The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

Abstract

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Keywords: N,N-dimethyltryptamine; ibogaine; lysergic acid diethylamide; mescaline; molecular docking; psilocin; psilocybin; psychedelic assisted psychotherapy; psychedelics.

Figure 4

(A) Three-dimensional model representing hSERT (PDB ID: 6DZZ). Residues coloured in blue are those located in a zone within 5 Å of the serotonin. (B) Magnification depicting ibogaine (in purple) and serotonin (in orange) fitted into the central binding pocket of hSERT. The image was obtained by aligning the PDB ID 6DZZ and 7MGW structures. The highlighted residues are those most relevant to the interaction of the two molecules [57]. The superimposition (RMSD 1.152 Å) was completed using the MatchMaker tool in UCSF Chimera [70]. The artworks were produced using the same software.

Figure 1

Number of papers published per year from 1952 to 2022 reported on PubMed (https://pubmed.ncbi.nlm.nih.gov, accessed on 13 December 2022) by searching for “psychedelic therapies”. Although the research on this topic has flourished increasingly throughout the years, a decrease in the number of papers can be observed in the early 70s. In that period, research on psychedelic drugs was partially abandoned for several reasons, including tighter regulations connected to Richard Nixon’s ‘War on Drugs’ [34].

Figure 2

Tabernanthe iboga with orange fruits (A); chemical structures of ibogaine (B); tabernanthine (C); ibogamine (D); ibogaline (E).

Figure 3

The receptor and molecular mechanisms involved in ibogaine activity requires: (A) neurotrophic factors, (B) opioid receptors and (C) transporters and receptors of monoamine. The figure was partly generated using Servier Medical Art, provided by Servier and licensed under a Creative Commons Attribution 3.0 unported license.

Figure 5

Flowered Echinocactus williamsii (A); chemical structure of mescaline (B).

Figure 6

Three-dimensional model depicting the 5-HT2A receptor (PDB ID 7WC4). Residues coloured in pink are those involved in interactions with mescaline determined by the RRA method (A,B) and the FRA method (C,D) [70,101].

Figure 7

Psychotria viridis with red infructescences (A); chemical structure of N,N-dimethyltryptamine (B).

Figure 8

Graphical representation of DMT’s mechanism of action. DMT is a partial agonist of serotonin receptors (5-HT2) and its mechanism of action involves the second messenger pathway of PLC and A2 in post-synaptic neurons. DMT also acts as an inhibitor of SERT and VMAT2 transporters of serotonin at the pre-synaptic level. On the left of the figure, additional targets of DMT and their intracellular pathways are represented: mGluR2/3, NMDA, sigma-1 receptor and TAARs. Finally, DMT can promote synaptic plasticity by increasing the expression of the transcription factors c-fos, egr-1 and egr-2 and of the neurotrophic factor BDNF. The figure was partly generated using Servier Medical Art, provided by Servier and licensed under a Creative Commons Attribution 3.0 unported license.

Figure 9

Three-dimensional model depicting 5-HT2A receptor (PDB ID 7WC4). Residues coloured in green are those involved in interactions with DMT determined by the RRA method (A,B) and FRA method (C,D) [70].

Figure 10

Three-dimensional model depicting 5-HT1B receptor (PDB ID 4IAR). Residues coloured in green are those involved in interactions with DMT, determined by Contreras et al. 2022 [70,142].

Figure 11

Psilocybe cubensis (A); chemical structure of psilocybin (B); psilocin (C).

Figure 12

After oral administration, psilocybin loses its phosphate group and is totally converted to psilocin, which consequently represents the main derivative responsible for its pharmacological activity. (A) Psilocin has a good affinity for the 5-HT2A receptor, and this binding is responsible for the “mystical” hallucinatory effects induced by psilocin. In increasing order of affinity, psilocin can also bind to 5-HT2B, 5-HT1D, dopamine D1, 5-HT1E, 5-HT1A, 5-HT5A, 5-HT7, 5-HT6, D3, 5-HT2C and 5-HT1B receptors. (B) Activation of the 5-HT2A receptor in the prefrontal cortex by psilocin results in increased glutamatergic activity with glutamate release with AMPA and NMDA receptors on cortical pyramidal neurons. (C) Psilocin has been observed to exert its pharmacological action by enhancing neuroplasticity and neuritogenesis by acting through BDNF and mTOR pathways. This figure was partially generated using Servier Medical Art, provided by Servier and licensed under a Creative Commons Attribution 3.0 unported license.

Figure 13

Three-dimensional model depicting the 5-HT2A receptor (PDB ID 7WC5) (A). (B) Detailed view of residues (in magenta) involved in interactions with psilocin (pink) determined by Cao et al. 2022 [70].

Figure 14

Three-dimensional model depicting 5-HT2C receptor (PDB ID 8DPG) (A). (B) Detailed view of residues (in magenta) involved in interactions with psilocin (pink) determined by Gumpper et al. 2022 [70].

Figure 15

Sclerotium of Claviceps purpurea on an ear of grass (A); chemical structure of lysergic acid (B); lysergic acid diethylamide (synthetic compound) (C).

Figure 16

LSD can agonistically bind the serotonin 5-HT1A receptors in the locus coeruleus, raphe nuclei, and cortex causing the inhibition of serotonin’s activation and release. Simultaneously, through the thalamic afferents, LSD can activate the 5-HT2A receptor, inducing an increase in cortical glutamate levels. Furthermore, it has been observed that the activation of 5-HT2A receptors in the cortex triggers the psychedelic response in genetically modified mice expressing 5-HT2A receptors only at the cortical level. Moreover, LSD also has a high affinity for other serotonergic receptors such as 5-HT1B, 5-HT1D, 5-HT1E, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7. This figure was partially generated using Servier Medical Art, provided by Servier and licensed under a Creative Commons Attribution 3.0 unported license.

Figure 17

Three-dimensional model depicting 5-HT2B receptor (PDB ID 5TVN) (A). (B) Detailed view of residues (in pink) involved in interactions with LSD (green) determined by Wacker et al. 2017 [70].

Figure 18

Three-dimensional model depicting 5-HT2A receptor (PDB ID 6WGT) (A). (B) Detailed view of residues (in pink) involved in interactions with LSD (green) determined by Kim et al. 2020 [70].