The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines
Federico Zamberlan, Camila Sanz, Rocío Martínez Vivot, Carla Pallavicini, Fire Erowid, Earth Erowid and Enzo Tagliazucchi
Frontiers in Integrative Neuroscience, 2018, 12, 54.
doi : 10.3389/fnint.2018.00054
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 crosstolerance 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.
Keywords : psychedelics, consciousness, phenomenology, binding affinity profile, semantic analysis
‘‘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. With musical instruments, these components can be shown as sine waves on an oscilloscope. (: : 🙂 But in psychopharmacology? There is no psychic oscilloscope. There are no easily defined and measured harmonics or phase angles. Certainly, any eventual definition of a drug will require some such dissection into components each of which makes some contribution to the complex whole. The mental process may some day be defined by a particular combination of these components.’’
—(Shulgin and Shulgin, 1995).
Psychedelics are psychoactive substances remarkable for their capacity to elicit a wide range of idiosyncratic effects on consciousness of the self and the environment, as well as changes in perception, emotion and cognition (Nichols, 2016; Carhart-Harris et al., 2018; Preller and Vollenweider, 2018). For millenia, different cultures have adopted the ceremonial use of plants and fungi containing psychedelic molecules. These ‘‘classic’’ psychedelics include mescaline (present in cacti such as peyote, Lophophora williamsii), psilocybin (primarily found in the mushrooms of Psilocybe genus) and N,N Dimethyltryptamine (DMT; an orally inactive compound enabled by the combination with b-carbolines in ayahuasca, a brew originally from the Amazon basin; Schultes and Hofmann, 1979; Rätsch, 2005; Nichols, 2016). The discovery of the psychedelic properties of lysergic acid diethylamide
(LSD) by A. Hofmann in 1943 provided the first example of a semi-synthetic classic psychedelic, and signaled a period of intense scientific investigation on the subjective effects1 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). These experiments, together with the observation of cross-tolerance between classic psychedelics (Balestrieri and Fontanari, 1959; Isbell et al., 1959, 1961; Appel and Freedman, 1968), led to the consolidation of the serotonergic hypothesis of psychedelic action (Nichols, 2016). This hypothesis states that psychedelics elicit their effects via a common mechanism based on agonism at a relatively small set of 5-HT receptor subtypes. The existence of such mechanism agrees with early studies showing that, in spite of substantial variation in chemical structure, the subjective effects induced by classic psychedelics such as mescaline, psilocybin, DMT and LSD can be considered as similar (Wolbach et al., 1962). Though distinctions have been reported (Coyle et al., 2012; Sanz et al., 2018), they have been attributed to variations in the internal state of the user (‘‘set’’) and the surrounding (‘‘setting’’; Studerus et al., 2012), as well as dose, which can be difficult to control in non-laboratory settings.
The objective of the present work is to investigate the variety of subjective effects elicited by different psychedelic molecules and to empirically study possible mechanisms underlying such diversity. A large body of anecdotal experiences supports the existence of differences in the subjective effects of serotonergic psychedelics, in particular concerning those elicited by relatively novel synthetic derivatives of phenethylamines (i.e., mescaline analogs) and tryptamines (i.e., DMT analogs). A frequently cited example is that of N,N-Diisopropyltryptamine (DiPT), a substituted tryptamine and 5-HT1A=2A agonist remarkable for producing auditory distortions, in contrast to the predominantly visual effects of classic psychedelics (Shulgin and Carter, 1979; Shulgin and Shulgin, 1997; Kometer and Vollenweider, 2016). Adding to this particular example, over 200 psychoactive substituted phenethylamines and tryptamines presenting an ample range of reported subjective effects are described in the work of A. Shulgin (Shulgin et al., 1961, 1969; Shulgin and Shulgin, 1995, 1997). While most of these compounds are either confirmed or suspected serotonergic psychedelics, others (such as 3,4-methylenedioxyamphetamine [MDA] and 3,4-methylenedioxymethamphetamine [MDMA]) act primarily as monoamine transporter substrates that facilitate the presynaptic release of 5-HT, dopamine (DA) and norepinephrine and have received the alternative denomination of ‘‘entactogens’’ (Nichols, 1986).
The aforementioned evidence for the variety of subjective effects elicited by serotonergic psychedelics presents a challenge to the single-receptor hypothesis of psychedelic action. 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).
As stated by D. Nichols: ‘‘Specific agonists with particular substitution patterns may be able selectively to activate a subset of effectors, a phenomenon now known as functional selectivity. It seems likely that functional selectivity can at least partially explain some of the differences reported for the human psychopharmacology of hallucinogens. To date there has been no attempt to correlate specific signaling pathways with any aspect of human psychopharmacology of hallucinogens’’ (Nichols, 2017). A complementary possibility (i.e., not mutually exclusive) to that of functional selectivity is that different psychedelic molecules present distinct binding affinity profiles for receptors of neuromodulators and neurotransmitters other than 5-HT (e.g., DA, norepinephrine, histamine, glutamate) and may also act as monoamine transporter substrates.
This work presents a quantitative evaluation of this possibility. We first tested the correlation between the similarity of the reported subjective effects elicited by 18 psychedelic compounds and the similarity of their binding affinity profiles assayed at 42 possible binding sites, as well as the correlation of both with a metric of molecular structure similarity. We also replicated the main result using an independent set of binding affinity measurements at 14 different receptors. In spite of limitations affecting the binding affinity data (see the ‘‘Discussion’’ section), the observation of a significant positive correlation represents preliminary support for the involvement of different receptors in the reported subjective effects. Our work also introduces a novel quantitative and data-driven method based on natural language processing tools to study correlations between pharmacological action and reported subjective experiences.