Effects of psychedelics on neurogenesis: A systematic review of pre-clinical studies

Major Depressive Disorder (MDD) is a leading cause of global disability and current pharmacotherapies such as benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) fail to produce adequate benefit in around 50–60% of patients, a situation often labelled treatment-resistant depression (TRD). Earlier antidepressant research led to the monoamine hypothesis, but this has been reframed by some investigators as the neurogenic hypothesis, which links improvements after chronic antidepressant treatment to restoration of adult neurogenesis, the ongoing generation of new neurons in restricted brain zones such as the dentate gyrus. Psychedelic compounds—spanning cannabinoids, NMDA antagonists, harmala alkaloids, tryptamines and entactogens—have re-emerged as candidate therapeutics for neuropsychiatric disorders and are reported to modulate brain plasticity, including neurotrophic signalling, neuritogenesis and synaptic remodelling. Vitor Lima da Cruz and colleagues set out to systematically review preclinical and available human experimental studies that assess the effects of psychedelics on neurogenesis and related plasticity measures. Following PRISMA guidance, the investigators searched PubMed and ScienceDirect for articles combining the terms “psychedelics” and “neurogenesis” (including MeSH terms), screened titles and abstracts, extracted experimental details and outcomes, and classified findings by chemical group to provide an integrated picture of how diverse psychedelics influence the birth, survival and maturation of new neurons as well as associated molecular and behavioural endpoints. The review emphasises differences by dose, developmental window and experimental model and aims to highlight gaps relevant to therapeutic development.

The review applied PRISMA-standard search and selection. The team searched PubMed and ScienceDirect in January 2023 for articles containing both “psychedelics” and “neurogenesis” (including MeSH terms), with no date limits. Titles and abstracts were screened for original experimental work assessing neurogenesis after psychedelic intervention in in vivo or in vitro models; non-English articles were considered but none met inclusion. Excluded items included duplicates, absent abstracts, conference notes, editorials, book chapters, case reports and studies not reporting effects of psychedelics on neurogenesis or neuronal plasticity. Reference lists of retrieved reviews were also screened. After full-text checks the final sample comprised 68 original research articles. Data extraction was performed into Excel capturing bibliographic metadata, experimental methods (dose/concentration, regimen, model, techniques) and a summary of reported outcomes (neurogenesis measures and related plasticity/behavioural findings). Descriptive analyses included mapping study locations and plotting publications by year using standard software. For quality assessment the investigators applied SYRCLE’s Risk of Bias tool to in vivo animal studies and an appropriate RoB tool for human studies (OHAT), while in vitro studies were not assessed for risk of bias. Electrophysiological acute-slice experiments were treated as ex vivo and included in the animal RoB assessment; long-term cultured neurons were treated as in vitro. For SYRCLE criteria the reviewers adopted pragmatic grading: studies that at least mentioned some form of randomisation were scored positively, and baseline similarity was judged primarily on reporting of age and sex (and disease onset where relevant).

Overall sample and quality: Sixty-eight experimental articles were included: 6 human studies, 44 in vivo non-human animal studies, 11 in vitro-only studies and 7 combining in vivo and in vitro work. The largest share of papers originated from the USA (n=18) and Brazil (n=9). The in vivo literature showed common reporting deficits: most studies did not report a robust method of randomisation and few described housing conditions adequately; several SYRCLE domains therefore scored poorly, highlighting risk of bias concerns in the animal literature. CB1 agonists (cannabinoids): Twenty-one studies addressed cannabinoids (synthetics HU210, Win55212-2, O-2545; endocannabinoid AEA; phytocannabinoid THC). Most were in vivo and often used adolescent rodent models. Findings were mixed and highly dependent on dose, timing and sex. Several studies reported negligible effects of acute or chronic CB1 agonists on neurogenesis, while others observed reduced proliferation or survival (notably with chronic adolescent exposure or highly potent HU210 regimens). Parolaro’s group reported sex-dependent effects of escalating adolescent THC on BDNF signalling and reduced adult-born granule cell (abGC) proliferation/survival in females; Antoniou and colleagues described disrupted dopamine transmission after adolescent THC. In vitro and ex vivo studies more consistently showed cannabinoid-mediated reductions in neurite outgrowth and ERK/Akt signalling, effects reversible with CB1 antagonists in some models. Some prenatal or early-life exposures produced long-term mitochondrial dysfunction and teratogenic changes in high-dose models. NMDA antagonists (ketamine, PCP): Twenty studies examined NMDA antagonists, with ketamine the dominant focus. Most ketamine experiments used a single subanesthetic dose paradigm (commonly 0.25–10 mg/kg) and reported facilitation of plasticity—upregulation of BDNF, enhanced synaptogenesis, neuritogenesis and positive behavioural effects in adult animals. However, high doses or early-life exposure produced detrimental effects: neonatal or adolescent high-dose regimens (for example 30 mg/kg in specific ontogenetic windows) were associated with reduced proliferation, oxidative stress markers (NOX2 upregulation), mitochondrial damage and persistent behavioural impairments. Human studies were few: a cross-sectional study associated ketamine addiction with low-grade inflammation; controlled trials in TRD patients showed an acute increase in serum BDNF in responders after 0.5 mg/kg, but nonresponders exhibited lower BDNF at 7 and 14 days after the infusion. PCP studies largely indicated that early exposure impairs neurogenesis and plasticity. Harmala alkaloids: Six studies examined harmala compounds (harmine, harmaline, tetrahydroharmine and related β-carbolines), several from a Brazilian group. In vivo harmine treatment produced antidepressant-like behavioural effects in rodents (reduced immobility in forced swim test, improved sucrose preference after chronic stress) and in some reports increased hippocampal BDNF and promoted survival of newborn cells (DCX labelling). In vitro work showed harmine increased proliferation of human neural progenitor cells and enhanced proliferation, migration and differentiation of adult-derived neurospheres. Timing of biochemical sampling produced some inconsistencies in BDNF findings, but the aggregated evidence within depression models tended toward pro-neurogenic effects. Psychoactive tryptamines (psilocybin, DMT and analogues, ibogaine, ayahuasca, 5‑MeO‑DMT): Eleven studies investigated tryptamines, with a substantial proportion examining ayahuasca/DMT analogues or 5‑MeO‑DMT. The majority reported enhancements of neuroplasticity: increased neuritogenesis and spinogenesis in cultured neurons, upregulation of neurotrophic markers (BDNF, NGF) in some regions, and behavioural effects consistent with facilitated extinction or reduced anxiety in certain paradigms. Dose-dependent outcomes were common: low doses of psilocybin facilitated fear extinction whereas higher doses reduced BrdU-labelled cells in the dentate gyrus in one report. The authors’ own series on 5‑MeO‑DMT found increased proliferation and survival of abGC in the ventral dentate gyrus after a single intracerebroventricular injection and electrophysiological evidence that new neurons displayed more mature membrane properties. Work by Olson’s group and others showed that certain DMT derivatives and isoforms can promote neurite growth without producing classic head‑twitch responses in mice, suggesting separation of psychoplastogenic and hallucinogenic effects. Entactogens (MDMA): Studies of MDMA (n varied across ontogenetic windows) showed dose- and development-dependent effects. High or binge-like dosing produced enduring reductions in proliferation and survival of abGC (reductions of roughly 40–50% at follow-up in several studies) and long-term behavioural or cognitive deficits when exposure occurred during development or combined with alcohol. Lower doses showed fewer detectable morphological changes. Maternal exposure studies indicated reduced adult neurogenesis in offspring after some prenatal regimens. Other psychedelics (DOI, LSD, 25I‑NBOMe): Findings were heterogeneous. In vitro and ex vivo work reported neuritogenesis, spine remodelling and 5‑HT2A-mediated synaptic changes; DOI induced long‑term depression (LTD) in medial PFC layer 5 pyramidal neurons via 5‑HT2A and PKC-dependent AMPA receptor internalisation. In vivo proliferation measures were sometimes null; the substituted phenethylamine 25I‑NBOMe reduced BrdU+/NeuN+ cells only at the highest tested dose. Across categories the extracted evidence emphasises strong dependence on dose, timing (ontogenetic window), sex and experimental model, with therapeutic-range regimens generally associated with pro‑neurogenic and pro‑plasticity markers and high-dose or early-life exposures tending toward adverse outcomes.

The investigators interpret the aggregated literature as showing that psychedelics can modulate neuroplasticity and, in many preclinical paradigms, enhance processes related to adult neurogenesis—neurotrophic factor induction, proliferation and survival of newborn neurons, neuritogenesis and synaptic remodelling—when administered at therapeutic-like doses. They stress, however, that outcomes are highly context-dependent: dose, frequency, developmental stage, sex and the particulars of the experimental model all shape results. Early-life exposures or very high doses frequently produced neurotoxic or teratogenic findings in several chemical classes, whereas single subanesthetic ketamine doses and certain tryptamine regimens produced plasticity benefits in adult models. The authors place these findings alongside prior work linking neurogenesis and depression, suggesting that psychedelics’ capacity to open a transient window of enhanced plasticity may underlie therapeutic effects observed in some clinical settings. They also note mechanistic convergence across classes—many effects implicate BDNF, TrkB and downstream mTOR signalling—but caution that direct translation requires care because receptor targets and off‑target actions vary among compounds. Key limitations acknowledged include the heterogeneity of included studies (different drugs, doses, time-points and assays), frequent incomplete reporting in animal work (randomisation, housing, blinding), the small number of human experimental studies and the absence of risk-of-bias assessment for in vitro reports. The authors therefore emphasise uncertainty regarding reproducibility and translational generalisability. For future research and practice the paper highlights several priorities stated by the authors: rigorous preclinical studies with careful control of age, sex and dosing; mechanistic studies in disease-relevant models; expanded, well‑controlled human trials measuring neurotrophic and neurogenic biomarkers over appropriate time courses; and attention to set and setting in clinical translation. They further suggest that clinicians and developers should evaluate contraindications and interactions carefully and that supervised training for practitioners will be important if psychedelics are to be used therapeutically.

The review concludes that psychedelics can induce neuroplastic changes relevant to neurogenesis under many experimental conditions, but outcomes depend critically on dose, regimen, developmental timing and model. Therapeutic-range exposures—whether single or short-term—are generally associated with increased neurotrophic signalling, neuritogenesis and improved survival or maturation of newborn neurons in preclinical work, whereas excessive dosing or exposure during vulnerable developmental windows often yields adverse effects. The authors call for rigorous, well-reported preclinical and clinical studies, attention to ontogenetic factors and experimental parameter calibration, and careful clinical implementation (including training and consideration of set and setting) as these compounds progress toward therapeutic application.