Psychedelics are compounds acting by serotonin 5-hydroxytryptamine (5-HT)2A receptor activation and induce several behavioral responses. They are of special interest because of their positive effects on neuropsychiatric disorders (depression and posttraumatic stress disorder). However, several findings revealed that some psychedelic actions are similar to symptoms observed in schizophrenia (psychosis, sensorimotor gating impairments, attention, and working memory deficits) which might limit their clinical applications. Psychedelics activate some neurotransmitters, i.e., serotonergic, and glutamatergic, that are also impaired in schizophrenia. Therefore, the neurobiological background of psychedelics and schizophrenia is partially similar. Another important aspect to discuss is the perspective of using psychedelics in schizophrenia therapy. Postmortem studies showed a loss of synapses in schizophrenia, and the positive effects of psychedelics on neuroplasticity (synaptogenesis, neurogenesis, and neuritogenesis) might be essential in the context of schizophrenia therapy. However, because of psychedelics' psychotic action, the recommended doses of psychedelics in schizophrenia treatment are not established, and subpsychedelic dosing or microdosing are considered. Exploratory studies are needed to determine the tolerability of treatment and appropriate dosing regimen. Another therapeutic option is using non-hallucinogenic psychedelic analogs that also induce neuroplastic outcomes but do not have psychotogenic effects. Further preclinical and clinical studies are needed to recognize the potential effectiveness of 5-HT2A agonists in schizophrenia therapy.

Major Depressive Disorder (MDD) and chronic pain are independently debilitating conditions that frequently co-occur. This comorbidity poses a significant clinical challenge, resulting in greater symptom severity, higher disability, and worse prognosis than either condition alone. Current therapies often address each disorder in isolation, leaving individuals with comorbid MDD and chronic pain underserved. Serotonergic psychedelics such as psilocybin, N,N-dimethyltryptamine (DMT), and Lysergic Acid Diethylamide (LSD) have reemerged as promising therapeutic targets for a range of neuropsychiatric disorders. When combined with psychological support, psychedelics show rapid and sustained antidepressant potential, and preliminary evidence supports analgesic effects. Despite substantial overlap in the biological and psychological processes underlying MDD and chronic pain, research on psychedelics for this comorbidity remains largely unexplored. This narrative review examines putative mechanisms through which psychedelics target symptoms of both MDD and chronic pain. Mechanisms considered include serotonergic modulation via the 5-HT2A receptor, anti-inflammatory effects, neuroplastic changes, altered brain network dynamics, psychological effects, and the influence of set and setting. While most existing evidence comes from populations with either depression or pain alone, the breadth of proposed mechanisms supports psychedelics as a unified therapeutic approach for comorbid MDD and chronic pain. This review provides a compelling rationale for future clinical trials to evaluate psychedelic-assisted therapies for complex neuropsychiatric and medical conditions.

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various other types of hallucinogens as well, such as thos Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline. During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants. Since then, research regarding the effectiveness of psychedelic therapy has been conducted under strict ethical guidelines, with fully informed consent and a pre-screening to avoid people with psychosis taking part. Psychedelics, particularly psilocybin, show potential therapeutic benefits for depression, anxiety, and other mental disorders, with generally mild and transient adverse effects. It has long been known that psychedelics promote neurite growth and neuroplasticity and are potent psychoplastogens. There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits. The British critical psychiatrist Joanna Moncrieff has critiqued the use and study of psychedelic and related drugs like psilocybin, MDMA, and ketamine for treatment of psychiatric disorders. She has highlighted concerns including excessive hype around these drugs, questionable biologically-based theories of benefit, blurred lines between medical and recreational use, flawed clinical trial findings, financial conflicts of interest, strong expectancy effects and large placebo responses, small and short-term benefits over placebo, and their potential for difficult experiences and adverse effects.