Natural Psychoplastogens As Antidepressant Agents

Depression is described as a common, disabling and rising global health problem for which existing antidepressants are imperfect: they typically require several weeks to produce benefit, have substantial side effects, and fail to help roughly one-third of patients. The extracted text frames multiple biological contributors to major depressive disorder (MDD), including monoamine dysregulation, hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, chronic low-grade inflammation and impaired neuroplasticity, and summarises how traditional antidepressants (TCAs, MAOIs, SSRIs) address some but not all of these mechanisms. Against this background, the paper introduces the concept of psychoplastogens — chemically diverse compounds that rapidly induce structural and functional neural plasticity and converge on downstream pathways such as TrkB and mTOR. Benko and colleagues set out to review naturally occurring psychoplastogens (notably serotonergic psychedelics such as psilocybin and DMT, and the flavone 7,8-dihydroxyflavone) with respect to their mechanisms, animal and human evidence, and potential therapeutic relevance for depression and related conditions.

The authors first define psychoplastogens as agents that rapidly promote neural plasticity and then describe two traditional mechanistic frameworks for depression: the monoamine hypothesis (historical observations linking monoamine depletion to depression and the action of monoaminergic antidepressants) and the neurotrophic hypothesis (reduced BDNF/TrkB signalling, impaired long‑term potentiation, dendritic atrophy in PFC and hippocampus, and stress‑related changes). These sections provide the biological rationale for targeting plasticity pathways. Mechanistically, the review emphasises that serotonergic psychedelics exert broad receptor activity with 5-HT2A receptor activation playing a central role. Activation of 5-HT2A (a Gq/11-coupled receptor) increases intracellular calcium, activates PLCβ and PKC, and stimulates MAPK; psychedelics also induce a distinct receptor conformation that engages phospholipase A2 (PLA2) in addition to PLCβ, a form of "biased agonism". Psilocin, for instance, was reported to activate PLA2 with 30-fold greater potency relative to PLCβ when compared with serotonin. The authors note that psychedelics ultimately engage pathways including mTOR and TrkB and that these downstream effects are linked to increased neurite length, dendritic spine number and overall network complexity. Animal studies summarised by Benko show that 5-HT2A receptors are highly expressed on layer V pyramidal neurons in prefrontal cortex (PFC) and that their activation raises excitatory post-synaptic potentials. Psychedelics (and synthetic 5-HT2A agonists such as DOI) produced anxiolytic-like effects in some rodent tests and facilitated cue‑based fear extinction, whereas results varied across models and strains. Notably, some substances produce anxiogenic effects in the immediate post-acute period, but positive behavioural changes persist for hours to days after the drugs are eliminated, implying durable functional remodelling. Knock-out models lacking 5-HT2A show increased anxious and depressive‑like behaviour, supporting a role for this receptor in mood regulation. Human evidence emphasises the perceptual and psychological effects of psychedelics that are mediated by 5-HT2A receptors and blocked by ketanserin or atypical antipsychotics. Clinical trials and experimental studies have produced promising results for psilocybin in treatment‑resistant depression and existential distress in terminal illness: reductions in depressive and trait anxiety measures have been reported from 1 week up to at least 6 months post-treatment in some studies, with improvements in well-being and life satisfaction. Psilocybin has been designated a ‘‘breakthrough therapy’’ for MDD by the U.S. FDA and progressed to Phase III, while LSD trials are in Phase II. Ayahuasca (DMT plus MAOI) produced rapid reductions in anxiety and depression symptoms with benefits reported up to 3 weeks in clinical studies. Neuroimaging findings indicate acute disruption of the default mode network (DMN) during psychedelic experience with evidence of post‑acute DMN strengthening; the authors highlight the hypothesis that DMN disruption may enable remodelling of networks underlying negative rumination. Some sustained clinical improvements were correlated with mystical‑type experiences during dosing sessions. The review then turns to 7,8-dihydroxyflavone (7,8-DHF), a small‑molecule TrkB agonist. 7,8-DHF binds the TrkB extracellular domain and produces prolonged TrkB phosphorylation in vivo, unlike the transient effect of BDNF. Bioavailability limitations due to rapid hepatic conjugation are noted; a prodrug, R13, increased oral bioavailability from 4.6% to ~10.5% and improved plasma and brain exposure, with beneficial effects in animal models of amyloid pathology and cognition. In vitro studies, however, failed to reproduce TrkB phosphorylation, and the authors report proposed explanations including in vivo metabolism to an active species or methodological artefacts. Animal data for 7,8-DHF include TrkB‑dependent antidepressant‑like effects in forced swim and tail suspension tests, rescue of synaptic plasticity and cognitive deficits in aged or disease models, neuroprotective effects across several neuronal populations, and improvements in models of neurodegeneration and stroke. The extracted text states that no human clinical trials of 7,8‑DHF for MDD have been reported. Safety considerations summarised in the review indicate that physiological effects of psychedelics are usually moderate (transient increases in heart rate and blood pressure, headaches, gastrointestinal symptoms). Psychological adverse effects — transient anxiety, confusion, and perceptual disturbances — can occur but trials under controlled conditions report low rates of serious adverse events; the authors cite approximately 2000 administered doses of psilocybin without serious adverse events in the studies referenced. Population data reportedly show no association between lifetime psychedelic use and increased mental illness or suicidal behaviour and even a lower need for recent mental health treatment in psychedelic users. Nonetheless, strict exclusion criteria are advised for individuals with personal or family histories of schizophrenia, mania or bipolar disorder because of a potential risk of precipitating psychosis in susceptible people. The authors also discuss theoretical concerns for 7,8-DHF: BDNF–TrkB signalling is implicated in neuropathic pain and could conceivably strengthen pathological nociceptive pathways, a potential contraindication.

Benko and Vranková interpret the collected evidence as supportive of psychoplastogens being a promising new class of rapid‑acting antidepressant agents. They position psychedelics and TrkB agonists within the broader shift away from slow‑onset monoaminergic treatments toward interventions that directly modulate neuroplasticity through mTOR and BDNF–TrkB signalling. The authors note that ketamine’s clinical adoption provides precedent for fast‑acting, plasticity‑focused treatments and that clinical findings for psilocybin, ayahuasca and related agents extend this paradigm. The authors acknowledge several uncertainties and limitations. Clinical data for serotonergic psychedelics are still emerging, with many positive findings coming from small or open‑label studies; the review does not report a systematic search strategy or quantitative synthesis in the extracted text. For 7,8‑DHF, translational gaps are highlighted: in vivo TrkB activation and behavioural benefits are promising, but in vitro failures to replicate TrkB phosphorylation, poor oral bioavailability, and the need for improved prodrugs underscore the need for further pharmacokinetic and mechanistic work. Safety limitations include the potential for transient psychological distress during sessions, and the authors caution about use in individuals at risk for psychosis or bipolar disorder. They further raise a specific biological concern for 7,8‑DHF because BDNF–TrkB signalling can exacerbate neuropathic pain in some contexts. Implications the authors emphasise are the need for more rigorous clinical trials (including larger, controlled studies and longer follow-up), improved medicinal chemistry for TrkB agonists (as exemplified by the R13 prodrug), and careful patient selection and psychotherapeutic integration when using serotonergic psychedelics. The review also notes ongoing medicinal chemistry efforts to develop DMT isosteres with psychoplastogenic but reduced hallucinogenic properties, while recognising that the subjective, mind‑altering experience may itself contribute to therapeutic outcomes.

The authors conclude that natural psychoplastogens — particularly serotonergic psychedelics and TrkB‑targeting flavones — offer a compelling, mechanistically distinct approach to treating depression because of their ability to rapidly induce neural plasticity and produce durable psychological benefits after a small number of sessions. They caution that while initial safety data are reassuring under controlled conditions, further research is required to confirm efficacy, refine dosing and delivery (for example via prodrugs such as R13), and delineate contraindications. Ultimately, Benko and colleagues call for additional preclinical and clinical studies to determine whether these agents can be integrated into psychiatric practice as alternatives or complements to conventional long‑term antidepressant treatments.