Psychedelic Drugs in Biomedicine

Psychedelic drugs such as LSD, mescaline and psilocybin produce profound alterations in perception, cognition and behaviour and were first studied in humans before animal models. Kyzar and colleagues describe a history in which early clinical and experimental work in the 1950s–60s suggested therapeutic potential, but legal restrictions from the 1970s halted most research for decades. A resurgence of preclinical and human studies in recent years has rekindled interest in the biology and potential clinical uses of these compounds. This paper sets out to summarise contemporary preclinical and clinical findings, evaluate the therapeutic promise of classic serotonergic psychedelics, discuss pharmacological mechanisms (with emphasis on the 5-HT2A receptor), and identify critical questions for future translational research. The authors limit their scope to classic psychedelics whose principal neural effects are mediated via 5-HT2A, and they aim to integrate molecular, cellular, circuit-level and human-imaging data to frame how these drugs might produce sustained changes in mood, addiction and other disorders.

The extracted text indicates this is a narrative, integrative review of recent preclinical and clinical literature rather than a systematic review or meta-analysis with a reported search strategy. Kyzar and colleagues synthesise findings from animal models (rodents, zebrafish, flies), human psychometric and neuroimaging studies, and small clinical trials and pilot studies. They also discuss cellular and molecular experiments including gene expression profiling and targeted pharmacology. The review focuses on evidence that links 5-HT2A receptor agonism to behavioural and circuit effects, and it draws on antagonist, knockout and pharmacological substitution studies to infer mechanism. Where available, the authors incorporate quantitative results from clinical cohorts (for example, follow-up outcomes in psilocybin trials) and from molecular studies (for example, transcriptional changes and cell-type activation percentages). The extracted text does not report systematic inclusion/exclusion criteria, databases searched, or formal risk-of-bias assessment, so the review should be understood as a selective, expert synthesis rather than a reproducible systematic review.

Effects in animal models: In rodents, selective 5-HT2A agonists such as DOI produce anxiolytic-like effects but can also enhance fear conditioning and, depending on timing, facilitate extinction of fear memory. LSD shows a biphasic temporal pharmacology: early effects mediated via 5-HT2A and later effects involving dopamine D2 receptors, with drug-discrimination and antagonist data supporting this view. Chronic LSD exposure in animals can induce persistent behavioural abnormalities reminiscent of some psychosis models. The authors also highlight other receptor families (for example, TAARs) as potential contributors to psychedelic pharmacology. Receptor pharmacology and behavioural assays: Kyzar and colleagues review evidence that 5-HT2A is the principal site mediating classical psychedelic effects. The 5-HT2A receptor is a G-protein-coupled receptor with downstream phospholipase C, intracellular calcium and MAPK signalling and can show biased signalling (for example, LSD favouring beta-arrestin pathways). Genetic and pharmacological manipulations (HTR2A knockout mice, ketanserin blockade) abrogate many psychedelic effects. Common rodent readouts such as the head twitch response (HTR) and two-lever drug discrimination assay are discussed, with caveats about strain dependence and specificity. Non-mammalian models: Fruit flies and zebrafish are noted as emerging translational models; DOI, LSD and psilocybin alter fly behaviours (visual processing, social interaction, circadian behaviours) and produce dose-dependent anxiolytic-like and social effects in zebrafish, supporting cross-species conservation of some serotonergic mechanisms. Human cognition, physiology and imaging: Psychedelics increase scores on validated altered-states questionnaires (for example, domains of oceanic boundlessness, anxious ego dissolution, visionary restructuralization). LSD and psilocybin increase positive mood and visual imagery, and transiently raise heart rate, blood pressure, temperature and several endocrine markers. Pretreatment with the 5-HT2A antagonist ketanserin attenuates some subjective effects, supporting 5-HT2A mediation. Neuroimaging studies report widespread changes in BOLD signal and metabolism, reduced thalamic BOLD, altered cerebral blood flow (notably increased visual-cortex flow with LSD), and marked changes in resting-state functional connectivity (RSFC). Decreases in default mode network (DMN) activity and reduced segregation between established networks are consistently reported; decreased parahippocampal-retrosplenial connectivity correlates with ego-dissolution measures. Clinical/pilot therapeutic studies: Small trials and pilot studies suggest potential efficacy in mood and addiction disorders. A single psilocybin dose combined with psychotherapy improved anxiety and depression in terminal cancer patients, with 60–80% showing improved measures at about 6.5 months in one report and another report of 80% maintaining improvements at 6 months after high-dose treatment. Psilocybin produced sustained symptom reduction in an open-label treatment-resistant depression cohort at 3 months. In addiction, meta-analyses of historical LSD trials (1950s–60s) indicate benefit for alcoholism; modern pilot work with psilocybin-assisted psychotherapy reported increased abstinence in alcohol use disorder. A small smoking-cessation pilot found 80% of participants smoke-free at 6 months after two or three psilocybin sessions plus CBT. In these cohorts, the intensity and mystical/spiritual quality of the acute experience correlated with longer-term behavioural change. Molecular and cellular mechanisms: Transcriptomic studies in rodent cortex show rapid upregulation of immediate-early and synaptic-plasticity genes after LSD or DOI exposure, including Krox20/Egr2, Sgk1, Ikb-a, Nor1, Ania3, cFos and Arc; follow-up work added Mkp1, C/ebp-b and Arrdc2. Regional differences are reported: for example, Arc increases more in prefrontal cortex (PFC) than hippocampus, and some genes rise in PFC and thalamus but not hippocampus. Cell-type analyses using flow cytometry indicate that only about 5% of cortical excitatory neurons become transcriptionally active after psychedelic exposure; this ‘‘trigger population’’ expresses roughly 4-fold higher Htr2a mRNA than nonactivated neurons and may initiate broader circuit changes. Psychedelics also activate subsets of inhibitory GABAergic interneurons (5–10% reported) and non-neuronal cells such as astrocytes, with region-specific gene-expression profiles. Systems-level effects and the ‘‘entropic brain’’: Functional imaging reveals that psychedelics reduce within-network stability and network segregation across multiple established networks (DMN, visual, auditory, sensorimotor), while promoting novel connectivity patterns between regions that are normally weakly associated. The authors describe this as increased ‘‘entropic’’ brain activity — a breakdown of conventional network organisation and formation of transient hubs — which could transiently reopen a state of global plasticity and allow maladaptive network patterns underlying psychiatric illness to be reset. Subjective/mystical experiences and safety: Psychedelics commonly evoke experiences described as mystical or spiritually meaningful; these subjective qualities often correlate with sustained clinical benefit. Modern controlled trials have not reported serious adverse reactions in clinical settings, but the prevalence and mechanisms of hallucinogen persisting perception disorder (HPPD) remain unclear. An online survey cited in the text found 4.2% of past psychedelic users reporting persistent visual disturbances, though the authors caution the estimate may be biased. Peripheral immunomodulatory effects: Unexpectedly, psychedelics (including LSD and (R)-DOI) show potent anti-inflammatory effects in vitro and in vivo. In cell culture, psychedelics inhibited TNF-alpha-induced proinflammatory marker expression (ICAM1, VCAM1, IL6, iNOS), and (R)-DOI produced anti-inflammatory effects in human cells. In animal models, sub-behavioural doses of inhaled (R)-DOI prevented asthma-like pathology in mice, reducing eosinophilia, mucus overproduction and airway hyperresponsiveness and suppressing select cytokines (for example IL-5, IL-6). The anti-inflammatory effects appeared at doses far below those producing hallucinogenic behaviours, suggesting a possible therapeutic window for peripheral indications.

Kyzar and colleagues integrate molecular, cellular and imaging data to propose that psychedelics initiate synapse-related gene expression in small, high-5-HT2A-expressing neuronal populations which then propagate changes across circuits and produce the large-scale connectivity alterations seen in human imaging. They hypothesise that this cascade — immediate-early gene induction, modulation of excitatory and inhibitory cell subsets and engagement of hub regions such as the claustrum and medial PFC — underlies both the acute subjective effects and the potential for durable therapeutic change by transiently increasing brain plasticity. The authors position these findings relative to earlier work by noting replication across species and modalities but also emphasise gaps in knowledge: the precise molecular steps linking 5-HT2A agonism to long-term behavioural effects are not fully defined; regional differences in transcriptional responses, and the specific contributions of interneurons and glia, remain unresolved. They further highlight the novel observation that psychedelics exert peripheral anti-inflammatory effects at sub-behavioural doses, which could open non-psychiatric therapeutic avenues. Limitations acknowledged in the text include the early-stage and small-sample nature of many clinical trials, the difficulty of modelling subjective psychedelic states in animals, incomplete understanding of long-term adverse events (for example HPPD), and the absence of systematic reporting or standardised methods in some preclinical datasets. Consequently, the authors call for rigorous, larger-scale clinical trials to validate efficacy, and for translational ‘‘reverse-translation’’ experiments that use human imaging and clinical endpoints to guide mechanistic animal and cellular work. Implications discussed by the authors include prioritising brain regions implicated in fMRI (visual cortex, hippocampus, amygdala) for mechanistic study, exploring the role of non-neuronal cells in psychedelic responses, and investigating the therapeutic potential of sub-behavioural dosing for peripheral inflammatory diseases. Overall, they urge a translational research agenda to clarify mechanisms and establish safety and efficacy in more definitive clinical trials.