Could a 5-HT2C Receptor Antagonist Decrease Anxiety When Used with Hallucinogens? Krystle A. Cole 2007 NeuroSoup Trust.

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Abstract

A 5-HT2C receptor antagonist, when used with a lysergamide or tryptamine, could decrease the anxiety experienced during a trip without eliminating the desired hallucinogenic effects. This could lead to psychedelics being able to be used more safely and with fewer adverse reactions.

Introduction

The word hallucinogen covers a wide variety of psychoactive substances, including the cannabinoids, sedative-hypnotics, phenethylamines, tryptamines, and lysergamides. All of these substances vary greatly in pharmacological action. That is why we will narrow the field and only discuss decreasing anxiety with the lysergamides and tryptamines, namely LSD, DMT, and psilocybin. The American Psychiatric Association currently recognizes several mental health disorders that can be caused by hallucinogens. Two of these, Hallucinogen Persisting Perception Disorder (HPPD) and Hallucinogen-Induced Anxiety Disorder, are directly linked to anxiety. Also, anxiety is often the catalyst that turns a productive trip into a very difficult one. If we could find a way to reliably reduce the anxiety during a psychedelic experience without reducing the desired effects, many anxiety ridden trips and mental health disorders could be avoided. Psychedelics could then be used much more safely and with fewer adverse reactions. In order to discuss this topic, we must first understand the neuropharmacology of hallucinogens. Hallucinogens are partial agonists of the neurotransmitter serotonin; they activate both the 5-HT2A receptor and the 5-HT2C receptor. Most of the desired hallucinogenic effects are linked to the 5-HT2A receptor, while the undesired anxiogenic effects are linked to the 5-HT2C

receptor. Therefore, a specific 5-HT2C receptor antagonist would theoretically be able to reduce the anxiety without disrupting the desired psychedelic effects.

Most Hallucinogenic Effects are Caused by the Activation of the 5-HT2A Receptors Marek and Aghajanian (1996) studied the effects of LSD in the brains of rats. They concluded that it is a partial agonist of the 5-HT2A receptors. This means that LSD activates the receptors, but not to the same extent that serotonin does. Also, the tolerance to hallucinogens that occurs with chronic use develops because of down regulation of 5-HT2A receptors and not 5HT2C receptors (Smith et al. 1999). The 5-HT2A receptors are mostly located in the cerebral cortex. The cerebral cortex is a sheet of brain tissue about 2-5mm thick that forms the outer inch of the human brain. It is made up six distinct layers, labeled I through VI. Jakab and Goldman-Rakic (1998) examined the cellular and subcellular distribution of 5HT2A receptors in the cerebral cortex of macaque monkeys. They found two bands throughout the cortical sheet, consisting of layer II and III, and layer V and VI. The majority of the receptorlabeled cells were pyramidal neurons and the most intense labeling was consistently confined to their parallel aligned proximal apical dendrites. The cerebral cortex is the area of the brain that interprets incoming sensory information, integrates sensory information with preexisting associations, and controls motor output1.

5-HT2c Receptor Has Been Associated with Anxiogenic Effects In animal studies, the 5-HT2C receptor has been associated with anxiogenic, or anxietyproducing, effects. It is mostly found throughout the pyriform cortex and the amygdala1. Many prescription anti-anxiety and antipsychotic medications are 5-HT2C receptor antagonists. However, they often also have an affect on other neurotransmitters and receptors throughout the brain. This has created interest in developing substances that only have an affinity for only the 5-HT2C receptor. Some scientists believe that this is the future of anxiolytic pharmacotherapy (Kunovac et al. 1995).

Some of the Hallucinogenic Effects May be Decreased

Although most of the evidence indicates that the desired effects of hallucinogens are mediated by the 5-HT2A receptor, hallucinogens do also have a high affinity for the 5-HT2C receptor (Egan et al. 1998) and it has a wide distribution throughout the CNS (Clemmet et al. 2000). In one study, mice were trained to discriminate DOI from saline. DOI is a phenethylamine with a similar pharmacological action to LSD (Marek et al. 1996). The mice lost some of their accuracy when the hallucinogen was given in combination with a 5-HT2C antagonist (Smith et al. 2003). Also, as mentioned before, many of the currently available 5-HT2C antagonists are not specific enough. They are often also 5-HT2A receptor antagonists which, if taken with a hallucinogen, would eliminate or at least greatly decrease the desired effects.

Conclusion

If we could find a way to reliably reduce the anxiety during a psychedelic trip without reducing the desired effects, many anxiety ridden trips and mental health disorders could be avoided. Psychedelics could then be used much more safely and with fewer adverse reactions. One substance that would be interesting to study further is Agomelatine. It is an antagonist specific to the 5-HT2B and 5-HT2C receptors (Milan et al. 2003). It also has direct agonist activity at the melatonin MT1 and MT2 receptors (Banki 2006). This agonist activity at the melatonin receptors could possibly even enhance the desired effects of the hallucinogen. From personal experience, whenever I have pre-dosed with melatonin or 5-HTP before a trip, it has added more texture and layers to the overall experience.

Notes 1. From a 1996 telephone interview with George Aghajanian, M.D., Ph.D in the book, Trips: how hallucinogens work in your brain, by Cheryl Pellerin. Page 115.

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