Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Serotonergic Psychedelics in Neural Plasticity

“…Since the early 20th century, there has been considerable interest in using psychedelics to treat mental illnesses (Carhart-Harris and Goodwin, 2017 ; Bogenschutz and Ross, 2018 ; Nichols and Walter, 2021 ). Numerous clinical studies have shown encouraging therapeutic potentials of psychedelics, particularly LSD and psilocybin, and to a lesser extent ayahuasca, ibogaine, and dipropyltryptamine (DPT), in treating disorders including addiction to alcohol, nicotine, or illicit drugs, anorexia nervosa, depression, distress and anxiety concerning death, obsessive-compulsive disorder, and post-traumatic stress disorder (Bogenschutz and Johnson, 2016 ; Johnson et al, 2019 ; Dos Santos and Hallak, 2020 ; Foldi et al, 2020 ; Krediet et al, 2020 ; Andersen et al, 2021 ; Dos Santos et al, 2021 ). The neuroplastic effects of psychedelics, however, have only been appreciated much more recently.…”

Trajectory of Antidepressant Effects after Single- or Two-Dose Administration of Psilocybin: A Systematic Review and Multivariate Meta-Analysis

“…In animal studies, 5HT2a receptor agonists enhanced the cognitive flexibility and response inhibition of individuals [7]. In addition, this mechanism has been associated with antidepressant-like effects in animal models [8]. Intravenous administration of psilocybin significantly decreases the positive coupling of the medial prefrontal cortex and the posterior cingulate cortex, and these brain regions are known to be involved in patients with depression.…”

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

“…Indeed, there is now considerable interest in exploring the psychotherapeutic potential of hallucinogens, with 13 trials of psilocybin ( 2 ) undertaken in 2020 alone [ 5 ]. The renewed exploration of hallucinogens in a therapeutic setting raises important ethical and scientific consideration, and highlights the need for basic research on the action of hallucinogens in human brain [ 6 , 7 ]. The only recent review on imaging of hallucinogen actions focusses mainly on the fMRI literature [ 8 ].…”