Much like the Holy Grail symbolised well-being, infinite wealth, and abundance of food in Arthurian literature, today the infamous neurotransmitter, serotonin, is linked with mood, attention, hunger and more (Young & Leyton, 2002; Wingen, et al., 2008; Feijó, et al., 2011). However, today serotonin may be accredited with too much. Just as Harmon (2009) described the effect of serotonin on the swarm process of locusts, serotonin seemingly has had the same effect on our neuroscientists (Harmon, 2009).
Serotonin is one of three reptilian monoamine neurotransmitters, alongside dopamine and norepinephrine (Kolb & I.Q., 2003). The serotonin receptor has seven main subfamilies, more than the other two monoamines, and has even more subtypes. Although serotonin is indeed a crucial neurotransmitter, it is important to note that it is merely a modulator of other neurotransmitters. Serotonin fine-tunes the action of glutamate and GABA, the principal neurotransmitters, mediating the excitatory and inhibitory signals in the brain. The exception is 5HT3, which mediates the flow of ions (Ciranna, 2006). As a multifunctional neuromodulatory transmitter, to truly understand its function, there is a need to better understand the second-messenger pathways downstream to reveal the successive key biochemical steps. Serotonin is not the magic bullet for mental health, as penicillin was for gram-negative bacteria. It may only be one of several fingers on the trigger.
Much of serotonin’s claim to fame in the world of mental health is related to LSD findings. Only four years after Hofmann’s famous discovery, LSD was used to model psychosis (Miller, 2014). Almost a decade later, the remarkable similarity between the structures of LSD and serotonin led to the discovery of serotonin in the brain. From this, the scientific community began to infer the relationship between the brain’s chemistry and behavioural outcomes (Miller, 2014). More than 70 years later, there are over one million papers that contain ‘serotonin’ in their titles.
It is reminiscent of the days leading up to the first full sequencing of the human genome, when the scientific community was excited about finding the faulty gene that led to each and every illness. Currently, the neuroscience community has become infatuated with a simple molecule’s role in a variety of complex mental disorders. However, today we understand that disorders are polygenic, and the outcome is dependent on several variables, such as protein production, compensatory mechanisms and environmental influences (Bethesda, 1998). Serotonin may play a significant role in mental illness, but several other factors likely also influence the outcome of disease presentation. The modelling of schizophrenic-like psychosis induced by phencyclidine (PCP) and ketamine demonstrates that glutamate receptors and dopamine can also play a pivotal role in mental health (Javitt, 2007). As much as the driver plays a key role in manoeuvring an automobile, some researchers have not yet acknowledged the importance of the fuel, engine, road taken and other seemingly mundane variables.
Thomas Ray expands extensively on the variegated mannerism of psychedelics. In his paper on “Psychedelics and the Human Receptorome”, he illustrates the multifaceted interaction that psychedelics have with various receptors (Ray, 2010). In conjunction with the National Institute of Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP), he has presented the receptor affinity and promiscuity for 35 psychedelic drugs. The results demonstrate that these 35 drugs do not selectively interact with a single receptor, but rather with a wide range of different classes simultaneously. Even compounds with very similar molecular structures have very different mechanisms (See figure 1 for a comparison between DOB and DOI).
For example, DOB’s highest affinity is for 5HT2B, 5HT2A and 5HTC, and it interacts to a lesser extent with 21 other receptors. As for DOI, its highest affinity is for 5HT2C and two other non-serotonergic receptors, with 23 other receptors affected (Ray, 2010). What is more surprising is that for many popular hallucinogens and empathogens, their highest affinity was not necessarily for serotonin. The highest affinity of mescaline, MDMA and ibogaine was for Alpha-2C, Imidazoline 1 and Sigma-2 receptors, respectively. In addition, only one of the 35 drugs displayed a selective receptor affinity, which was the atypical psychedelic Salvinorin A, which solely affects the κ-opioid receptor (KOR) (Ray, 2010). All other 34 tested substances were more promiscuous with their range of receptors.
From Ray’s 2010 paper, we can tell that psychedelics in fact interact with a diverse range of receptors. Although phenylalkylamines are more selective than ergolines and tryptamines, only DOB and MEM can fit today’s framework of radically selective psychedelics, as they are highly selective and the least promiscuous. Furthermore, this study truly highlights the molecular pharmacology community’s vague understanding of the complexity of psychedelics. In the 1990s, DOI was the hallucinogen of choice when illustrating the molecular mechanisms of hallucinogens, as it was widely assumed to be a 5HT2 selective agonist (Glennon, et al., 1991; Darmani, et al., 1994). However, Ray’s study revealed that DOI is the most promiscuous of all psychedelic substances. Hence, when reviewing papers that solely focus on the relationship between psychedelics and serotonin prior to 2010, it’s important to verify whether the authors presumed the psychedelic at hand was selective or not.
The emphasis should not be on the relationship between a psychedelic and its receptor of choice, but on its mechanism as a whole. It is not enough to state that the alteration of consciousness lies within the agonistic effects on the 5HT2A receptor. Lisuride, a drug typically used for Parkinson’s disease, is also a 5HT2A agonist and regulates the same cortical neurons as these classic hallucinogens, but leads to no psychoactive effects (Gonzalez-Maeso, et al., 2007). The difference between the hallucinogenic and non-hallucinogenic properties lies within the regulation of protein subunits and cytoplasmic enzymes. It is crucial to bear in mind that the essence of the mechanism is not how the receptor is manipulated, but how the whole neuronal pathway is influenced.
This article does not mean to simply dismiss the importance of serotonin in the understanding of psychedelic mechanisms or the neurobiology of the mind. Indeed, the use of the 5HT2A antagonist ketanserin alone can inhibit the psychedelic actions of hallucinogenic 5HT2A agonists, such as LSD and DOI (Sadzot, et al., 1989; Borroto-Escuela, et al., 2014). When subjects were treated with ketanserin prior to psilocybin ingestion, the hallucinogenic effects also did not ensue. However, the other effects of psilocybin, such as multiple-object tracking impairment and reduction of arousal and vigilance, were not affected by the ketanserin. This demonstrates how non-5-HT2 receptor sites mediate some of the perceptible mental effects of psilocybin (Carter, et al., 2005). More importantly, it indicates that the hallucinations induced by 5HT2A receptors are moderated by the drug’s interactions with non-5HT receptor subtypes as well. It is time for neuroscientists to look at the pathways downstream of 5-HT2A receptors to not only understand how LSD and psilocybin induce hallucinations, but how they are modulated as well.
In sum, Ray’s 2010 paper illustrates that not all serotonergic agonists lead to psychedelic effects, and not all hallucinogens are serotonergic agonists. The principle of the drunkard’s search, in which the drunk will only look for his keys under the streetlight although his keys are across the street in the dark, describes the current state of the neuroscience community. The questions in the field of neuroscience are too often linked only to the neurotransmitters we understand, but not the lesser known receptors such as imidazole and sigma. Much like the complex correlation between genes and disorders, one must be cautious not to draw an all too simple connection between the psychedelic experience and its neurotransmitters. Although we do have serotonin to praise for demonstrating that behaviour is largely determined by neurochemistry, its partner biochemical processes must be acknowledged as well. In order to fully understand the complexity of the mechanisms of psychedelic tools, the complete tapestry of the brain needs to be unravelled. Serotonin is not the “Holy Grail” of neurotransmitters, but one of the many specific components.
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