Research on Hallucinogens for Mental Health

Based on existing data, it is estimated that 1 in 5 people will experience a mental health disorder at some point in their lives, with about 17% of the global population being affected in any given 12-month period [1]. Research on psychedelics was stagnant for decades due to its negative reputation and illegality; however, the field is now facing a renewal in research and clinical fields with regards to its therapeutic potential for psychiatric disorders [2]. Hallucinogenic drugs are placed in two categories: the “serotonergic classic hallucinogens,” which primarily agonize the 5-HT2A receptor, and the “dissociative hallucinogens,” which exert their pharmacological effects through the glutamatergic system [2]. Data on the neural effects of these hallucinogens have led to interest in their potential impact on the pathways involved in mental health disorders. 

Classic psychedelic compounds interact with the 5-HT system, primarily as agonists of the 5-HT2A receptor; however, they exert other influences on the serotonin system as well. For example, LSD, psilocin, psilocybin and N,N-dimethyltryptamine (DMT) are known to interact with 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors [2,3]. Clinical studies suggest the hallucinogenic properties induced by these drugs is a result of their interaction with the 5-HT receptors that impact translocation of β-arrestin, a family of intracellular proteins that are crucial in G-protein coupled receptor signaling [3,4]. In contrast to psilocin and DMT, LSD additionally shows affinity to dopaminergic D1-3 receptors, which suggests dopamine and the brain DA system plays a role in LSD’s effects [5].  

Rodent studies indicate classic psychedelics, including LSD, psilocin, psilocybin, and DMT, as well as dissociative hallucinogens, i.e. ketamine, can induce anti-depressant effects, thus exerting influence on mental health outcomes [2,6]. Another preclinical study showed LSD could normalize anomalies in hippocampal monoamine receptor signaling that were present in a murine model of depression. Further, the authors suggested psychedelics may restore impaired avoidance learning, a behavioral effect of many depressive disorders, particularly major depressive disorder [2,7]. Mice with DMT in their system show some evidence of enhanced coping strategies in a forced swim test, the classic behavioral paradigm for depressive symptomology [8]. Recent neuroimaging studies suggest psychedelics such as LSD increase functional connectivity between the thalamus and sensory-somatomotor cortical regions, providing support for the theory that psychedelics exert anti-depressive influences through their strengthening of specific thalamocortical connections [9].  

Ketamine is unique among hallucinogens, in that it is used at moderate to high doses for anesthesia. In low doses, some research reports that it exhibits fast-acting anti-depressant effects. In 2019, the FDA approved the first new anti-depressant medication in decades: esketamine, which is derived from ketamine compounds [10]. Most psychiatric medications are only effective while they are in the body; patients on medication therapies alone who stop briefly are at high risk of quickly relapsing. In contrast, ketamine’s effects may be more long-lasting, making it uniquely effective as an anti-depressant [11]. Ketamine is an antagonist of N-methyl-D-aspartate receptor (NMDAR), a glutamatergic receptor type expressed in the CNS [12]; research suggests that NMDAR antagonists improve symptoms by restoring excitatory connections in the brain, specifically by causing mTORC1 pathway activation [13]. In mice, ketamine’s anti-depressant effects were nullified when it was unable to metabolize to (2S,6S;2R,6R)-hydroxynorketamine (HNK) [14]. The value of repeated doses of ketamine over time as an anti-depressant is unclear [15].  

Recent research has illuminated intricacies of hallucinogens for mental health; in addition to having anti-depressive effects, these drugs are being studied for the treatment of other mental disorders. For example, studies examining the use of psilocybin to treat alcohol-use disorder and obsessive-compulsive disorder seem promising [2]. It becomes paramount to look past the notoriety and stigma surrounding hallucinogens because they represent an important tool to better understanding brain pathology in mental health and psychiatric illness.  

References 

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