Classical psychedelics refer to psychoactive compounds with converging affinity for a subset of serotonergic receptors in addition to other possible targets. The mechanisms leading to the altered sensory experience and ‘mind manifesting’ effects remain elusive and are subject to debate. These drugs are still characterized based on their chemical class (e.g. ergolines, tryptamines, indolamines, phenylalkylamines), as were antipsychotic drugs some decades ago, before their mechanism of action was better understood. The interest in these compounds extends beyond their psychedelic effects as there is growing evidence of their antidepressant, anxiolytic, and anti-addictive properties, to cite a few (Bogenschutz et al., 2022, Carhart-Harris et al., 2021, Goodwin et al., 2022, Holze et al., 2024, Holze et al., 2023, Raison et al., 2023, Seybert et al., 2023). However, the acute and long-term effects of classical psychedelics are complex. In this review, we summarize data mostly reporting on the acute effects of these compounds on central monoaminergic systems to determine whether their impact has a specific signature on neuromodulatory transmission.
Monoaminergic systems, encompassing neuronal populations synthesizing dopamine (DA), serotonin (5-HT), or noradrenaline (NA), are divergent and highly complex systems of neurotransmission. From cell bodies located in the brainstem, they innervate vast territories in the brain and spinal cord via large axonal domains harbouring numerous en–passant synapses. These systems are central to the mechanisms of action of antidepressants, anxiolytics, antipsychotics, and antiparkinsonian drugs, and are considered to contribute to numerous other brain afflictions (Di Giovanni et al., 2016). Knowing that psychedelic drugs bind monoaminergic receptors (Table 1), and display efficacy in multiple psychiatric diseases, it is conceivable that monoaminergic transmission participates in the mechanism of action of classical psychedelics.
The involvement of monoaminergic systems in the mechanism of action of lysergic acid diethylamide (LSD) started with evidence that LSD was a ligand of 5-HT receptors (5-HTR), which had just been described in the brain (Woolley and Shaw, 1954). Most classical psychedelics bind a subset of 5-HTR, the 5-HT2AR subtype being recurrently proposed for the underlying effects of these agents. The preferential 5-HT2AR agonist N-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN-NBOH, Hansen et al., 2014) is a psychedelic compound in humans (Nichols, 2016). However, other drugs also binding and stimulating 5-HT2AR do not have clear psychedelic properties such as lisuride, meta-chlorophenylpiperazine (mCPP), quipazine or lorcaserin (Halberstadt and Geyer, 2018). These distinct abilities of 5-HT2AR agonists to promote psychedelic effects could be explained through their specific influence on different intracellular signalling pathways, most of these compounds displaying biased agonist properties (Cao et al., 2022, González-Maeso et al., 2007). Additionally, this diversity within 5-HT2AR agonists may be related to their differing pharmacological profiles, each with a unique combination of targets, some perhaps able to mask ‘psychedelic’ effects (Halberstadt and Geyer, 2018, Saraf et al., 2021). Irrespective of the inconsistent psychedelic effects triggered by 5-HT2AR agonists, the 5-HT2AR remains a likely substrate for these effects. 5-HT2AR antagonist ketanserin, blocks the acute experiential effect in humans and head twitch response (a proxy for the hallucinogenic effects) in rodents (Becker et al., 2023; Vollenweider et al., 1998; Halberstadt, 2015; Murnane, 2018). However, other 5-HTR targets (5-HT2BR, 5-HT2CR, 5-HT1AR and possibly 5-HT5R and 5-HT6R) are also known to modulate the effects of these drugs (Canal et al., 2010). Table 1 summarizes affinities of 5-HT2AR agonists which are classical psychedelics and non-psychedelic drugs studied through electrophysiological and neurochemical exploration of the monoaminergic systems, as well as affinities of commonly used 5-HT2AR antagonists.