Non-hallucinogenic Psychedelic Analog Design: A Promising Direction for Depression Treatment

Depression is the most common neuropsychiatric disorder, affecting 350 million people worldwide; it has been a leading cause of suicide, causing serious harm to family members and consuming a large amount of social resources. The onset time of traditional antidepressants is usually 3–4 weeks, and there is no ameliorating effect in nearly one-third of patients with depression. Therefore, the discovery of fast and effective antidepressants has become an international research hotspot [1]. Currently, there are two pathways for developing novel and more desirable antidepressants. First, the most common strategy is to identify new therapeutic targets by uncovering the underlying mechanisms of depression, resilience to stress, and drugs with ideal anti-depressive but serious side-effects. Secondly, retrofitting existing substances with antidepressant potential is also an important tactic. The natural hallucinogen psilocybin extracted from mushrooms has been reported to have a fast and lasting therapeutic effect on treatment-resistant depression and major depressive disorder in clinical studies [2, 3]. Moreover, it has been suggested that increased spine density at the cellular level and improved brain network integration at the organismal level may underlie the therapeutic effect [4, 5]. Based on this, psychedelic drugs seem to have promise for healing depression. However, their hallucinogenic effects mean that they act as a double-edged sword, which limits their wide application. So, it would be a significant achievement if their hallucinogenic effects could be eliminated while their anti-depressive effects are maintained.

Classic hallucinogens, such as psilocybin and D-lysergic acid diethylamide (LSD) mainly bind to the 5-hydroxytryptamine 2A receptor (5-HT_2AR) [6], a G protein coupled receptor. Even with the 5-HT_2AR structure in hand [7], and two recent studies reporting non-hallucinogenic psychedelic analogs with antidepressant effects in rodents [6, 8], it remains unclear how to reasonably design such compounds. Besides, whether the hallucinogenic effect is necessary for the anti-depressive effect needs further exploration. Gratifyingly, scientists from China recently explained the possible mechanisms through which hallucinogens generate anti-depressive effects by structural biology, and designed some small molecule drugs that retain antidepressant effects, but without hallucinogenic effects (Fig. 1) [9]. First, the researchers purified 5-HT_2ARs, then added the hallucinogenic drugs psilocin (the active metabolite of psilocybin) and LSD, as well as the non-hallucinogenic psychedelic analogs lisuride and serotonin separately. Subsequently, relatively high-resolution density maps of different ligand-receptor complexes were obtained through X-ray crystallography. By comparing the conformations of four different substance-bound 5-HT_2AR complexes, the researchers found two binding pockets inside the 5-HT_2AR, named the orthosteric binding pocket (OBP) and the extended binding pocket (EBP), which can accommodate and bind to ligands. The hallucinogen LSD can occupy both pockets at the same time, while the hallucinogen psilocin is smaller and can bind to either OBP or EBP. For the two drugs that do not produce hallucinations, although the binding modes of lisuride and serotonin are similar to those of LSD and psilocybin, respectively, both molecules bind EBP less strongly. Functional study showed that the binding of OBP activates the G protein signaling pathway whereas the binding of EBP activates the β-arrestin pathway. The hallucinogenic effect of the drugs may be achieved through the simultaneous strong activation of both signaling pathways. The second binding mode that serotonin and psilocin can be accommodated at the EBP of 5-HT_2AR is newly discovered and non-classical. Therefore, designing ligands that bypass the OBP and target the EBP may identify 5-HT_2AR ligands that specifically activate the β-arrestin signaling pathway, and these EBP-targeting molecules may not have hallucinogenic effects.

Fig. 1.

Mechanisms of action of hallucinogens and designed compounds. 5-HT_2AR is a G protein coupled receptor, which possesses seven transmembrane helices. Inside the receptor, an orthosteric binding pocket (OBP) and an extended binding pocket (EBP) have been identified (Pocket 1 refers to OBP and Pocket 2 refers to EBP), which binds with hallucinogenic drugs psilocin and LSD, as well as the non-hallucinogenic psychedelic analogs lisuride and serotonin. The binding to OBP triggers Gq-mediated signaling while binding to EBP induces activation of the β-arrestin pathway. The hallucinogens LSD and psilocin bind to both the OBP and the EBP, and this leads to strong activation of both the G-protein and the β-arrestin pathway and produces hallucinatory and anti-depressive behaviors in mice. The compounds designed based on the structure of the EBP mainly bind to EBPs and prefer to activate the β-arrestin pathway. Meanwhile, these compounds show significant anti-depressive effects, but do not cause hallucinations [9].

Based on the structural characteristics of the EBP in the 5-HT_2AR, the researchers designed a molecule named IHCH-7086 that mainly binds to the EBP and avoids binding to the OBP. By analyzing the crystal structure of the IHCH-7086-bound 5-HT_2AR complex, it was found that the binding site of IHCH-7086 in the 5-HT_2AR is consistent with the assumption, and there is a significant preference for β-arrestin signaling. Subsequently, with the help of a magnetometer-based detection system, the researchers examined the effects of IHCH-7086 and IHCH-7079 (analogues of IHCH-7086) on the head twitch response (HTR) in mice, which aims to evaluate the hallucinogenic effects of the designed small molecules, and found that even high doses of IHCH-7086 and IHCH-7079 did not induce HTR in mice. Finally, the researchers found that both IHCH-7086 and IHCH-7079 significantly improve depression-like behavior in mice subjected to acute restraint stress or corticosterone injection, and an antagonist of 5-HT_2ARs (MDL100907) blocks this improvement. Overall, the specific and modest 5-HT_2AR arrestin-biased activation may be sufficient for antidepressant effects, but not for hallucinogenic action.

This work not only illuminates the molecular mechanisms underlying the anti-depressive effects of hallucinogens in depth, but also provides important theoretical guidance into the development of fast- and long-acting antidepressants. However, there are some interesting issues worth discussing. First of all, chronic social defeat stress and chronic mild stress are more classical and widely-used rodent models of depression [10, 11]. Beyond this, the forced swim test alone, which is similar to the tail suspension test, is gradually being recognized as a paradigm for evaluating the stress-coping response, not depression-like behavior [12]. Therefore, drawing support from widely-used rodent models of depression and evaluating multiple indicators of depression, such as anhedonia and social avoidance will make this significant work more persuasive for the treatment of depression. Second, hallucinations in humans are often defined as high-confidence false visual or auditory percepts, and visual and auditory hallucinations have been reported in mice [13, 14], so if subsequent studies of designed psychedelic analogs include the detection of sensory-related hallucinations, they will increase the awareness of novel designed drugs. Third, this study demonstrated that strong activation of both the G protein signaling pathway and the β-arrestin pathway have hallucinogenic and antidepressant effects, while modest β-arrestin pathway activation only has an anti-depressive effect. Therefore, is there a regulatory mechanism specific to hallucinogenic effects? Also, the effect of activation of the G protein pathway alone on hallucinogenic responses and depressive-like behaviors in mice is worth exploring.

Recently, it has been suggested that this study provides a roadmap for eliminating hallucinations in healing through a mind-shift approach [15, 16]. Furthermore, this study provides a good example for the development of new medications for mental illness through a strategy to circumvent side-effects. Ketamine, an NMDAR antagonist, has gained much attention due to its rapid and long-acting antidepressant effects. However, because of the abuse potential and side-effects such as hallucinations [17], its widespread use is limited, especially for the treatment of depression. Besides, in a phase III trial, assisted therapy with 3,4-methylenedioxymethamphetamine (MDMA) significantly improved the symptoms of patients with severe post-traumatic stress disorder. Just like ketamine, MDMA is also an illegal drug due to its strong hallucinogenic effects and other side-effects. Therefore, analog molecules may be designed based on the detailed structural features of the target sites, which confer therapeutic properties without side-effects. Consequently, structure-based non-hallucinogenic psychedelic analogs may be promising medications for the treatment of neuropsychiatric diseases.

Conflict of interest

The authors declare no conflicts of interest.