Possible psychedelic therapeutic mechanism

Classical psychedelic compounds, which include lysergic acid diethylamide (LSD), mescaline, psilocybin, and N,N-dimethyltryptamine (DMT), are broadly defined by their ability to produce altered states of consciousness and mood. They activate the 5-hydroxytryptamine (serotonin) 2A receptor (5-HT2AR), which can positively or negatively impact how an organism engages with its environment (1). There is evidence that medically supervised psychedelic assisted therapy may be efficacious for post-traumatic stress disorder (PTSD), substance use disorders, and treatment-resistant depression (2–5). However, there are gaps in our understanding of the neurobiological mechanisms engaged by psychedelic compounds, their therapeutic potential at scale, and whether their positive outcomes can be separated from undesirable effects (6, 7). On page 700 of this issue, Vargas et al. (8), reveal a potentially therapeutically-relevant mechanism of action for DMT and psilocin (the active form of psilocybin) involving 5-HT2AR, which when activated intracellularly, promotes dendritic growth and increases spine density of rat cortical neurons.

DMT is endogenously synthesized in mammals from the essential amino acid L-tryptophan and has been measured in the rat cortex at levels similar to other monoamine neurotransmitters (such as serotonin) (9). DMT is the main psychoactive component of ayahuasca, a potent hallucinogenic plant-based brew that has been consumed for thousands of years by indigenous people of South America for spiritual and healing ceremonies (10). Despite its long history of consumption and presence in the mammalian brain, the endogenous function of DMT is currently unknown. A key focus of Vargas et al. is the importance of how the chemical structure of DMT, and the structurally similar psilocin, permits them to easily pass through the cell membrane, unlike serotonin.

5-HT2AR is expressed intracellularly on multiple organelles, including endosomes and the Golgi apparatus. Vargas et al. find that the chemical properties of serotonin and DMT produce altered signaling according to the cellular localization HT2ARs in cortical neurons to produce distinct effects. Using cultured cells, they determined that intracellular receptors engaged by DMT are involved in rapidly enhancing structural neuroplasticity, specifically increased dendritic growth and spine density, relative to membrane localized receptors (see the figure). Bestowing cortical neurons in vivo with serotonin transporters allowed serotonin to access the intracellular receptors, mimicking the changes in structural neuroplasticity observed when cells were treated with DMT. The relevance of this phenomenon to changes in mouse behavior were assessed using a forced swimming test (FST), a widely used approach that is thought to have predictive value of antidepressant effects in humans, although the actual clinical predictive validity is questionable (11). Providing serotonin access to intracellular 5-HT2ARs reduced immobility in the FST, which is considered an antidepressant-like effect. Given that serotonin cannot normally access intracellular 5-HT2ARs in cortical excitatory neurons owing to a lack of serotonin transporters, a role of endogenous DMT may be to engage the intracellular receptor pool and facilitate neuroplastic changes. Further assessment of the role of this mechanism in mediating circuit activity and resulting behaviors relevant to depression is necessary.

Psychedelics activate intracellular signalling.

Serotonin readily activates 5-hydroxytryptamine 2A receptors (5-HT2ARs) on the cell membrane, but its unmethylated amino group (red) restricts its membrane permeability. This functional group is methylated (red) In classical psychedelics such as N,N-dimethyltryptamlne (DMT) and psllocln (produced from psilocybin), which increases membrane permeability. Activation of Intracellular 5-HT2ARs by these psychedelics leads to sustained Increases In dendrite growth and spine density. Credit to A. Mastin/Science.

Depression has an ~20% lifetime prevalence and is a leading cause of disability worldwide. First-line treatments such as selective serotonin reuptake inhibitors are taken daily for weeks before therapeutic effects are potentially observed and lead to sustained remission in only ~30% of cases; they also have side effects that impact patient adherence (12). This has led to a shift in the search for depression therapeutics in favor of rapid-acting compounds such as ketamine, which can result in sustained therapeutic effects for days or longer following a single dose (13). Similarly, recent clinical trials have suggested that DMT and psilocybin are rapidly efficacious in treating major depression with psilocybin appearing to have sustained therapeutic effects for weeks after treatment sessions consisting of a combination of psilocybin with supportive therapy (2, 3).

Unfortunately, clinical trials with psychedelics are commonly statistically underpowered and mostly do not represent common patient populations. Moreover, it is impossible to adequately include a placebo control given the profound effects these compounds have on perception, which can easily unblind both study participants and experimenters (6, 7). As a result, it is difficult to predict how the existing clinical findings will be extrapolated to a wider population. Thus, psychedelic assisted therapy should be embraced with cautious optimism; although the thousands of years of human psychedelic use and the positive outcomes of modern, though early stage, clinical trials point towards therapeutic potential, scaling psychedelic use to potentially millions of people with depression, for example, requires a careful and rigorous scientific approach.

The study conducted by Vargas et al. is a key achievement in the understanding of the mechanism of action of psychedelics. However, much needs to be done to affirm the sufficiency of signaling through intracellular 5-HT2ARs as mediators of the properties in humans, either hallucinogenic or medical, and to determine whether positive therapeutic outcomes can be separated from the classical psychedelic properties of such drugs. This will require interrogation of the specific signaling cascades engaged by intracellular 5-HT2ARs that lead to increased dendritic growth and spine density and defining the mechanistic relationship of such changes to cognitive processes. Moreover, understanding if the findings for DMT are fully shared with all psychedelics (such as the structurally dissimilar mescaline), which was only partially explored by Vargas et al., will be needed before the proposed mechanism can be described as a common psychedelic mechanism. Nevertheless, these findings are an important step forward for a rapidly expanding and much needed field of study.