Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2A R), a well-documented target for modulation of drug see...
Psychedelics (hallucinogenic 5-HT2A agonists such as psilocybin) are gaining recognition for their potential to treat a range of conditions, including anxiety-related psychopathology. Despite early promising results, the mechanisms by which psychedelic therapy alleviates anxiety are not well understood. Here, we review neural and cognitive mechanisms underly...
Psychedelics (hallucinogenic 5-HT2A agonists such as psilocybin) are gaining recognition for their potential to treat a range of conditions, including anxiety-related psychopathology. Despite early promising results, the mechanisms by which psychedelic therapy alleviates anxiety are not well understood. Here, we review neural and cognitive mechanisms underly...
There is controversy about a causal role of serotonin (5-HT) in depression, some arguing that there is no proof for impaired brain 5-HT function in depressed patients. Major depressive disorder comes with multiple endophenotypes; not surprisingly classical antidepressants (tricyclics, MAO inhibitors, SSRIs, SNRIs) are not universally effective. Most antidepr...
Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the beha...
ABSTRACT Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has al...
Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due to their therapeutic applications in the treatment of major depressive disorder, substance use disorder, end-of-life anxiety,= and anxiety symptoms, and obsessive-compulsive disorder. In this review, the current state of preclinical research on the mechanism of action, neur...
Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR ago...
Since its emergence in the 1960s, the serotonergic theory of depression bore fruit in the discovery of a plethora of antidepressant drugs affecting the lives of millions of patients. While crucial in the history of drug development, recent studies undermine the effectiveness of currently used antidepressant drugs in comparison to placebo, emphasizing the lon...
Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the invo...
Depression remains one the most commonly diagnosed mental health disorders in the United States. The Food and Drug Administration granted psilocybin breakthrough therapy status four years ago as a possible solution to this pervasive disorder. Since then, psilocybin, and hallucinogens in general, have produced promising results as alternatives to classical an...
Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet...
The recent increase in clinical research on the potential therapeutic uses of classic psychedelics has prompted the need to revisit the assessment of the abuse potential of these drugs. The term "classic psychedelic" is used in this manuscript to describe serotonergic 5-HT2A agonists that alter perception, cognition, and mood (i.e., psychedelic effects) and ...
Several lines of evidence suggest that classic psychedelics (5-HT2A receptor agonists or partial agonists) such as psilocybin might facilitate behavior change in individuals with substance use disorders. We conducted a multi-site, double-blind, randomized controlled trial (RCT) to assess the effects of psilocybin-assisted psychotherapy in alcohol-dependent v...
Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain's c...
The last decade has seen a remarkable resurgence of interest in psychedelic drugs such as psilocybin (from magic mushrooms) LSD and DMT (dimethyl tryptamine - the active ingredient of ayahuasca). This has been driven by the discovery that these psychedelics all act agonists of 5-HT2A receptors. Human imaging studies have revealed this action leads to profoun...
Aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium) is an analogue of psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) that has been identified in several species of psilocybin-containing mushrooms. Our team previously reported the synthesis, structural characterization, and biological activity of the putative metabolite of aeruginascin (4-hydroxy...
Prepulse inhibition (PPI) of startle is a sensorimotor gating phenomenon perturbed in a variety of neuropsychiatric conditions. Psychedelics disrupt PPI in rats and humans, but their effects and involvement of the serotonin 5-HT receptor (5-HTR) in mice remain unexplored. We tested the effect of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (...
Recent clinical and preclinical evidence points towards empathogenic and prosocial effects elicited by psychedelic compounds, notably the serotonin 5-HT2A agonists lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), and their derivatives. These findings suggest a therapeutic potential of psychedelic compounds for some of the behaviour...
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous ne...
