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

J Psychopharmacol. 2023 Jul;37(7):687-697. doi: 10.1177/02698811231179800. Epub 2023 Jun 30.


Background: Evidence suggests that serotonergic psychedelics (e.g. psilocybin), have rapid-acting and long-lasting antidepressant effects after a single dose. However, the mechanism underlying these effects remain unclear. One proposed mechanism is that these drugs promote neuroplasticity. However, this has not been conclusively demonstrated in humans.

Aims: We hypothesized that relative to placebo, psilocybin would: (1) increase electroencephalographic (EEG) correlates of neuroplasticity, (2) reduce depression symptoms, and (3) changes in EEG would correlate with improvements in depression.

Methods: In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder (MDD; n = 19) were administered placebo followed by psilocybin (0.3 mg/kg) in a fixed order (placebo, followed by psilocybin 4 weeks later). EEG indices of neuroplasticity (tetanus-induced long-term potentiation) as assessed via auditory evoked theta (4-8 Hz) power and measures of depression (GRID Hamilton Rating Scale for Depression-17 (GRID-HAM-D-17)) were measured at several time-points after placebo and psilocybin (24 h and 2 weeks after each session).

Results: EEG theta power doubled in amplitude 2 weeks after a single psychedelic dose of psilocybin but not after placebo. Further, improvements in depression symptoms 2 weeks after psilocybin were correlated with increases in theta power.

Conclusions: The increased theta power observed represents evidence of sustained changes in the brain following psilocybin. Given the correlation with enhancement in depressive symptoms, changes in theta may represent an EEG biomarker of the sustained effects of psilocybin, and may shed light on potential mechanisms of psilocybin's antidepressant effect. Taken together, these results complement the emerging notion that psilocybin, and perhaps other psychedelics, can produce long-term alterations in neuroplasticity.

Keywords: Psilocybin; electroencephalography (EEG); major depressive disorder; neuroplasticity; psychedelics; theta.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Depression
  • Depressive Disorder, Major* / drug therapy
  • Electroencephalography
  • Hallucinogens* / pharmacology
  • Hallucinogens* / therapeutic use
  • Humans
  • Neuronal Plasticity
  • Psilocybin / pharmacology
  • Psilocybin / therapeutic use


  • Psilocybin
  • Hallucinogens
  • Antidepressive Agents