Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

Psychiatric disorders impose a heavy global burden, and progress in new therapeutic approaches has been slowed by regulatory restrictions that curtailed research on hallucinogens for decades. Since the 2000s there has been a renewed research interest, with two broad pharmacological groupings commonly distinguished: classic serotonergic hallucinogens (psychedelics), which primarily act at 5-HT2A receptors, and dissociative anesthetics such as ketamine, which act principally on glutamatergic systems. Compounds that produce prosocial or entactogenic effects, most notably MDMA, are typically classed separately because their mechanisms and behavioural profiles differ from classic psychedelics. This review by Hibicke and colleagues sets out to summarise preclinical and clinical evidence for LSD, psilocybin, MDMA and ketamine, emphasising pharmacology, behavioural effects in animals and humans, and neuroimaging findings. The authors focus particularly on three domains: (1) effects of psychedelics in rodents and their impact on human brain functional connectivity; (2) preclinical and clinical data on ketamine's antidepressant effects; and (3) the prosocial actions of MDMA and its therapeutic applications, notably in PTSD.

Psychedelics and receptor pharmacology: Hibicke and colleagues describe classic serotonergic psychedelics (LSD, psilocin/psilocybin, DMT) as primarily 5-HT2A receptor agonists, while underscoring that their pharmacology is broader. These compounds also interact with 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 subtypes and can trigger intracellular signalling cascades (for example, involving β-arrestin and early growth response proteins EGR1/EGR2) in cortical pyramidal neurons. LSD shows dose-dependent effects on serotonergic and dopaminergic neuronal firing in animal work and binds to dopamine receptors (D1, D2, D4) in vitro; possible interactions with TAAR1 are noted but require further study. The overall message is that psychedelic pharmacology is pleiotropic and extends beyond simple 5-HT2A agonism. Preclinical behavioural evidence for psychedelics: Rodent studies indicate that LSD, psilocin/psilocybin and DMT can produce long-term behavioural changes relevant to antidepressant effects, coping strategies and cognitive functions, and can enhance associative learning. However, the literature is heterogeneous: outcomes depend strongly on model choice, dosing regimen and timing. Examples reported include chronic low-dose LSD (0.13 mg/kg/day) and intermittent dosing regimens such as 1 mg/kg DMT every third day; conversely, intermittent LSD (0.16 mg/kg every other day) increased aggression and reduced sociability in one study. Single doses (psilocybin 1 mg/kg, LSD 0.15 mg/kg) produced long-term, time- and context-dependent behavioural changes in Wistar-Kyoto rats. The authors emphasise the influence of ‘‘set and setting’’ even in rodents, illustrating that prior testing experience and timing of behavioural assays (for example, forced swim tests at different intervals after dosing) altered outcomes, consistent with a window of increased behavioural plasticity after psychedelic administration. Human neuroimaging and network effects: Functional neuroimaging studies in healthy volunteers show that LSD and psilocybin alter large-scale brain connectivity rather than uniformly increasing or decreasing it. LSD increased thalamic connectivity with sensory-somatomotor cortical regions and posterior cingulate cortex while decreasing thalamic connectivity to temporal cortex. Data-driven voxelwise analyses reveal increased interactions among sensory and somatomotor networks and reduced communication within associative networks, including the Default Mode Network (DMN). These changes are hypothesised to heighten sensory processing (possibly via reduced thalamic gating) while diminishing integrative associative function, which could underlie altered self-experience and reduced rigid or ruminative thinking. Psychedelic-induced visual alterations associate with reductions in posterior alpha oscillations, indicating increased visual pathway excitability. Seed-based studies linked subjective psilocybin effects to changes in claustrum low-frequency BOLD fluctuations and to altered amygdala–frontal connectivity that correlated with positive mood. Neuroimaging in clinical populations remains limited: in one MDD cohort, decreased PFC–parahippocampus connectivity and increased PFC–inferior parietal connectivity one day after psilocybin predicted treatment response at five weeks, and decreased amygdala cerebral blood flow correlated with symptom reduction, although amygdala reactivity showed complex temporal dynamics that may relate to emotional processing prior to integration therapy. Ketamine: mechanisms and clinical effects: Ketamine is framed as a rapid-acting antidepressant that acts as a noncompetitive NMDAR antagonist and engages the mTORC1 pathway. Preclinical data implicate both NMDAR-dependent and NMDAR-independent mechanisms: metabolism to hydroxynorketamine (HNK) enantiomers, especially (2R,6R)-HNK, appears necessary for some antidepressant-like effects in rodents and produces antidepressant actions with reduced NMDAR-associated side effects. In rodents, ketamine and HNK transiently increase phosphorylated mTOR and downstream targets (p70S6K, 4E-BP1) in prefrontal cortex and hippocampus; intracerebroventricular rapamycin blocks ketamine-induced synaptic and behavioural changes in animals, supporting a role for mTORC1 in mediating synaptic plasticity. Clinically, subanesthetic ketamine (commonly 0.5 mg/kg infused over 40 minutes) produces rapid antidepressant onset measurable at about 4 hours and a therapeutic response rate of 50%-70% at 1 day after a single infusion. Repeated treatments can prolong benefit, although overall response rates may be similar to single-dose regimens. Open-label data report a 69% decrease in suicidal ideation with repeated injections. Safety concerns include abuse liability and bladder/neurologic toxicity. Translational complexity is highlighted by a clinical study where peripheral rapamycin coadministration enhanced rather than blocked ketamine's antidepressant effect, indicating species differences or more complex pharmacodynamics in humans; other receptor systems such as opioid receptors may also contribute. The role of the subjective dissociative experience in ketamine's antidepressant action remains debated, with some studies linking dissociation to efficacy and others finding it neither necessary nor sufficient. MDMA: preclinical and clinical evidence for prosocial and therapeutic effects: MDMA is characterised as an entactogen that induces large releases of serotonin, dopamine and norepinephrine via transporters (SERT, DAT, NET) and increases hormones such as oxytocin. In animal models, MDMA enhances affiliative and prosocial behaviours, can increase sensitivity to social reward via nucleus accumbens 5-HT mechanisms, and facilitates fear-extinction processes via basolateral amygdala 5-HT release. Rodent studies suggest that SERT-mediated 5-HT release is necessary and perhaps sufficient for key therapeutic-like effects; oxytocin signalling may not be required for acute prosocial effects but could contribute to longer-term processes. Early clinical work in the 1970s and later Phase 1 studies (doses roughly 0.25–1.0 mg/kg p.o. in experienced subjects) established tolerability; common acute side effects include jaw clenching, headache, nausea and fatigue, usually mild-to-moderate and transient. A series of approximately a dozen Phase 2 trials in treatment-resistant PTSD have reported encouraging and durable reductions in symptoms, with pooled analyses contributing to FDA Breakthrough Therapy designation and enabling a Phase 3 programme. Preliminary open-label lead-in data from the Phase 3 trials show robust attenuation of core PTSD symptoms. MDMA-assisted psychotherapy is thus presented as a promising adjunctive approach for PTSD, with ongoing trials in alcohol use disorder and autism spectrum disorder. Barriers to broad adoption include abuse potential and interactions with SSRIs, and the authors stress the need to define optimal therapeutic frameworks (set and setting) and specific psychotherapeutic approaches.

Hibicke and colleagues conclude that hallucinogenic compounds differ in mechanism and behavioural outcomes but share the capacity to produce profound subjective and neural changes that can be harnessed therapeutically. They emphasise that the mechanisms are more complex than was traditionally assumed: psychedelics involve multiple 5-HT receptor subtypes and intracellular signalling pathways, ketamine engages both NMDAR-related and NMDAR-independent mechanisms (including active metabolites and mTORC1-dependent synaptic plasticity), and MDMA exerts prosocial effects primarily via transporter-mediated 5-HT release with downstream neural-circuit consequences. The authors position ketamine as an established rapid antidepressant with clear clinical data in treatment-resistant MDD, and present MDMA-assisted psychotherapy as having strong Phase 2 evidence in PTSD with Phase 3 trials underway. Evidence for psilocybin and LSD in depression and anxiety is promising but still limited; the authors note a recent meta-analysis suggesting more trials are required to confirm efficacy, and ongoing clinical trials for alcohol use disorder and obsessive–compulsive disorder are highlighted. Limitations and uncertainties are acknowledged throughout: preclinical literature is heterogeneous with respect to dosing, models and timing, clinical neuroimaging in patient populations is sparse, and translational gaps remain (for example, differences between rodent and human pharmacology and the surprising clinical rapamycin result for ketamine). Safety concerns (abuse liability, organ toxicity) and drug–drug interactions (notably with SSRIs in MDMA trials) are cited as practical barriers to widespread clinical implementation. The authors call for further mechanistic work and controlled clinical trials to clarify therapeutic mechanisms, optimise dosing and psychotherapeutic context, and better define safety and durability of benefits. They also highlight the value of these compounds for probing neural circuits relevant to psychiatric disorders as well as for developing novel interventions.