The History of Psychedelics in Psychiatry

Inserra and colleagues place this review in the context of a renewed clinical and scientific interest in psychedelic compounds over the past three decades. They note that ketamine's recent regulatory approval and ongoing Phase II and III trials of agents such as MDMA and psilocybin signal the beginning of clinical implementation; at the same time, psychedelic treatments raise distinctive challenges because they can produce profound, sometimes transformative, changes in consciousness as well as rapid therapeutic effects. Earlier research has shown promising signals of rapid antidepressant, anxiolytic, anti‑addiction, and PTSD benefits, but the mechanisms, optimal clinical models, and long‑term safety remain under active investigation and debate. This review aims to synthesise current understanding of the neurobiology and therapeutic mechanisms of compounds either approved or under active evaluation for psychiatric use. The authors restrict the scope to compounds most relevant to contemporary psychiatric development (for example, ketamine, psilocybin, MDMA, LSD, ayahuasca/DMT and related tryptamines) and describe clinical delivery models, pharmacology, neuroplasticity, immunomodulation, neurotransmitter effects, neural circuits, sleep and safety considerations. They also identify gaps in the evidence base and outline priorities for future research and policy changes that would support evidence‑based clinical translation.

The extracted text presents a narrative, mechanistic review rather than a formal systematic review or meta‑analysis. The authors state that they narrowed the scope to compounds already approved as medicines or under active clinical scrutiny; beyond that, the extracted text does not report a formal search strategy, databases searched, inclusion/exclusion criteria, date range, or prespecified risk‑of‑bias assessment. Therefore, the methods are those of a selective scholarly review, integrating preclinical studies, historical human research, contemporary randomised controlled trials, ongoing clinical trials registries and mechanistic work (molecular, cellular and neuroimaging). Evidence types synthesised include: historical clinical studies from the 1950s–1970s, animal and in vitro pharmacology, receptor and signalling studies (including biased signalling and phosphoproteomics), preclinical models of neuroplasticity and immunomodulation, contemporary RCT results and ongoing Phase II/III trials (for example MDMA‑assisted psychotherapy and psilocybin for MDD), and observational work on long‑term users (for example ayahuasca cohorts). Where dosing or trial details are reported in the extracted text (for example MDMA dosing regimens used in trials), the authors incorporate these descriptively. Because a formal methods section and systematic search details are not present in the extraction, the summary conservatively reports the review type and the kinds of evidence surveyed rather than a prespecified meta‑analytic approach.

Inserra and colleagues summarise evidence that psychedelic compounds show therapeutic potential across several psychiatric indications and act through multiple, sometimes overlapping, biological mechanisms. Key clinical and epidemiological points include: psychiatric disorders are highly prevalent (the review cites roughly 350 million affected worldwide and a lifetime diagnostic rate around 50% in high‑income countries) and current treatments are often only partly effective, creating demand for faster‑acting and more restorative therapies. Contemporary RCTs and ongoing trials report rapid and often sustained antidepressant and anxiolytic effects, reductions in suicidality and emotional distress, positive personality changes, and neuroimaging and morphologic changes that correlate with improved outcomes. The authors note that as of August 2020 there were about 260 registered clinical trials of ketamine on ClinicalTrials.gov and multiple active trials for MDMA, psilocybin and LSD across indications such as treatment‑resistant MDD, PTSD, OCD, substance use disorders and end‑of‑life anxiety. Clinical delivery model: the review describes a four‑step treatment framework used in contemporary trials: patient assessment for suitability, therapist‑led preparation, the drug‑assisted experience session (comfortable setting, music, eyeshades, continuous therapist support), and post‑session integration with further psychotherapeutic follow‑up as needed. In most trial paradigms, a small number of dosing sessions (often only one or two over weeks) are combined with multiple non‑drug psychotherapeutic sessions. Neuroplasticity and neurotrophic effects: multiple compounds increase markers of neuroplasticity. Ketamine produces rapid antidepressant effects thought to involve NMDA antagonism, mTOR activation and BDNF‑mediated synaptogenesis and spine formation. Ayahuasca/DMT and 5‑MeO‑DMT have been reported to elevate circulating BDNF in humans or to increase hippocampal BDNF in animals; psilocybin and LSD also induce transcriptional changes in neurotrophic and immediate‑early genes in cortex and hippocampus. Some dose‑dependent and sex‑dependent biphasic effects are reported in preclinical models (for example psilocybin and DMT effects on neurogenesis), and repeated dosing can produce tolerance or differing outcomes versus single administration. Immunomodulation and anti‑inflammatory effects: serotonergic psychedelics frequently engage anti‑inflammatory programmes, often through 5‑HT2A‑mediated biased signalling and, for some compounds, sigma‑1 receptor (S1R) engagement. Reported effects include reductions in proinflammatory cytokines (IL‑1β, IL‑6, TNF‑α), increases in anti‑inflammatory IL‑10, suppression of NF‑κB signalling and modulation of the HPA axis (for example ayahuasca normalising blunted awakening cortisol responses and lowering CRP). These immunologic shifts are proposed as one pathway by which psychedelics may ameliorate depression and PTSD symptoms. Receptor pharmacology and neurotransmitter systems: classical serotonergic psychedelics are characteristically 5‑HT2A receptor agonists, with additional actions at 5‑HT1A/1B/2B/2C and other receptor subtypes; many also modulate SERT, VMAT2 and other monoaminergic targets to varying extents. MDMA primarily increases synaptic 5‑HT via SERT reversal and has empathogenic effects relevant to psychotherapy augmentation; MDMA also increases oxytocin and has mixed dopaminergic effects dependent on dose and metabolites. Ketamine’s primary pharmacology involves NMDA antagonism and downstream AMPA/mTOR/BDNF signalling with secondary modulation of monoamines. Dopaminergic, glutamatergic, GABAergic and noradrenergic systems are all affected by different agents and dose regimes, with implications for both therapeutic action and side‑effect profiles. Bias and receptor complexes: the review discusses biased signalling (functional selectivity), compound‑specific phosphoproteomic fingerprints and homo‑/heteroreceptor complexes (for example proposed 5‑HT2A–mGluR2 and 5‑HT2A–D2L interactions) as mechanisms by which psychedelic ligands produce distinct transcriptional and circuit‑level effects compared with canonical 5‑HT agonists. Neural circuits and systems‑level effects: imaging and physiological data indicate consistent effects on networks implicated in self‑referential processing and affect regulation. Psychedelics decrease default mode network (DMN) integrity and PCC connectivity (correlating with reports of ego‑dissolution), alter cortico‑striato‑thalamo‑cortical (CSTC) gating and thalamocortical connectivity, and modulate claustrum activity and connectivity. The authors propose a “reset” model in which acute network disintegration permits subsequent neuroplastic reintegration and therapeutic benefit. Dosing paradigms and microdosing: most clinical studies use full psychedelic doses that induce altered consciousness. The review contrasts full dosing with microdosing (loosely defined in the text as about 1% of an active dose up to a 100 mg ceiling in one quoted definition), noting growing public interest but limited rigorous evidence. Preliminary human and preclinical data suggest possible mood and cognitive benefits but also raise concerns including anxiogenic effects, metabolic impacts, reduced synaptic plasticity in some models and potential cardiac 5‑HT2B receptor stimulation with repeated low doses. Historical and contemporary trials: hundreds of human studies were performed between the 1950s and 1970s across psychotherapy augmentation, schizophrenia models, alcoholism and other areas, though many lacked modern methodological rigour. Modern RCTs and ongoing trials address treatment‑resistant MDD, PTSD (notably MDMA‑assisted psychotherapy in Phase III), OCD, substance use disorders and end‑of‑life anxiety, among others. Long‑term outcomes and population data: observational data from long‑term serotonergic psychedelic users (notably ayahuasca ceremonial populations) generally report no increased psychopathology and, in many measures, lower rates of psychiatric symptoms, reduced substance use, improved well‑being and reductions in suicidality. Neuroimaging studies in long‑term users report region‑specific morphologic differences such as ACC increases and PCC decreases. However, causality and selection effects are acknowledged as unresolved. Safety and adverse effects: in controlled clinical settings acute adverse effects are generally mild and transient: headaches, nausea and vomiting (particularly with ayahuasca/psilocybin), transient increases in blood pressure, heart rate and temperature, and short‑lived psychosis‑like experiences. Significant risks arise primarily in uncontrolled settings or with abuse: serotonin syndrome (particularly with interactions such as SSRIs or MAOIs), cardiovascular complications (concerns about 5‑HT2B‑mediated valvulopathy on repeated exposure), MDMA‑related neurotoxicity linked to metabolites in high‑dose or binge models, potential risk of precipitating mania in bipolar disorder and the rare but recognised hallucinogen‑persisting perception disorder (HPPD). The abuse liability of classical psychedelics appears low in most preclinical paradigms, though MDMA carries higher concern. The review reports no deaths from medical‑grade compounds in clinical trials to date but emphasises need for systematic long‑term safety data.

Inserra and colleagues interpret the assembled evidence as converging on a plausible therapeutic role for several psychedelic and related compounds in psychiatry. They highlight common therapeutic themes: rapid modulation of neuroplasticity (mTOR/BDNF pathways), immunomodulatory/anti‑inflammatory effects (biasing from Th1 toward Th2 responses and downregulating NF‑κB/TNF‑α), and broad modulation of monoaminergic, glutamatergic and GABAergic systems. At the systems level, acute network disintegration (for example DMN perturbation and CSTC modulation) followed by synaptic and behavioural reintegration is offered as a mechanistic account linking subjective experiences to durable clinical benefit. The authors position these findings relative to existing treatments by noting partial pharmacological overlap with SSRIs and atypical antipsychotics (for example serotonergic receptor interactions), but they emphasise psychedelic‑specific features such as biased receptor signalling, heteroreceptor complex engagement and the often single‑ or few‑dose therapeutic regimens accompanied by intensive psychological support. They also argue that S1R engagement across some compounds provides an additional, underappreciated route for neuroprotective and immunomodulatory effects. Key limitations and uncertainties are acknowledged: much of the mechanistic evidence derives from preclinical or in vitro studies; historical human studies frequently lack modern controls; long‑term safety and effects of repeated or microdose regimens are insufficiently characterised; and the regulatory classification of many psychedelics as Schedule 1 hinders research. The authors call for more rigorous, larger‑scale RCTs (Phase II–III), mechanistic translational work, systematic assessment of acute and chronic safety (including cardiovascular, immunologic and neurotoxic endpoints), and exploration of pharmacogenomic and pharmacoepigenomic predictors of response and adverse events. They also emphasise the practical need for therapist training, standardised preparation/integration protocols and policy engagement to de‑stigmatise and enable evidence‑based clinical deployment. Finally, the authors suggest two translational paths: 1) continued development and regulatory approval of existing compounds where trial evidence supports efficacy and acceptable safety, and 2) rational design of novel ligands or structural analogues that aim to separate therapeutic effects from hallucinogenic effects by exploiting biased signalling and receptor selectivity. They conclude that, provided future trials corroborate initial positive findings and safety is acceptable, psychedelic therapies could substantially alter psychiatric practice and research priorities.

The authors conclude that, based on current evidence, psychedelic compounds challenge existing psychiatric paradigms and hold promise as novel therapeutics. They state that if larger randomised controlled trials confirm preliminary efficacy and if acute and long‑term safety profiles are comparable to or better than existing psychiatric drugs, several psychedelic agents may progress through clinical development and ultimately gain regulatory approval for medical use.