Abstract
Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user (“set”) and the surroundings (“setting”). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of “set” and “setting,” to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands (“functional selectivity”). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to “in silico” estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid’s Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.
Highlights
‘‘But there are many components of a drug’s action, like the harmonics from the fundamental to the inaudible which, taken in concert, defines the drug
We first computed the similarities between the compounds in terms of the reported subjective effects, binding affinity profiles and molecular structures based on the data provided in Ray (2010)
We have performed a novel synthesis of data on the reported subjective effects of 18 psychedelic compounds, their affinities at 42 possible binding sites and their molecular structure (Ray, 2010)
Summary
‘‘But there are many components of a drug’s action, like the harmonics from the fundamental to the inaudible which, taken in concert, defines the drug. Hofmann in 1943 provided the first example of a semi-synthetic classic psychedelic, and signaled a period of intense scientific investigation on the subjective effects elicited by these substances, their mechanism of action in the brain, and their therapeutic potential (Hofmann, 1980) Experiments both in humans and animal models have provided strong evidence that the psychedelic effects of these molecules are mediated by at least partial agonism at serotonin (5-HT)2A receptors, with a possible role for agonism at other 5-HT receptor subtypes such as 5-HT2C and 5-HT1A (Glennon et al, 1983, 1984; Spencer et al, 1987; Fiorella et al, 1995; Vollenweider et al, 1998; Halberstadt et al, 2011; Hanks and González-Maeso, 2012; Quednow et al, 2012; Kometer et al, 2013; Rickli et al, 2016; Kraehenmann et al, 2017a,b; Preller et al, 2017). It has been suggested that such variety could be explained by functional selectivity, i.e., ligand-dependent selectivity for certain intracellular pathways (Urban et al, 2007; Seifert, 2013; Zhou and Bohn, 2014; López-Giménez and González-Maeso, 2018)
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