Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

The paper opens by situating major depressive disorder (MDD) as a highly prevalent, disabling condition for which many patients do not achieve adequate response with current monoaminergic treatments. These conventional antidepressants often take weeks to produce benefit and can cause adverse effects that reduce adherence. The discovery of rapid and sustained antidepressant effects with ketamine sparked renewed interest in alternative mechanisms of action, and serotoninergic psychedelics such as LSD, psilocybin and ayahuasca have re-emerged as candidate rapid-acting therapeutics based on recent human and preclinical data. Guimarães and colleagues set out to review evidence that hallucinogenic/psychedelic drugs acting as 5-HT2A receptor agonists produce antidepressant effects and to summarise plausible mechanisms of action. The authors integrate receptor-level, preclinical, neuroimaging and clinical trial evidence to evaluate whether these compounds can act as fast-acting antidepressants and to identify biological and psychological pathways that might underlie therapeutic effects.

The extracted text presents a narrative synthesis rather than a clearly described systematic review protocol. It organises evidence by domain: receptor-level molecular studies, preclinical animal and primate models, human neuroimaging and pharmacology, and clinical trials (historical and recent). The paper draws on both early (1950s–1970s) human work and contemporary controlled and open-label clinical trials, as well as cellular and animal experiments addressing mechanisms such as neuritogenesis, synaptogenesis and neurotrophic signalling. The authors report and discuss findings from specific trial designs where available (open-label trials, randomized double-blind placebo-controlled trials, cross-over designs and waiting-list-controlled trials) but the extracted text does not provide a formal description of search strategies, inclusion/exclusion criteria, dates or databases searched. Risk-of-bias assessment methods or meta-analytic statistical procedures are not described in the included extraction, so it is not possible to confirm whether the review followed systematic-review methodology. Where trial details are summarised, the paper reports sample sizes, treatment regimens (for example single or two-dose psilocybin schedules, and single-dose ayahuasca administration), measured outcomes (standard depression and anxiety scales such as HAM-D, MADRS, BDI, STAI) and timing of follow-up assessments (hours to months). Preclinical methods cited include receptor antagonist blockade, measures of dendritic arbor complexity, BDNF assays, and behavioural paradigms in rodents and non-human primates. The authors also draw on neuroimaging studies using radiotracers and functional connectivity analyses in healthy volunteers.

Receptor-level and molecular evidence: The review emphasises that classical serotoninergic psychedelics share agonism at cortical 5-HT1A/2A/2C receptors but that 5-HT2A receptors appear to be the principal mediators of their effects. Activation of 5-HT2A receptors in prefrontal and cingulate cortices, hippocampus and amygdala is reported to induce glutamate release, stimulate c-fos expression, and increase brain-derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC). Agonism at 5-HT2A by LSD and DMT is associated with increased dendritic arbor complexity, dendritic spine growth and synapse formation. A separate pathway involving sigma-1 receptor signalling was reported for DMT-driven hippocampal neurogenesis in mice. Preclinical and animal-model findings: Rodent studies show antidepressant-like effects after administration of DOI, LSD, psilocybin and DMT, although one study with psilocin/psilocybin returned null results that the authors attribute to the use of a rat strain with very low central 5-HT2A mRNA expression. A DMT-rich ayahuasca preparation produced rapid (24 h) and prolonged (14 days) antidepressant effects in a juvenile primate model. At the molecular level, psychedelics increase glutamatergic tone, AMPA receptor activation, TrkB (BDNF receptor) signalling and mTOR activation, converging on enhanced neuritogenesis, spinogenesis and synaptogenesis in the PFC—mechanisms the authors note are shared with ketamine and have been termed 'psychoplastogenic'. The review also reports that 5-HT2A receptor antagonists block many psychedelic behavioural effects in animals. Human pharmacology and neuroimaging: Human studies indicate that 5-HT2A antagonists largely block the subjective effects of psychedelics. Neuroimaging in healthy volunteers shows increased excitatory tone in frontolateral/frontomedial cortex, medial temporal lobe and occipital cortex, reduced functional connectivity within key default mode network (DMN) hubs, reduced amygdala reactivity to threat, disrupted hierarchical neural organisation and increased brain entropy. In one open-label trial of psilocybin in treatment-resistant depression (TRD), changes in amygdala reactivity and reductions in reaction time to face recognition were associated with antidepressant response. Clinical trial outcomes and tolerability: The review summarises historical studies (1950s–1970s) and modern trials. Early systematic reviews reported promising fast and enduring symptom reductions but noted methodological heterogeneity. Contemporary trials include randomized, double-blind, placebo-controlled cross-over trials of psilocybin or LSD for anxiety and depression associated with life-threatening illness, reporting significant reductions in anxiety and/or depression at follow-ups ranging from days to 6 months. For MDD/TRD specifically, an open-label ayahuasca trial (n = 17) found rapid reductions in depressive symptoms lasting up to 21 days; a randomized trial in TRD (Palhano-Fontes et al., 2019) with 29 patients reported significant reductions in HAM-D and MADRS at 1, 2 and 7 days post-dose compared to placebo. An open-label two-dose psilocybin study in 12 TRD volunteers observed rapid improvements sustained to 3 months; a waiting-list-controlled randomized trial with 24 patients reported rapid and sustained decreases in depression with two doses. Across trials, psychedelics were generally well tolerated: no serious adverse events were reported in the cited studies, with transient nausea, vomiting (noted with ayahuasca), anxiety, confusion and headache among the more common adverse effects. The authors also note that in one ayahuasca randomized trial, 76% of participants had comorbid personality disorder, a factor that could influence placebo response. Finally, the review reports that ayahuasca increased serum BDNF 48 h after intake in a TRD trial, with negative correlations between BDNF levels and depressive symptoms and relationships between BDNF, cortisol and C-reactive protein suggesting interplay between neurotrophic, neuroendocrine and inflammatory pathways. Limitations of the current evidence base: The extracted text highlights heterogeneity in early studies (diagnostic definitions, dosing, lack of controls) and the predominance of open-label designs in some modern trials, implying that larger, well-controlled randomised trials are still needed. Dose–response effects on BDNF and the role of psychotherapeutic context remain incompletely characterised.

The authors interpret the assembled evidence as converging on 5-HT2A receptor agonism as a plausible mechanistic route for rapid antidepressant effects of classical psychedelics. They argue that 5-HT2A activation increases glutamate release and engages AMPA, TrkB and mTOR signalling, producing structural and functional plasticity in the PFC similar to effects attributed to ketamine. Such 'psychoplastogenic' changes could underlie rapid symptomatic improvements and longer-term benefits by enabling relearning and increased cognitive flexibility; decreased DMN activity after acute psychedelic administration may facilitate reductions in rumination and promote novel thought patterns. Guimarães and colleagues also discuss alternative or complementary mechanisms: repeated psychedelic administration can lead to 5-HT2A desensitisation and downregulation, and because many psychedelics are partial agonists they can functionally modulate receptor signalling in ways that may differ from non-hallucinogenic 5-HT2A agonists. The paper highlights potential synergistic effects within ayahuasca preparations—DMT-driven neuroplasticity together with harmine-related increases in hippocampal BDNF and neurogenesis. Neuroimaging correlates linking amygdala responsivity and PFC–amygdala functional connectivity to clinical change are presented as provisional support for enhanced emotional responsiveness as part of the antidepressant mechanism. The authors acknowledge key uncertainties and limitations: many historical studies suffer from methodological shortcomings; several contemporary trials are small or open-label; dose-dependent effects on biomarkers such as BDNF are inconsistent across studies; and the contribution of psychotherapeutic support versus pharmacological effects remains unresolved. They call for larger, rigorous randomised controlled trials to clarify efficacy, safety, optimal dosing and the role of adjunctive psychotherapy, and for careful monitoring and reporting of adverse effects during renewed clinical investigations. Finally, the discussion places psychedelics alongside ketamine as promising rapid-acting treatments that operate via neuroplasticity-related mechanisms, while noting that each compound class has distinct safety and tolerability considerations that must inform clinical development.

The authors conclude that psychedelics acting as 5-HT2A receptor agonists represent promising candidates for rapid-acting antidepressant therapeutics. Given the limitations of current treatments and the preliminary evidence of fast and enduring benefits from both historical and modern studies, they urge the scientific community to re-open clinical research into these compounds under rigorous, credible oversight. The conclusion emphasises caution: investigations should be conducted by qualified researchers with meticulous recording of both therapeutic effects and adverse events.