A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

Keywords : hallucinogens; psychedelics; LSD; psilocybin; ketamine; MDMA

Introduction

Psychiatric disorders are a major public health concern affecting ;350 million people and imposing social and economic burdens worldwide (Wittchen et al., 2011; Whiteford et al., 2013; Vigo et al., 2019). Despite tremendous efforts to uncover pathophysiologi- cal determinants, our understanding of psychiatric diseases and their treatment remains limited. After a long hiatus stemming from regulations that placed psychedelics in a restrictive regulated drug schedule (Belouin and Henningfield, 2018), investigation of these compounds is experiencing a renaissance in the research and clinical communities, especially with regard to their therapeutic application in mental disorders. Generally speaking, since the 1960s, hallucinogenic drugs have been classified into two groups: the “serotonergic classic hallucinogens” or “psychedelics,” and the “dissociative anesthetics.” Classic hallucinogens exert their pharma- cological effects primarily through the 5-HT system, acting as ago- nists of the 5-HT2A receptor (Vollenweider et al., 2007; Passie et al., 2008; Vollenweider and Kometer, 2010). In contrast, “dissociative anesthetics,” including ketamine, are considered to act on the glutamatergic system and not on the 5-HT system, and they do not produce the same so-called “trip” as psychedelics, but are still con- sidered hallucinogens (Vollenweider and Kometer, 2010). In the last decade, numerous studies in laboratory animals and humans have confirmed the usefulness of ketamine for the treatment of re- sistant depression. Research has also suggested potential antide- pressant and mood-modulating properties of psilocybin and LSD, respectively, as well as the ability of these compounds to modulate functional brain connectivity (Carhart-Harris et al., 2016a, 2017). Other compounds, including 3,4-methylenedioxymethamphetamine (MDMA), are called entactogens. They produce psycho- tropic effects, but they do not share the same mechanism of action as hallucinogens (Kyzar et al., 2017). MDMA has been demon- strated to increase sociability in animals (Morley et al., 2005; Pitts et al., 2017; Curry et al., 2018; Heifets et al., 2019) and humans (Mithoefer et al., 2016) and to be useful in treating posttraumatic stress disorder (PTSD) (Mithoefer et al., 2011).

This review summarizes the pharmacological mechanism of psychedelics, nonpsychedelic hallucinogens, and entactogens as well as their impact on psychiatric research. In particular, we overview: (1) data on the effects of psychedelics in rodents and on brain functional connectivity in humans; (2) preclinical and clinical data on the antidepressant effects of ketamine; and (3) data on the prosocial effects of MDMA and its therapeutic appli- cations in both animals and humans.

Psychedelics: the 5HT2A receptor

Figure 1. Schematic overview of the main pharmacological targets of LSD, psilocybin, DMT, MDMA, and ketamine, the signaling cascades involved, hormonal modulation, as well as main behavioral outcomes following their administration in both animals and humans. Abbreviations are reported in the main text.

Psychedelics, also defined as “classic serotonergic hallucinogens” because they interact with the 5-HT system, are strongly involved in the treatment of psychiatric disorders, including depression (Meltzer, 1990), anxiety (Charney et al., 1990), and cognitive def- icits (Meltzer et al., 2011). Psychedelics primarily act as 5-HT2A receptor agonists, but their mechanism of action is more com- plex than originally thought. Indeed, psychedelics, including LSD, psilocin, psilocybin (a prodrug of psilocin), and N,N-dime- thyltryptamine (DMT), have been demonstrated to also interact with 5HT1A, 5HT2B, 5HT2C, 5HT6, and 5HT7 receptors (Passie et al., 2002, 2008; Nichols, 2004; Rickli et al., 2015; Wacker et al., 2017). Furthermore, a growing body of evidence demonstrates that both nonhallucinogenic (e.g., lisuride) and hallucinogenic 5-HT2A agonists can activate intracellular signaling cascades in cortical pyramidal neurons, thus modulating downstream signal- ing proteins, including b -arrestin, early growth response protein 1 (EGR1), and EGR2 (González-Maeso et al., 2007; Schmid et al., 2008). Moreover, the activation of 5HT2A and 5HT1A receptors by LSD in the mPFC activates both the serotonergic and dopaminer- gic activity in the dorsal raphe nucleus and VTA, respectively. In particular, low doses of LSD (up to 30 mg/kg) decrease the firing of 5-HT neurons without affecting the dopaminergic firing rate of VTA neurons, whereas higher doses (40-60mg/kg) decrease the firing of dopaminergic VTA neurons (De Gregorio et al., 2016b). While the 5-HT system is implicated in mood and anxiety regulation, the dopaminergic system plays an important role in the mechanism of action of psychedelics (De Gregorio et al., 2016a, 2016b, 2018). Drug discrimination tasks in rodents revealed that the behavioral effects of LSD involve 5-HT2A receptors in an initial phase, followed by a second phase that requires the dopamine D2 receptor (Marona-Lewicka et al., 2005). Furthermore, in vitro studies showed that LSD binds to the recombinant human D2 re- ceptor in HEK 293 cells (Rickli et al., 2015, 2016). A similar experi- mental approach demonstrated that LSD also shows affinity for dopamine D1 (Rickli et al., 2015) and D4 (Passie et al., 2008) recep- tors. Finally, in vivo and in vitro evidence indicates a potential interaction of psychedelics, particularly LSD, with the trace amino associate receptor 1 (TAAR1) (Bunzow et al., 2001; De Gregorio et al., 2016b; Rickli et al., 2016), although more research is needed to understand the role of TAAR1 in the mechanism of action of psychedelics. A schematic representation of LSD, psilocybin, and DMT mechanism of action is shown in Figure 1.

Overall, psychedelic compounds display a pharmacological activity that goes beyond their action as 5HT2A agonist, and further investigations are needed to better elucidate their pleiotropic mechanisms of action (for a detailed discussion of the mechanism of action of psychedelics, see Passie et al., 2002, 2008; Nichols, 2016).

(…)