Towards an understanding of psychedelic-induced neuroplasticity

Summary & key facts

This review looks at studies about classic psychedelics (like LSD, psilocybin, and DMT/ayahuasca) and their effects on neuroplasticity — the brain’s ability to change. Animal studies show these drugs can raise genes tied to plasticity and cause dendrite and synapse growth. Human results are mixed, especially when studies use blood levels of BDNF (a plasticity protein). The authors describe likely biological steps (involving 5‑HT2A receptors, glutamate/AMPA, and mTOR) and say more direct human measures are needed to know how strong and lasting these changes are and what they mean for therapy.

Key facts:

• Animal studies report that LSD, psilocybin, DMT and DOI increase expression of plasticity-related genes (including immediate early genes and BDNF) and produce bursts of dendritic and synaptic growth, sometimes with stronger long-term potent
• Results for adult neurogenesis differ by drug and species: LSD and DOI showed no effect on adult neurogenesis in rats; psilocybin slightly reduced neurogenesis in mice; DMT and 5‑MeO‑DMT increased neurogenesis in mice in some studies.
• Human studies that measured peripheral (blood) BDNF after psychedelic use gave mixed results: some studies (including one with ayahuasca and some LSD/psilocybin studies) found increases, while others found no change.
• Peripheral BDNF is an imperfect marker of brain plasticity because blood platelets can store and release BDNF and peripheral levels may not match brain BDNF or other measures of cortical plasticity.
• The review highlights the 5‑HT2A receptor as a key mediator: a drug’s affinity for 5‑HT2A predicts its potency as a psychoplastogen, and 5‑HT2A knockout mice do not show enhanced neuroplasticity after psychedelics.
• Higher doses of the 5‑HT2A antagonist ketanserin can block psychedelic-induced neuroplasticity, while relatively low doses do not fully block it.
• A leading proposed mechanism is: 5‑HT2A activation raises extracellular glutamate, stimulating AMPA receptors, which can increase BDNF and activate TrkB and mTOR pathways; sustained AMPA and mTOR activity appears necessary for dendritic gro
• The authors note that clinical improvements after psychedelic-assisted therapy for depression, anxiety, and addiction can last months or years, and they suggest that drug-induced neuroplasticity could help explain these lasting effects, but
• The review recommends future human studies use more direct measures of neuroplasticity (for example paired associative stimulation or tetanic sensory stimulation to index LTP-like changes, and PET markers of synaptic density such as SV2A) r

Abstract

Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psychedelics promote neuroplasticity, particularly discussing the prefrontal cortex and hippocampus. We also examine what doses are required to produce this effect (e.g., hallucinogenic doses vs. "microdoses"), and how long purported changes in neuroplasticity last. Finally, we discuss the likely consequences of psychedelics' effects on neuroplasticity for both patients and healthy people, and we identify important research questions that would further scientific understanding of psychedelics' effects on neuroplasticity and its potential clinical applications.

Topics

Biochemical Analysis and Sensing Techniques Neurotransmitter Receptor Influence on Behavior Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Addiction Hallucinogen Neuroplasticity Neuroscience Psilocybin Psychiatry Psychology