The neurobiology of psychedelic drugs: implications for the treatment of mood disorders

Psychedelic drugs have long been of scientific and cultural interest because they induce profound alterations in perception, selfhood and emotion. Traditionally used in indigenous medical and religious practices, systematic research began in the 1950s after the discovery of LSD. Early work explored both the phenomenology of drug-induced states and potential therapeutic uses; classical hallucinogens (for example, LSD and psilocybin) and dissociative anaesthetics (for example, ketamine and PCP) were studied as tools to model psychosis and as adjuncts to psychotherapy. By the late 1960s and 1970s, however, regulatory restrictions and social controversy curtailed clinical research, leaving many questions about mechanisms and therapeutic utility unresolved. This Perspective takes stock of renewed research since the 1990s that combines modern neuroimaging, molecular pharmacology and clinical studies. Vollenweider and colleagues set out to review early and contemporary evidence on the therapeutic effects of classical hallucinogens and dissociative anaesthetics, and to synthesise mechanistic data relating to serotonergic and glutamatergic systems. The paper aims to evaluate how these neurobiological mechanisms could translate into treatments for mood and anxiety disorders, and to identify directions for future research and clinical development.

The paper is a narrative Perspective rather than a systematic review or meta-analysis. The study team synthesised findings from multiple domains: preclinical pharmacology and electrophysiology, animal models of synaptic plasticity, human neuroimaging studies, and published and archival clinical trials and case reports from both historical and contemporary sources. Clinical evidence reviewed includes double-blind trials, open-label studies and case series for ketamine, psilocybin, LSD and related compounds, as well as psychotherapy-augmented interventions. The extracted text does not describe a formal search strategy, selection criteria, or risk-of-bias assessment typical of systematic reviews. Instead, the authors integrate mechanistic data (receptor pharmacology, intracellular signalling, glutamate dynamics, BDNF expression), behavioural and neuroimaging results (activation patterns in prefrontal and limbic circuitry), and clinical outcomes (symptom scales, response and relapse rates) to build a conceptual framework linking acute drug effects with longer-term therapeutic adaptations.

Clinical findings reviewed emphasise a rapidly onset antidepressant effect of subanaesthetic ketamine. A single intravenous infusion of ketamine (0.5 mg per kg) produced significant reductions on the Hamilton Depression Rating Scale (HDRS) within 3 hours and maintained improvement for at least 72 hours in the initial small placebo-controlled study; subsequent work replicated rapid effects in larger and treatment-resistant samples, with about 71% of patients meeting response criteria (≥50% HDRS reduction) within 24 hours. Most patients, however, relapsed within about 2 weeks after a single dose; relapse-prevention attempts such as repeated ketamine infusions or daily riluzole were variably successful. Predictors of stronger ketamine response included patterns of anterior cingulate cortex (ACC) activation during cognitive and emotional tasks and a positive family history of alcohol abuse. Extension of ketamine therapy to bipolar disorder and addiction is being investigated; a randomized trial in 90 heroin addicts compared high-dose (2.0 mg per kg) versus low-dose (0.2 mg per kg) ketamine given alongside existentially oriented psychotherapy and reported higher abstinence and reduced craving over 2 years in the high-dose group. For classical hallucinogens, clinical evidence is more limited but promising. Moreno and colleagues synthesised historical case reports and performed a study in which psilocybin administered on four occasions (escalating from sub-hallucinogenic to hallucinogenic doses) produced marked reductions in obsessive-compulsive disorder symptoms (23–100% decreases on the Yale–Brown Obsessive Compulsive Scale), with rapid onset by about 2 hours and sustained reduction up to 24 hours post-treatment. Early trials and recent controlled studies (including research in patients with advanced cancer) have reported reductions in anxiety and depression lasting from weeks to months after single or few doses of psilocybin; one completed study reported mood improvement and anxiety reduction variably lasting between 2 weeks and 6 months (personal communication cited). Case reports also suggested that psilocybin and LSD can abort cluster headaches or extend remission periods. At the receptor and circuit level, classical hallucinogens act primarily as agonists at serotonin 5-HT2A receptors. Antagonism of 5-HT2A with ketanserin abolishes virtually all psilocybin-induced subjective effects in humans, and selective expression of 5-HT2A receptors in cortical pyramidal neurons restores hallucinogen-driven behaviours in receptor-deficient mice. Activation of 5-HT2A receptors on deep-layer (layer V) pyramidal cells in the prefrontal cortex (PFC) drives a glutamate-dependent increase in pyramidal neuron activity and extracellular glutamate. This enhanced glutamatergic tone can be blocked by AMPA receptor antagonists, modulators of metabotropic glutamate receptor 2 (mGluR2), and NR2B-selective NMDA antagonists, indicating complex serotonin–glutamate interactions. Dissociative anaesthetics such as ketamine primarily block NMDA receptors, apparently on GABAergic interneurons, leading to disinhibition of cortical glutamatergic neurons and increased extracellular glutamate in the mPFC. The resultant relative activation of AMPA over NMDA receptors is crucial for antidepressant-like behavioural effects in animals; AMPA antagonists block ketamine’s antidepressant-like actions. Both classes of drugs therefore increase extracellular glutamate in prefrontal-limbic circuits and enhance pyramidal cell activity, and human neuroimaging studies show PFC, ACC and insula activation and relative deactivation of striato-limbic networks following psilocybin and ketamine. Importantly, preclinical data indicate that both classical hallucinogens and dissociative anaesthetics can induce neuroplastic adaptations: increased AMPA receptor trafficking and elevated brain-derived neurotrophic factor (BDNF) levels in prefrontal and limbic areas have been observed in rodents. Human data on peripheral BDNF after ketamine are mixed; one study did not detect an increase in plasma BDNF in the first 4 hours after infusion. The authors therefore propose a shared glutamate-driven neuroplasticity mechanism that could underpin the relatively sustained antidepressant effects that outlast acute psychotropic phenomena. Safety and tolerability observations in controlled research settings are summarised: in psychotherapeutically prepared healthy subjects, large samples reported no indication of prolonged psychosis, persisting perception disorders or subsequent drug abuse after psilocybin or ketamine; small patient samples showed similar findings. Nevertheless, dissociative effects are often viewed as limiting factors for clinical use. Dose-response notes include that low to moderate oral psilocybin (<0.215 mg per kg) rarely produced anxious dissociative symptoms in controlled settings while reducing anxiety and depression, and that low doses of NR2B antagonist CP-101,606 had transient antidepressant effects with infrequent dissociative symptoms.

Vollenweider and colleagues interpret the assembled evidence to suggest that psychedelics may have real therapeutic potential for major depression, anxiety disorders and OCD. They argue that, despite distinct primary targets (5-HT2A agonism for classical hallucinogens and NMDA antagonism for dissociative anaesthetics), a convergent mechanism appears to be modulation of glutamatergic neurotransmission in prefrontal–limbic circuits that supports neuroplastic adaptations. The authors posit that increased AMPA-mediated throughput and elevated BDNF could normalise dysregulated networks implicated in mood disorders and thereby produce effects that persist beyond the acute drug state. The Perspective situates these conclusions relative to earlier literature: historical clinical reports suggested broad therapeutic effects but suffered methodological shortcomings, and contemporary controlled studies—especially with ketamine—provide stronger evidence for rapid antidepressant efficacy. The authors acknowledge several limitations and uncertainties. Earlier clinical work often lacked adequate controls and standardised outcomes; regulatory constraints (Schedule 1 classification) have slowed contemporary research; clinical durability is variable (ketamine relapse within about 2 weeks after a single dose); and translational gaps remain between animal measures of BDNF and human peripheral biomarkers. They also note that safety data are largely drawn from well-prepared research settings with small patient numbers, so generalisability to broader clinical practice is uncertain. In terms of implications, the authors call for studies that link glutamatergic measures with clinical outcomes, investigations of genotypes and 5-HT2A expression as biomarkers for personalised approaches, and research to define structure–activity and dose–response relationships. They highlight two complementary clinical strategies: developing novel ligands that retain therapeutic plasticity-promoting properties but minimise hallucinogenic or dissociative side effects, and combining psychedelics with psychotherapeutic interventions to leverage drug-facilitated neuroplasticity. Finally, the authors recommend well-controlled, blinded clinical trials to test mechanistic and therapeutic hypotheses while acknowledging the controversial history of these substances.

The authors conclude that accumulating clinical and mechanistic evidence converges on the hypothesis that classical psychedelics (for example, psilocybin) and dissociative anaesthetics (for example, ketamine) may be useful treatments for depression, anxiety and OCD. They propose that both drug classes alter glutamatergic transmission in prefrontal–limbic circuits and thereby promote neuroplastic adaptations—likely via enhanced AMPA receptor function and increased BDNF—that could explain sustained antidepressant effects observed in clinical studies. To validate this glutamate-induced neuroplasticity hypothesis, the authors call for research linking in vivo measures of glutamatergic activity to clinical endpoints, exploration of 5-HT2A receptor involvement and genotypic biomarkers for personalised interventions, and further work on dose-response, structure–activity relationships and the role of psychotherapeutic integration. Well-controlled clinical studies are urged to test these concepts and to develop treatments that maximise benefit while minimising unwanted subjective effects.