While traditional pharmacotherapy for depression poses adverse side effects and requires repeated dosing, psychedelic therapy produces persistent relief and lasting personality changes, even after as little as one or two treatment sessions. However, there’s debate within the field as to whether the antidepressant effects of psychedelics require a subjective mystical experience. That is to say, are peak psychological experiences necessary to produce an antidepressant effect, or are they merely correlated to the antidepressant action? To this end, a 2020 study published in ACS Chemical Neuroscience directly compared the extent and duration of antidepressant-like effects of a single dose of LSD, psilocybin, and ketamine in an animal model of depression. This study comes in the wake of multiple human clinical trials that have demonstrated that these compounds are effective in relieving treatment-resistant depression. However, the classic psychedelics (LSD, psilocybin) sport a different mechanism of action than ketamine. LSD and psilocybin produce their effects on mood, cognition, and behavior by binding to and activating serotonin 5-HT2A receptors. On the other hand, ketamine blocks NMDA receptors, which paradoxically produces a surge in glutamate neurotransmission in the brain at sub-anesthetic doses. Glutamate is the major excitatory neurotransmitter in the brain.
Therefore, increased signaling of this neurotransmitter results in enhanced neuronal communication and connectivity, a mechanism which may underlie its established antidepressant properties.
The researchers found that both LSD (0.15mg/kg) and psilocybin (1mg/kg) significantly reduced depressive-like behavior in rats five weeks after a single administration. On the other hand, ketamine transiently reduced depressive behavior at the lowest dose evaluated (5mg/kg), with effects lasting less than two weeks. To measure depressive-like behavior, the researchers used the Forced Swim Test. In this test, the animals are placed in an inescapable chamber of water, and the researchers observe their active coping strategies to avoid the threat of drowning. Depressive-like behavior is indicated by the amount of time the animal spends immobile in the water, which reflects a passive coping strategy. In the study, the antidepressant efficacy of LSD, psilocybin, and ketamine was seen as reduced immobility (more swimming and escape behavior) under these stressful conditions compared to the administration of control saline. The researchers noted that the antidepressant effects of LSD and psilocybin did not decrease over time, suggesting that a single dose was likely to last longer than the five weeks tested. However, a greater effect was seen in psilocybin compared to LSD at the doses used in the study. Indeed, the psilocybin-treated rats were significantly less immobile than saline rats at 1 week and 5 weeks after psilocybin administration, suggesting that the behavioral effects are established in the first week after psilocybin administration. In contrast, the ketamine-treated rats showed an increase in active escape behaviors within the Forced Swim Test when tested one week after administration, but its effect was indistinguishable from saline controls when tested at five weeks. In this way, ketamine may transiently increase functionality, but its effect wears off quickly.
These findings recapitulate the antidepressant effects from these compounds in humans. Multiple clinical trials have demonstrated that psilocybin produces long-lasting antidepressant and anxiety-reducing effects after just one or two sessions. In light of these studies, psilocybin has received Breakthrough Status by the FDA, an action that will substantially accelerate the process of drug development and review. Human clinical trials evaluating LSD therapy for major depression are ongoing. Ketamine consistently produces rapid but short-lived relief for humans with major depressive disorder. Its short-acting relief means individuals require multiple clinical visits to maintain the effect. On this front, the FDA recently approved the nasal spray esketamine (the S-enantiomer of ketamine) for treatment-resistant depression. In the last week of the study, the researchers tested anxiety-like behavior in all drug-treated groups using the elevated plus-maze (EPM), a popularly used behavioral model to characterize approach and avoidance behavior. This maze is composed of four equally sized arms, two of which are open runways and two of which are enclosed by walls.
The EPM is based on the natural aversion of rodents for open and elevated areas, so increased exploration of the open arms of the maze signals reduced anxiety-like behavior. Nearly all of the drug-treated rats showed no reduction in anxiety-like behavior when tested in the EPM, preferring instead to spend time in the closed arms of the maze. However, different results were seen in a subset of the psilocybin-treated rats that were given weekly access to an open field arena prior to testing in the EPM. For this group of psilocybin-treated animals, the weekly exposure to a non-homecage environment resulted in significantly less anxiety-like behavior when tested in the EPM. This suggests that post-drug treatment environmental factors play a crucial role in the drug’s anti-anxiety effects. The researchers note that psilocybin, but not ketamine, was able to open up a window of behavioral neuroplasticity that reduced anxiety in future novel environments (the EPM, that is). Overall, the study’s results suggest that a large portion of the ability of psychedelics to produce long-lasting antidepressant effects has a biological basis and can be effectively studied in animal models. The study authors state, “We posit that the basis for the antidepressant effects in humans is at its core biological in nature, and that while correlated to antidepressant effect, peak ego dissolution subjective experiences following psilocybin administration is not causational to antidepressant effect.” They go on to cite several biological factors that may account for the antidepressant effects observed in the psilocybin and LSD-treated animals, including cellular proliferation, increased synaptic connectivity, and anti-inflammatory effects. Further tissue-specific studies will help to identify the biological mechanisms contributing to the observed mental health benefits. Though, the study’s findings also underscore the importance of “set and setting”. Set refers to the mind state going into a psychedelic experience, while setting refers to the social and physical environment in which the psychedelic experience takes place. While the subjective experience of the rat given a psychedelic can’t be known, the contextual experiences the animals are exposed to after drug treatment appear to shape the effects observed, particularly after the first week of drug administration.
Therefore, the antidepressant effects of these compounds are likely derived from both neurophysiological effects and subjective, contextual experiences. It’s important to note rodent models offer limited translational insight into the human situation, especially considering they don’t develop depression the same way humans do. However, they allow researchers to investigate the mental health benefits of these substances in controlled environments.
These models also help the researchers better understand the biological mechanisms that may account for their enduring therapeutic effects. In conclusion, the authors note that classic psychedelics offer the most potent antidepressant and anxiolytic effects, surpassing the transient effects offered by low-dose ketamine.
The study authors write, “Serotonin 5-HT2A receptor directed therapeutic strategies may be superior to ketamine-based treatments in the clinic for depression”.
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