Ewa Niedzielska-Andres, Angelika Ziaja, Stanisław Zielinski, Lucyna Beata Pomierny-Chamioło

Natural hallucinogens in clinical trials: A narrative review of therapeutic effectiveness and methodological limitations

 

2025-12-30

Research Subject. Recent years have witnessed a growing interest in the therapeutic use of natural hallucinogens (psychedelics) for psychiatric disorders, addictions, and pain. Substances such as psilocybin, ayahuasca, ibogaine, and mescaline are being evaluated in clinical studies that indicate their therapeutic potential, particularly for treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), existential anxiety, and substance use disorders.

The aim of the study. The aim of this review is to analyze the available clinical evidence on natural psychedelics, with attention to efficacy, safety, and mechanisms of action, and to provide a critical appraisal of limitations and future directions for development.

Materials and Methods. This paper conducted a literature review using scientific databases such as PubMed and Google Scholar. The search was conducted in both English and Polish, using keywords such as “hallucinogens”, “naturally occurring hallucinogens”, “psilocybin”, “ayahuasca”, “ibogaine”, “mescaline”, “salvinorin A”, “therapeutic potential”, “psychoactive substance addiction”, and “toxicology”. The final analysis included randomized clinical trials, open-label observational studies, experimental studies, and review articles published between 1972 and 2025.

Results. Among the described natural hallucinogens, the therapeutic effects of psilocybin have the most robust evidence base. Controlled trials show rapid, durable improvement in the TRD, reductions in existential distress, attenuation of obsessive-compulsive disorder symptoms, and support for addiction treatment, with a generally favorable safety profile. Ayahuasca demonstrates antidepressant and anxiolytic effects and potential in the treatment of addiction. Ibogaine alleviates withdrawal and craving in the treatment of opioid addiction and the PTSD symptoms in war veterans; however, it also requires additional precautions due to cardiotoxic side effects. Mescaline remains in the early stages of clinical trials assessing its safety and pharmacokinetics and is also in the early stages of assessing the benefits of its use in the treatment of mood disorders and addictions (surveys among users). Salvinorin A modulates gastrointestinal motility and, based so far on studies using animal models, seems to be potentially useful in intestinal dysfunctions.

Key mechanistic pathways include activation of serotonin 5-HT2A receptors, sigma 1 receptors, induction of neuroplasticity, modulation of dopaminergic and opioid systems, and anti-inflammatory effects. Despite promising findings, many studies are limited by small, selectively recruited samples, blinding challenges, inadequate placebos, non-standardized botanical/fungal preparations, short follow-up, and confounding effects of “set and setting” and adjunctive psychotherapy.

Outside controlled settings, risks include anxiety/psychotic reactions and misidentification poisonings; with ibogaine, serious arrhythmias. Regulatory and ethical barriers further impede progress.

Conclusion. Natural hallucinogens appear to have a therapeutic potential for treatment-resistant psychiatric conditions and pain. However, rigorously controlled trials with long-term follow-up, standardized preparations, vigilant safety monitoring, and integration with psychotherapy are required.

Keywords: hallucinogens, naturally occurring hallucinogens, therapeutic potential, psychoactive substance addiction, toxicology.

© Farm Pol, 2025, 81(6): 315–330