[Neurotrophic mechanisms of psychedelic therapy]

Psychedelic drugs, often referred to as hallucinogens, are quite distinct from other classes of psychotropic drugs. Although the subjective and behavioral effects they induce are quite dramatic, they possess little addictive potential when compared to nicotine, alcohol or opiates. Since the discovery of ketamine antidepressant effects, there has been growing interest for these molecules. Serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are gaining attention as potential treatments for depression and addiction, similarly to 3,4-methylenedioxymethamphetamine (MDMA) for post-traumatic stress disorder (PTSD), and ibogaine for addiction. Although they possess distinct pharmacological profiles, their kinetics of action are quite similar: the therapeutic effects are felt within the hours following administration, and last well beyond drug elimination by the organism. This strongly suggests the induction of neurogenic and plastic mechanisms, including the involvement of trophic factors. This review will explore the literature dealing with the effects of psychedelics on neurotrophins, as well as the plastic adaptations that they induce, in an attempt to understand their surprising therapeutic potential. We will show that although ketamine and serotonergic psychedelics have affinity for very different receptors (NMDA, 5-HT2A), they ultimately initiate similar plastic adaptations in the prefrontal cortex through the involvement of the brain-derived neurotrophic factor (BDNF). We will see that although MDMA uses the same receptors as serotonergic psychedelics to alleviate PTSD symptoms, its effect on BDNF levels seem paradoxical and quite different. Finally, we show how ibogaine could exert its anti-addictive properties through a completely different neurotrophic factor than other psychedelic drugs, the glial cell line-derived neurotrophic factor (GDNF). While the current literature concerning the psychiatric applications of psychedelic therapy is encouraging, it remains to be determined whether their benefits could be obtained without their psychotomimetic effects, or concerns over potential toxicity.