Psychedelics as Medicines: An Emerging New Paradigm

The paper is a narrative review that integrates findings from modern clinical trials, earlier clinical studies, pilot and open‑label investigations, historical randomized trials, and preclinical animal and cellular experiments. The extracted text does not present a formal systematic search strategy, inclusion criteria, or meta‑analytic methods; instead, the authors summarise representative clinical trials and relevant laboratory findings to develop mechanistic hypotheses. Clinical evidence discussed includes randomized double‑blind phase II trials, open‑label feasibility studies, proof‑of‑concept pilot trials, and historical randomised studies of LSD for alcoholism and opioid dependence. Preclinical data referenced comprise in vitro assays of cytokine signalling, rodent models of systemic inflammation and allergic asthma, and mechanistic cellular studies of 5‑HT2A receptor signalling. Neuroimaging results cited include BOLD‑fMRI, magnetoencephalography (MEG), and functional connectivity analyses in humans given psilocybin or LSD. Where key methodological details (for example, full search dates or explicit selection criteria for studies included in the review) are required to reproduce a systematic review, the extracted text does not clearly report them.

Anxiety and depression: Early and modern clinical investigations converged on antidepressant and anxiolytic signals after single or a few supervised psychedelic sessions. Grob et al. administered 0.2 mg/kg oral psilocybin versus niacin to 12 patients with cancer‑related anxiety; no clinically significant adverse events were reported, and trait anxiety (STAI‑T) decreased significantly at 1 and 3 months relative to baseline, with Beck Depression Inventory (BDI) scores improving significantly at 6 months versus baseline. Carhart‑Harris et al. conducted an open‑label feasibility trial in 12 patients with treatment‑resistant major depression who received two oral psilocybin doses (10 mg and 25 mg, 7 days apart); QIDS scores dropped significantly at 1 week and 3 months with maximal effect at 2 weeks, and 8/12 (67%) met remission criteria at 1 week. Two larger phase II, double‑blind, placebo‑controlled studies at Johns Hopkins University (JHU) and New York University (NYU) in patients with cancer‑related psychosocial distress reported sustained and large effect sizes up to 6 months posttreatment, with no significant adverse events; in the JHU crossover trial a high dose (22 or 30 mg/70 kg) versus a low dose produced sustained reductions on HAM‑A, STAI, HAM‑D and BDI, and intensity of an immediate ‘‘mystical’’ experience correlated with therapeutic benefit. Gasser et al. reported LSD‑assisted therapy in 12 patients with life‑threatening illness showing positive trends on STAI that persisted to 12 months in follow‑up, with most participants reporting sustained anxiety reduction. An open‑label trial of ayahuasca in patients with depression showed marked symptom improvement for up to 21 days after a single dose. Obsessive‑compulsive disorder: Moreno et al. conducted a small proof‑of‑concept study in nine patients with OCD using escalating oral psilocybin doses (including a very low dose intended as an active placebo). All participants experienced marked symptom reduction in at least one session (23–100% reduction on the Yale‑Brown scale) and one participant showed remission at 6 months; however, similar effects across dose conditions raise concerns about placebo effects and the need for true placebo‑controlled follow‑up. Addiction: Historical studies from the 1950s–1970s suggested improvements in alcoholism and in one residential study of heroin addiction; a meta‑analysis of six LSD trials (n=325) reported significant reductions in alcohol misuse with an example odds ratio of about 2 at initial follow‑up. The heroin study reported lower biologically confirmed use and higher 12‑month continuous abstinence (25% vs. 5% in LSD versus control). Modern pilot work includes a 15‑participant open‑label trial of psilocybin plus manualised cognitive behavioural therapy for tobacco dependence: after preparatory sessions participants received psilocybin (20 mg/70 kg on quit date, with subsequent 20–30 mg/70 kg sessions) and weekly CBT; biological measures showed abstinence in 12/15 (80%) at an incompletely specified early follow‑up time in the extracted text, with follow‑ups reporting 10/15 (67%) abstinent at 12 months and 9/15 (60%) at a mean 2.5‑year follow‑up. Abstinence was associated with higher scores on a measure of psilocybin‑occasioned mystical experience. An open‑label pilot of psilocybin with motivational enhancement therapy in 10 alcohol‑dependent participants reported significant reductions in self‑reported alcohol use versus baseline, sustained at 36‑week follow‑up (>40% days drinking at baseline to <20% at follow‑up); reductions correlated with measures of mystical experience. Larger randomized studies comparing psilocybin to active comparators, some including fMRI measures, are under way. Limitations and safety: A key practical limitation is that psychedelics induce profound altered states, so treatment requires supervised sessions, careful psychiatric screening, preparatory psychotherapy, and trained therapists present during dosing. The extracted text cites published safety guidelines but emphasises that self‑administration at home is inappropriate. Antiinflammatory preclinical findings: Nichols and colleagues report that psychedelics act as a novel fourth class of anti‑inflammatory agents via 5‑HT2A receptor activation. In vitro studies showed psychedelics (multiple structural classes) prevent TNF‑alpha‑elicited inflammation in rat aortic smooth muscle cells with IC50s in the 1–35 nM range; (R)‑DOI had an EC50 of 15 pmol in one assay. (R)‑DOI had little effect on LPS‑stimulated inflammation, suggesting selectivity for TNF‑alpha pathways. Systemic (R)‑DOI in mice potently blocked TNF‑alpha effects, especially in vascular and intestinal tissues, at doses below those producing behavioural effects. In a mouse model of allergic asthma, nebulised (R)‑DOI at 0.01 mg/kg prevented airway hyperresponsiveness, pulmonary inflammation and eosinophilia; cellular analyses showed reduced Th2 and eosinophil recruitment and suppression of certain cytokines (IL‑5, IL‑13, GM‑CSF) but not others (IL‑4). The authors note ongoing studies in models of atherosclerosis and other inflammatory diseases and suggest 5‑HT2A‑mediated anti‑inflammatory signalling differs from serotonin itself and from biologic cytokine ‘‘sponges." Neuroimaging and mechanistic results: Human imaging studies with psilocybin and LSD have reported decreased integrity of the default mode network (DMN), reduced activity in key hubs such as the posterior cingulate cortex and medial prefrontal cortex, and decreased segregation between multiple resting‑state networks. Decreases in DMN integrity correlated with subjective ratings of ego dissolution, and MEG showed reductions in delta and alpha power associated with those experiences. Network analyses showed increased global integration and more diverse intercommunity connectivity after psilocybin. Cellular work identified a small subset (<5%) of 5‑HT2A‑expressing excitatory ‘‘trigger’’ neurons directly activated by psychedelics; these recruit inhibitory interneurons and glia, plausibly producing regionally heterogeneous shifts in excitability and network dynamics. The authors report that psychedelics increase extracellular cortical glutamate and speculate that this, together with differential interneuron recruitment, may amplify neuronal avalanches and transiently push networks toward a supercritical or more entropic state, after which reorganisation may permit reconnection into healthier network configurations.

The investigators interpret the collected clinical and preclinical findings as indicating that serotonergic psychedelics have a unique therapeutic profile: single or a few supervised administrations, combined with psychological support, can produce rapid and sometimes enduring improvements across diverse psychiatric conditions. They argue these effects may represent a new therapeutic paradigm because benefit appears after acute treatment rather than requiring chronic pharmacotherapy. The authors advance a mechanistic synthesis in which 5‑HT2A receptor activation at specific cortical and subcortical hubs transiently destabilises local network hubs, increases global interconnectivity and network ‘‘entropy,’’ and amplifies neuronal avalanches; this creates an opportunity for networks to reconnect in less pathological configurations, a process that may be aided by psychotherapeutic integration and by concurrent anti‑inflammatory actions mediated by 5‑HT2A signalling. Authors situate this perspective relative to prior work by noting that conventional, receptor‑targeted chronic treatments do not readily explain the persistent, rapid effects seen with psychedelics. They highlight neuroimaging evidence of reduced DMN integrity and increased inter‑network connectivity, correlations between the intensity of mystical‑type experiences and clinical benefit, and animal data demonstrating selective anti‑TNF‑alpha signalling as convergent lines of evidence consistent with their hypothesis. The claustrum is proposed as a candidate hub whose perturbation could produce widespread network effects. Limitations acknowledged by the authors include the predominance of small open‑label studies and pilot trials in some indications, the potential for placebo and expectation effects particularly in uncontrolled designs, and the need for careful screening and supervised administration because of profound altered states. They describe some existing well‑powered double‑blind phase II trials (JHU, NYU) as a corrective to earlier methodological limitations but note that many mechanistic ideas remain untested. The extracted text also notes that the proposed mechanism is a hypothesis consistent with current data but requires direct testing — several human trials are under way using pre‑ and post‑treatment fMRI to map resting‑state functional connectivity changes and evaluate these mechanistic predictions. Implications discussed by the authors include the potential for psychedelics to address treatment‑resistant psychiatric disorders and, via peripheral and central anti‑inflammatory pathways, to treat inflammation‑related somatic diseases. They call for rigorous research to confirm efficacy, further delineate mechanisms, determine optimal therapeutic contexts and dosing regimens, and evaluate safety and long‑term outcomes. The authors emphasise that clinical application requires supervised therapeutic settings and adherence to safety guidelines rather than unsupervised use.