non‑human primate study reported rapid and persistent antidepressant‑like effects after a single ayahuasca dose in a juvenile social‑isolation model. Clinical work from the Ribeirão Preto group reported an open‑label trial in treatment‑resistant MDD: a single oral ayahuasca dose (2.2 mL/kg, 0.8 mg/mL DMT) produced symptom reductions within hours that remained significant for three weeks; vomiting occurred in 47% and no serious adverse events were reported. A subsequent placebo‑controlled trial (UFRN–USP collaboration) randomised 29 treatment‑resistant MDD patients to a single ayahuasca dose (1 mL/kg, 0.36 mg/kg DMT) or placebo: ayahuasca produced significant reductions in depressive and anxiety symptoms from hours after dosing up to seven days. Nausea (71%) and vomiting (57%) were more common with ayahuasca than placebo in that trial. Other therapeutic potentials: Preliminary and historical open‑label studies suggested LSD reduced cancer‑related pain acutely and up to 2–3 weeks. A small psilocybin trial in obsessive‑compulsive disorder (n=9) using four ascending doses (0.025–0.3 mg/kg) reported transient reductions in compulsive symptoms for 24 hours post‑dose. Observational studies among ritual ayahuasca users report improvements in personality traits (reduced impulsivity/shyness; increased openness, optimism), mindfulness capacities (decentering, acceptance), emotion regulation and some neuropsychological measures, and higher self‑reported general and mental health compared with population norms. The authors emphasise that these naturalistic findings cannot establish causality and are subject to self‑selection and contextual confounds. Biological findings: Preclinical and human evidence links the subjective and therapeutic effects of classical psychedelics to agonism at cortical 5‑HT2A receptors, which promotes glutamate release and downstream AMPA receptor activation, increased cortical activity, and expression of activity‑dependent genes (c‑fos) and BDNF. Rapid increases in neuritogenesis, spinogenesis and synaptogenesis in prefrontal neurons have been reported for LSD and DMT, mediated via 5‑HT2A, TrkB and mTOR pathways; the term "psychoplastogen" is applied to describe these neuroplastic effects. Harmine increases hippocampal BDNF and stimulates neural progenitor proliferation; DMT may act at sigma‑1 receptors and exert neuroprotective effects. The β‑carbolines inhibit peripheral MAO‑A allowing oral DMT bioavailability in ayahuasca. Neuroimaging and electrophysiological studies show reduced activity and connectivity in default mode network hubs (notably the posterior cingulate cortex, PCC), altered ACC and amygdala responses, suppression of parieto‑occipital alpha rhythms, and widespread changes interpreted as reduced top‑down control with increased bottom‑up information flow. These network changes frequently correlate with ego‑dissolution and mystical‑type experiences. Psychological mechanisms and psychotherapy: The review documents diverse psychotherapeutic models historically used with psychedelics (psycholytic vs psychedelic approaches) and notes heterogeneity in modern trials. Reported psychological mediators include intensity/quality of mystical experiences, personality traits (e.g. absorption, neuroticism), increases in mindfulness, enhanced emotion processing and social cognition, and greater psychological flexibility or self‑acceptance. Recent controlled and open trials report correlations between mystical experience intensity and clinical benefit, though replication is incomplete. The authors describe their own trials as employing nondirective, supportive preparation and integration without specialised psychedelic psychotherapy, and they highlight the need for studies that disentangle drug effects from psychotherapeutic context.

Guimar and colleagues interpret the assembled evidence as converging toward clinically relevant anxiolytic, antidepressant and antiaddictive effects of serotoninergic hallucinogens when administered in carefully controlled contexts, while emphasising that the overall evidence base remains limited by small sample sizes, heterogeneity of methods, and the predominance of open‑label designs in many studies. They position contemporary findings within the historical record, noting that early reports from the mid‑20th century suggested benefit but suffered methodological shortcomings that limited their credibility. The authors argue that biological data — notably 5‑HT2A‑mediated glutamatergic signalling, rapid induction of neuroplasticity, and changes in large‑scale brain networks (DMN, ACC, PCC, amygdala) — provide plausible mechanisms that could underlie rapid and sustained symptom improvements. Psychological processes such as mystical‑type experiences, improved emotion processing, and enhancements in mindfulness and social cognition are presented as likely mediators or moderators of clinical response. The review stresses that psychotherapeutic context (set and setting) is important but not yet standardised, and that the relative contributions of drug pharmacology and psychological support remain to be clarified. Key limitations acknowledged by the authors include small sample sizes, heterogeneous interventions and outcomes, limited long‑term safety data, and inability of observational studies to infer causality. They note rare reports of psychotic reactions in ritual contexts, typically linked to individual predisposition or concomitant drug use, and report the absence of prolonged psychotic reactions in contemporary experimental settings that use rigorous screening. The authors call for larger, controlled trials across indications, standardisation and evaluation of psychotherapeutic components, longer follow‑up for safety and durability of effect, and exploration of dosing strategies (including potential non‑psychedelic, subthreshold regimens).

The authors conclude that carefully conducted open and controlled trials indicate serotoninergic hallucinogens possess antidepressant, anxiolytic and antiaddictive properties that warrant further investigation in larger controlled trials. They emphasise the low incidence of severe adverse events in contemporary trials when strict screening and monitored settings are used, though longer‑term safety data are lacking. The review highlights practical and regulatory considerations for different compounds: psilocybin has received FDA Breakthrough Therapy designation for treatment‑resistant MDD and may progress to regulated clinical use pending larger trial results; LSD should follow a similar translational path. For ayahuasca, the authors note unique regulatory and cultural challenges because it is a plant‑based preparation used ritualistically, and they discuss the possibility of synthetic equivalents combining harmine and DMT or chemically modified DMT to improve oral bioavailability as alternative routes to medicalisation. Finally, they argue that new, rapidly acting treatments that sustain benefit after single or few doses could address unmet needs in mood, anxiety and substance use disorders, but they caution that further clinical trials and naturalistic studies are required to establish long‑term efficacy, safety and optimal therapeutic models.