On serotonin, psychedelics, entactogens and psychoplastogens in depression, anxiety, post-traumatic stress, and related disorders.

The serotonin (5-HT) system plays an essential but not unique role in major depressive disorder and related conditions. Classical antidepressants targeting 5-HT are not universally effective, and treatment-resistant depression remains a major issue. The newest class of potential rapid-acting treatments—psychedelics like psilocybin, LSD, and DMT, and entactogens like MDMA—all target the 5-HT system, primarily as 5-HT2A receptor agonists. Phase II/III clinical trials support psychedelic- and MDMA-assisted psychotherapy for generalized anxiety disorder, major depressive disorder, treatment-resistant depression, and PTSD. These drugs produce rapid and long-lasting antidepressant effects after one or two administrations, promote synaptogenesis and synaptic plasticity, and have anti-neuroinflammatory effects. Depression may be considered a biochemical, neurological, and immune condition.

Study at a glance

Abstract

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 antidepressants target the 5-HT system, partially if not exclusively, but treatment-resistant depression (TRD) remains a major issue. The most recent and heavily investigated class of potential rapid acting antidepressant, anxiolytic, and/or anti PTSD drugs, namely psychedelics (psilocybin, LSD, DMT, ayahuasca, etc..) or entactogens (MDMA, ibogaine), all target the 5-HT system, at least in part. Phase II / III clinical trials support psychedelics- and/or MDMA-assisted psychotherapy as a new class of rapid acting treatments for GAD, MDD, TRD, PTSD, and other disorders. Psilocybin and MDMA have FDA breakthrough status for TRD/MDD and PTSD, respectively, whereas LSD just received FDA breakthrough status for GAD. All psychedelics act as 5-HT2A receptor agonists, although LSD, DMT, psilocybin may also target other 5-HT and/or dopamine receptors. Psychedelics produce rapid onset and long-lasting antidepressant effects after one or two administrations. They all promote synaptogenesis and synaptic plasticity. Neuroinflammation plays a major role in anxiety, depression, PTSD. Interestingly, psychedelic-induced 5-HT2A receptor agonism has profound anti-(neuro)inflammatory effects. Altogether, the 5-HT system plays an essential, but not unique role in MDD and related disorders. MDD, TRD and PTSD may be considered as biochemical, neurological and immune conditions, given the emerging role of neuroplasticity and neuroinflammation, which until recently, have been overlooked.