Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

Paul Cumming, Milan Scheidegger, Dario Dornbierer, Mikael Palner, Boris B. Quednow and Chantal Martin-Soelch

Molecules, 2021, 26, 2451

doi : 10.3390/molecules26092451

 

Abstract :

Hallucinogens are a loosely defined group of compounds including LSD, N,Ndimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry andmolecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]- methoxybenzyl)-2,5-dimethoxy4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.

Keywords : hallucinogens; molecular imaging; PET; SPECT; serotonin receptors

 

Contents :

1. Introduction
2. Binding Sites of Hallucinogens in Vitro
2.1. The Nature of Agonist-Receptor Interactions
2.2. Affinities of LSD at Neuroreceptors in Vitro
2.3. Affinities of Hallucinogenic Phenylethylamines in Vitro
2.4. Affinities of Hallucinogenic Tryptamines in Vitro
2.5. The Strange Case of Ibogaine
3. Ex vivo/In vitro Binding Studies with Hallucinogens
3.1. LSD Derivatives
3.2. Phenyethylamine Derivatives
4. Molecular Imaging Studies in Vivo with Hallucinogens
4.1. LSD Derivatives
4.2. Phenylethylamine Derivatives
4.3. Tryptamine Derivatives
4.4. Competition from Hallucinogens at Dopamine Receptors in Vivo
4.5. Competition from Hallucinogens at Serotonin Receptors in Vivo
5. Metabolism of Hallucinogenic Compounds and Tracers
4.1. LSD
5.2. Phenylethylamine Derivatives
5.3. Tryptamine Derivatives
6. Ayahuasca and Pharmahuasca
7. Effects of Hallucinogens on Energy Metabolism and Perfusion
7.1. Cerebral Glucose Metabolic Rate
7.2. Cerebral Blood Flow
8. General Conclusions
References

 

1. Introduction

Structurally diverse ergolines, phenylethylamines, and tryptamines known collectively as hallucinogens induce perceptual and affective changes, extending from sensory distortions (illusions) to sensing of non-existent objects (hallucinations), with varying degree of control over or insight into the altered state. The sites of hallucinogen binding and action in the central nervous system are amenable to study by molecular imaging with positron emission tomography (PET) or single photon emission computer tomography (SPECT), and can now be studied by functional magnetic resonance imaging (fMRI) of
cerebral perfusion and connectivity [1]. A prohibition against hallucinogen research established in many countries the 1970s was until recently an impediment to progress in our understanding of the phenomenology and physiology of hallucinogen action [2,3]; PubMed hits for the search term “hallucinogen” peaked in 1974, troughed around 1990, and have sustained a high level since 2010. Analysis of the literature in the past decade shows a shift in emphasis from preclinical studies especially of lysergic acid diethylamide (LSD) (1) towards more clinical applications, especially involving psilocybin (2) [4]. Indeed, there is now considerable interest in exploring the psychotherapeutic potential of hallucinogens, with 13 trials of psilocybin (2) undertaken in 2020 alone [5]. The renewed exploration of
hallucinogens in a therapeutic setting raises important ethical and scientific consideration, and highlights the need for basic research on the action of hallucinogens in human brain [6,7]. The only recent review on imaging of hallucinogen actions focusses mainly on the fMRI literature [8]. Given this background, we now present a narrative review of the present state of the molecular imaging literature on hallucinogenic molecules. We emphasize first the selectivity and affinity of hallucinogenic compounds for serotonin receptors in vitro, discuss their fitness as radioligands for autoradiographic binding studies, and finally review the rather sparse literature on PET and SPECT studies with hallucinogens. Our aim is to extract general principles from the available results, and identify topics for future research in this domain.

While various ancient peoples knew about plant- and animal-derived hallucinogens, the modern era of interest in hallucinogens began with the accidental discovery of the mind-altering effects of the ergot derivative LSD (1) (Figure 1). The extraordinary nature of experiences provoked by hallucinogens naturally motivated scientists to seek an understanding of their psychopharmacology and mechanisms of action. Hallucinogens belong to a variety of structural classes, including ergolines, phenylethylamines, and tryptamines (Figure 1, Figure 2, Figure 3 and Figure 5). As presented below, there is a general agreement that hallucinogens of the psychedelics class are agonists at serotonin 5HT2A receptors;
although drugs of diverse other pharmacological classes can also induce hallucinations, we mainly confine this review to serotoninergic substances. However, the full spectrum of a given hallucinogen’s action may well entail actions at other serotonin receptors as well as receptors of dopamine, noradrenaline, histamine, trace amines, and neurotransmitter uptake sites (e.g., [9,10]). The spectrum of target engagement must somehow account for the overlapping and distinct aspects of the phenomenologies of different hallucinogenic drugs. Indeed, small structural modifications of certain molecules can decisively influence their hallucinogenic potency. For example, unlike N,N-diethyltryptamine (N,N-DET, 3), the corresponding diethyl compound, 6-fluoro-N,N-diethyltryptamine (4) is without hallucinogenic action in humans [11]. Similarly, 2-bromo-LSD (BOL-148, 5), despite its engagement with serotonin 5HT2A receptors, does not evoke hallucinations [12], except perhaps in rare
cases [13]. Recent investigation of this phenomenon indicated that halogenation of N,NDET (3) did not alter its affinity for serotonin 5HT2A receptors or various other receptor types, but disabled the intracellular response to agonism, i.e., stimulation of phosphotidyl inositol (PI) turnover [14], which may be a necessary property of effective hallucinogens.

However, hallucinogenic activity is not a simple binary phenomenon, but encompasses a range of visual and sensory experiences. For example, mescaline (6) tends to evoke a characteristic visual experience of “geometricization” of three-dimensional objects, as is depicted in certain Amerindian art traditions. Visual hallucinations hint at a pharmacological action in the visual cortex [15], which is a theme amenable to analysis using a neural network approach [16]. It remains unclear how the particulars of mescaline (6) pharmacology might account for its greater propensity to evoke a specific type of visual experience. Despite the broadly overlapping serotonin receptor binding profiles of hallucinogenic tryptamines, interactions at other receptor types may contribute to their overall psychopharmacology or
the particular phenomenology of hallucinogenic experiences [17]. Indeed, pretreatment of volunteers with the selective 5HT2A/C antagonist ketanserin (7), while largely abolishing the hallucinations elicited by psilocybin (2), did not attenuate binocular rivalry switching [18] or effects on attentional tracking performance [19]. Furthermore, a compilation of reports for a broad range of substances shows that interactions of serotonin, dopamine, glutamate, and opioid receptors all contribute to aspects of the subjective experience [20].

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