Sub-acute effects of psilocybin on EEG correlates of neural plasticity in major depression: Relationship to symptoms

Skosnik and colleagues situate this study within renewed interest in serotonergic psychedelics, particularly psilocybin, for neuropsychiatric disorders. Prior clinical studies have reported rapid and sustained therapeutic effects of one or two doses of psilocybin across conditions including depression, anxiety and substance use, but the biological mechanisms that could produce both fast onset and durable benefit remain uncertain. Preclinical work shows that psilocybin promotes structural synaptic changes (dendritic growth, spinogenesis, synaptogenesis) and increased synaptic strength, giving rise to the hypothesis that psychedelics act as "psychoplastogens"; however, electrophysiological evidence of increased neural plasticity in humans has not been conclusively demonstrated. The authors note that long-term potentiation (LTP) — a persistent increase in synaptic strength following high-frequency stimulation thought to support learning and memory — can be indexed non-invasively in humans using sensory stimulation and electroencephalography (EEG), for example via an auditory tetanus paradigm that elicits evoked theta-band activity. The study tested three linked hypotheses: that, relative to placebo, psilocybin would (1) increase EEG correlates of neuroplasticity, operationalised primarily as auditory-evoked theta (4–8 Hz) power and tetanus-induced LTP-like changes; (2) reduce depressive symptoms; and (3) show that EEG changes would correlate with clinical improvement. The work aimed to provide electrophysiological evidence in people with major depressive disorder (MDD) for sustained plasticity-related brain changes following a single moderate dose of psilocybin (0.3 mg/kg).

This was a double-blind, placebo-controlled, within-subject study with a fixed-order design: all participants received placebo first and then psilocybin approximately 4 weeks later. Fixed ordering was chosen to minimise potential carryover given the possibility of long-lasting effects after psilocybin. The trial ran under institutional approvals and an FDA Investigational New Drug application, and was registered on clinicaltrials.gov. Participants were adults aged 18–65 meeting DSM-5 criteria for Major Depressive Disorder by structured interview, experiencing a current moderate-to-severe episode (GRID-HAM-D-17 score ⩾17) of at least 6 weeks' duration, and having failed at least one adequate antidepressant trial during the current episode. Participants had to be off conventional antidepressant or antipsychotic medications for at least 2 weeks prior to enrolment (4 weeks for fluoxetine). Exclusion criteria included primary diagnoses other than MDD, active substance use disorder, personal or family history of psychotic or bipolar disorder, unstable medical/neuro conditions, or psilocybin exposure within the prior year. Dosing sessions occurred in a therapeutic setting with a study therapist and psychiatrist present. At the first dosing session participants received an opaque capsule containing microcrystalline cellulose (placebo); at the second they received 0.3 mg/kg psilocybin (maximum 35 mg). Participants were encouraged to have inward-directed experiences, had supportive music and optional eyeshades/headphones, and remained on site for at least 6 hours. Psychoeducation and psychotherapy were provided before, during and after dosing. EEG was recorded with a 64-channel system (1000 Hz sampling) during an adapted auditory LTP paradigm at 24 hours and 2 weeks after each dosing session. The paradigm comprised a pre-tetanus baseline (120 tone pips), an auditory tetanus (2 minutes of 13 Hz tone pips) designed to induce LTP-like potentiation, and a post-tetanus test phase (another 120 tones). Primary EEG outcome was evoked theta power (4–8 Hz, 80–250 ms window corresponding to the N100–P200 complex), computed via time–frequency analysis using complex Morlet wavelets and a temporal–spectral region-of-interest approach. Trials with artefacts were excluded and ocular correction applied. Clinical outcome was the clinician-rated GRID-HAM-D-17; adverse events and vital signs were monitored. Analyses followed an intention-to-treat approach using linear mixed models (LMM) to accommodate repeated measures. EEG analyses included within-subject factors of block (pre vs post tetanus), time (24 h vs 2 weeks), and drug (placebo vs psilocybin); evoked theta power was log-transformed due to non-normality. Clinical models included drug and time (baseline, 24 h, 1 week, 2 weeks). Correlations between EEG and clinical change used Pearson or Spearman methods as appropriate. Significance was evaluated at two-tailed alpha = 0.05.

Of 949 individuals initially screened by prescreening, 42 were assessed in person and 22 were enrolled. Nineteen participants completed at least one dosing session and one EEG recording; 15 completed both dosing sessions and 14 completed all four EEG sessions. The sample comprised 13 women and 6 men, mean age 42.8 (SD 13.8) years. Participants had a long illness history (mean duration ~20.0 years) and mean screening GRID-HAM-D-17 of 23.9 (SD 5.0). Eight participants (42.1%) reported prior psychedelic exposure, not within 3 years of enrolment. EEG: Grand-average plots were presented for context. In the main LMM there was a significant main effect of time on evoked theta power (F(1,102) = 4.57, p < 0.03), while the drug × time (F(1,102) = 3.06, p = 0.08) and block × drug (F(1,102) = 2.83, p = 0.10) interactions approached but did not reach conventional significance. No significant main effect of block (pre- vs post-tetanus) was observed, indicating that tetanic stimulation did not produce a clear LTP-like increase in this MDD sample. Visual inspection suggested increased theta power in both pre- and post-tetanus blocks 2 weeks after psilocybin relative to pre-psilocybin, prompting an exploratory analysis averaging across blocks. In that analysis there was a main effect of time (F(1,42) = 4.18, p < 0.05); the main effect of drug (F(1,42) = 3.53, p = 0.07) and the drug × time interaction (F(1,42) = 3.07, p = 0.09) approached significance. The authors report that EEG theta power approximately doubled in amplitude 2 weeks after psilocybin but not after placebo, as visualised in figures. Clinical outcomes: On the GRID-HAM-D-17 there were significant effects of time (F(3,99) = 17.82, p < 0.0001) and drug (F(1,99) = 49.9, p < 0.0001); no significant drug × time interaction was reported. Overall, depression scores decreased following psilocybin dosing. EEG–clinical relationship: Change in averaged theta power from 1 day to 2 weeks after psilocybin correlated with change in GRID-HAM-D-17 over the same interval (Spearman's rho = -0.57, p < 0.03), such that greater increases in theta power were associated with larger decreases in depressive symptoms.

Skosnik and colleagues interpret their principal finding as preliminary evidence that a single moderate dose of psilocybin produces increased auditory-evoked theta power 2 weeks after administration, and that this increase relates to clinical improvement in depressive symptoms. They stress that the observed theta elevation may reflect sustained changes in neural excitability or plasticity distinct from tetanus-induced LTP. Notably, the auditory tetanus did not elicit an LTP-like effect in these MDD participants in either condition, which the authors suggest could indicate an impairment of this form of plasticity in depression; however, they acknowledge that absence of a healthy control group prevents determination of whether this reflects an MDD-specific deficit or limitations of the assay. The discussion positions the theta findings within mechanistic frameworks: cortical theta oscillations are linked to hippocampal–prefrontal synchrony, memory encoding and long-range network communication, and interventions that enhance theta (for example, theta-burst TMS) have shown antidepressant utility. The authors contrast their results with prior work showing that ketamine enhanced tetanic-induced LTP 24 hours post-treatment, noting that ketamine is an NMDAR antagonist while psilocybin acts primarily at 5-HT2A receptors; this suggests that psilocybin may recruit different downstream pathways (for example, AMPA signalling or other mechanisms) that yield increased theta-band activity rather than classic tetanus-dependent LTP. Timing is emphasised: the delayed emergence of increased theta at 2 weeks aligns with preclinical/autographic data indicating that synaptic density changes after psilocybin peak days to weeks after dosing, consistent with downstream structural processes. Key limitations acknowledged by the authors include the fixed-order design (placebo always first) which was necessary to reduce carryover but could introduce order effects for behavioural measures, the relatively small sample size and attrition (19 with at least one session), and absence of a healthy control group to benchmark LTP responses. They also note that assessing resting theta power might have been informative and that enhanced blinding, while employed, remains an issue in psychedelic trials; future studies could use active controls or sub-psychedelic doses and should examine expectancy effects. The authors present their findings as intriguing but preliminary, calling for replication and further work to clarify whether evoked theta could serve as an EEG biomarker of sustained psilocybin effects and to unpack underlying molecular pathways.

In this double-blind, placebo-controlled, within-subject study of people with MDD, a single 0.3 mg/kg dose of psilocybin was associated with increased auditory-evoked theta power at 2 weeks but not at 24 hours, and improvements in clinician-rated depressive symptoms were correlated with those theta increases. The authors propose that the observed augmentation of theta oscillations may reflect sustained neuroplastic changes related to clinical benefit and that evoked theta could potentially serve as an objective EEG biomarker of psilocybin's enduring effects. They recommend replication and further mechanistic studies to validate these findings and to explore their relevance for other therapeutics that may modulate theta and synaptic plasticity.