The serotonin 5-HT_2C receptor and the non-addictive nature of classic hallucinogens

Abstract

Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT2C receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.

Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors

“…However, activation of 5-HT 2C receptors can activate differentially distinct signal transduction pathways, dependent on agonist characteristics, which may contribute to psychoactive properties of these compounds [36]. For example, Canal and Murnane recently hypothesized that the non-addictive nature of many hallucinogens is due to 5-HT 2C receptor activation inhibiting potassium Kv1.c channels on nucleus accumbens medium spiny neurons [37]. …”

Inclusion of people of color in psychedelic-assisted psychotherapy: a review of the literature

“…One common approach in defining psychedelic compounds is based on these substances’ neurobiological mechanism of action. Using this approach, psychedelics are generally categorized into two broad chemical classes: indolamines, such as psilocybin, DMT and LSD, which primarily act on monamine neurotransmitters such as serotonin (5-HT), and phenylalkylamines, such as MDMA and mescaline, that derive their name from their action on calcium channel blockage [ 55 , 56 ].…”

Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics

“…In addition to the 5-HT2A receptor, psychedelics have appreciable activity at other serotonergic receptors, such as serotonin2C (5-HT2C) and serotonin1A (5-HT1A) receptors. The 5-HT2C receptor is involved in anxiety, dopaminergic neurotransmission, regulation of body weight, and addiction ( Nichols and Nichols, 2008 ; Vengeliene et al, 2015 ; Canal and Murnane, 2017 ). Importantly, 5-HT2C receptors have been implicated in the lack of addictive properties of the hallucinogen drug class ( Canal and Murnane, 2017 ).…”

“…The 5-HT2C receptor is involved in anxiety, dopaminergic neurotransmission, regulation of body weight, and addiction ( Nichols and Nichols, 2008 ; Vengeliene et al, 2015 ; Canal and Murnane, 2017 ). Importantly, 5-HT2C receptors have been implicated in the lack of addictive properties of the hallucinogen drug class ( Canal and Murnane, 2017 ). The serotonin1A receptor has been associated with neurogenesis, neuroprotection, depression, anxiety, dopaminergic neurotransmission, thermoregulation, and endocrine function ( López et al, 1998 ; Nichols and Nichols, 2008 ).…”