Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

Abstract

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

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Fig. 1: Effects of psychedelic drugs on cortico-cortical and cortico-thalamic circuits.
Fig. 2: A working hypothesis of psychedelic-induced changes in brain connectivity.
Fig. 3: Functional psychedelic-induced alterations that may underlie therapeutic effects.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (to F.X.V. and K.H.P), the Swiss Neuromatrix Foundation (to F.X.V. and K.H.P.), the Heffter Research Institute (to F.X.V.) and the Carey and Claudia Turnbull Foundation N.Y. (to F.X.V.).

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Glossary

Substance-assisted psychotherapy

A therapy model that refers to the adjuvant use of one or a few doses of a classic psychedelic in combination with psychotherapeutic support. The process will commonly include a few drug-free preparation sessions, followed by a drug session and a few follow-up integration sessions of the psychedelic experience.

Positron emission tomography

A nuclear medicine functional imaging technique that uses radioligands to assess metabolic processes and receptor density and occupancy in the brain.

Excitatory postsynaptic potentials

Temporary depolarizations of the postsynaptic neuronal membrane potential that make it more likely that the neuron will exert an action potential.

Recurrent network activity

A self-generated network activity that arises from the recurrent synaptic architecture of the cortex. One form of such activity is the up state, in which neurons transiently receive bombardments of excitatory and inhibitory synaptic inputs that depolarize many neurons to the spike threshold before returning to a relatively quiescent down state.

Neuroplastic adaptions

The brain’s ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons in the brain to compensate for injury and disease, and to adjust their activities in response to new situations or to changes in their environment.

Long-term depression

Long-lasting, activity-dependent decreases in synaptic strength.

Functional MRI

(fMRI). A neuroimaging technique that measures brain activity by detecting changes associated with blood flow.

Dynamic causal modelling

A framework for inferring the causal architecture of coupled or distributed dynamic systems, which allows the coupling between brain regions to be estimated.

Priors

The prior probability distributions in Bayesian statistical inference, which express one’s beliefs before some evidence is taken into account.

Arterial spin labelling

An imaging method used to quantify cerebral blood perfusion by magnetic labelling of arterial blood.

Blood oxygen level-dependent signal

A signal detected in functional MRI and used to investigate regional brain activity changes.

Intrinsic brain networks

Brain networks determined by their spatially independent and temporally correlated functional connectivity.

Default mode network

(DMN). A brain network consisting of various large regions, such as the posterior cingulate cortex, precuneus, medial prefrontal cortex and angular gyrus.

Selective serotonin reuptake inhibitors

A class of drugs increasing the level of serotonin by inhibiting the reuptake into the presynaptic cell, used to treat depression and anxiety disorders.

Predictive processing

A framework that views the brain as an organ of inference that is constantly generating and updating a mental model of the environment.

Entropy

A measure of uncertainty about a dynamical phenomenon (in this context, neuronal fluctuations across time).

Magnetoencephalography

An imaging technique used to map brain activity by recording magnetic fields produced by electrical currents in the brain.

Electroencephalography

An electrophysiological imaging method that records the electrical activity of the brain using electrodes placed on the scalp.

Alpha oscillations

Neural oscillations in the frequency range of 8–12 Hz that can be measured using electroencephalography or magnetoencephalography.

Synaesthesia

A perceptual phenomenon in which stimulation of one sensory modality leads to experiences in a second sensory modality.

Pharmacological challenge studies

Studies involving the administration of a pharmacological substance.

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Vollenweider, F.X., Preller, K.H. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci 21, 611–624 (2020). https://doi.org/10.1038/s41583-020-0367-2

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