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5-HT2C Receptors: What Are They, And What Do They Do?

Written by Joe Cohen, BS | Last updated:
Matt Carland
Medically reviewed by
Matt Carland, PhD (Neuroscience) | Written by Joe Cohen, BS | Last updated:

5-HT2C receptors are one of many different types of serotonin receptors found throughout the brain. However, they have a number of key features that make them quite different from other serotonin receptors. Some early research also suggests that these receptors may play a role in some psychiatric disorders, such as depression and anxiety. However, there is still a lot we don’t know about these particular serotonin receptors work, and what role they play in the brain! Read on to learn more about what the latest science currently has to say about 5-HT2C receptors, how they work, and how they might potentially be involved in various aspects of health and disease!

Executive Summary

5-HT2C receptors are a specific type of serotonin receptor. They have a very wide range of different effects depending on where they are in the brain, as well as when- and how much they are stimulated.

In general, they form one critical part of the brain’s overall serotonin system, which wouldn’t function properly without them.

However, some research has associated relatively increased stimulation of these receptors with a variety of potentially negative effects, such as increased fatigue, reduced dopamine levels and lower motivation, elevated stress reactivity (increased HPA axis activity), undesired weight loss, and lower insulin levels.

Additionally, 5-HT2C receptor over-activation has been potentially linked to some psychiatric disorders, such as OCD and anxiety, although the exact role of these mechanisms are not fully clear yet.

Some research suggests that inflammatory cytokines may be one of the important factors that can contribute to 5-HT2C over-activation – which may partially explain why these receptors have been reported to play a role in chronic fatigue syndrome (CFS).

Finally, some studies have reported that chronic over-activation of 5-HT2C receptors may contribute to disturbances in the circadian rhythm, the “master clock” that your body relies on to regulate the sleep cycle and other important biological processes.

While you probably wouldn’t ever want to knock these receptors out entirely, there is some early evidence that there may be some “natural” ways to counteract over-active 5-HT2C receptor activity. Doing so could – in theory – potentially alleviate some of the symptoms or effects associated with elevated 5-HT2C receptor activity, such as fatigue, low motivation, chronic stress, or mild anxiety.

For example, some of the dietary and lifestyle factors that have been linked to reduced 5-HT2C receptor activity include social interaction, sexual activity, staying well-hydrated, and supplementing with fish oil or curcumin [1, 2, 3]. However, this research is still in a very early stage, and no firm conclusions can be drawn yet until a lot more studies are done to investigate these effects in healthy human users.

In the next few sections, we’ll review what the latest science currently knows about some of the potential functions of these interesting receptors. However, keep in mind that much of this research is still in a very early stage, and very few solid conclusions can be drawn yet. A lot more research will be needed to verify all of the reported findings below – and in the meantime it is not recommended to try to alter or change your own 5-HT2C receptor activity by experimenting with supplements or other lifestyle changes! If you believe you might have any health symptoms or conditions that might involve 5-HT2C receptors, talk to your doctor in order to determine the best treatment approach to take for your individual medical needs.

What Are 5-HT2C Receptors?

While some serotonin receptors are found both throughout the central nervous system and the “gut’s nervous system” (the enteric nervous system), the 5-HT2C type of serotonin receptor is found exclusively in the brain [4].

They can be found in several locations, including the choroid plexus (highest density), the nucleus of the solitary tract, the dorsomedial hypothalamus, the paraventricular nucleus (PVN) and the amygdala [4].

The choroid plexus is responsible for the production of cerebrospinal fluid (CSF), and it acts as a filtration system for removing metabolic waste, excess neurotransmitters, and any other foreign or toxic substances from the CSF [5].

Other brain areas with lots of 5-HT2C receptors, such as the hypothalamus, are highly involved in appetite and eating, sexual behavior, and regulating body temperature.

Other regions, like the amygdala, are highly involved in emotions (such as anxiety).

Based on this pattern of 5-HT2C receptor expression throughout the brain, these receptors are believed to play a role in many different functions and symptoms related to eating, anxiety, temperature regulation, sexual behavior and even the occurrence of seizures [4].

Another interesting and distinct feature of these receptors is that, unlike many other neurotransmitter receptors, 5-HT2C receptors appear to decrease in strength and number both when they are chronically stimulated or chronically blocked. Some researchers have reported that these receptors can even be chronically activated without any actual serotonin molecules or other drugs binding to them, which deepens the mystery of how they work and exactly what they are doing [4].

Possible Roles of 5-HT2C Receptors

5-HT2C Receptors In Appetite, Eating Behavior, and Weight

Some evidence suggests that 5-HT2C receptors may play a role in appetite and eating behavior.

For example, animal studies have reported that serotonergic drugs reduce total food intake in rodents, presumably by reducing appetite (or increasing satiety). Similar effects have also been reported in humans. These effects appear to be mediated, at least in part, by the 5-HT2C receptor [6], which in turn works via the melanocortin-4 receptors [7].

In contrast, several common antipsychotic drugs are believed to block the 5-HT2C receptor, which may be one of the reasons why these medications are sometimes associated with weight gain in certain psychiatric patients.

In addition to potentially reducing appetite, some evidence suggests that 5-HT2C receptor activation may also reduce the release of insulin from the pancreas [8]

Finally, some 5-HT2C SNPs appear to determine levels of the appetite-related hormone leptin, providing a potential mechanism underlying some of the genetic associations between 5-HT2C receptor genes with body weight and weight gain [9].

5-HT2C Receptors and Other Neurotransmitters

Activation of 5-HT2C receptors may affect the release of dopamine and norepinephrine in certain areas of the brain. For example, 5-HT2C receptors have been reported to regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others [4].

Some researchers believe that 5-HT2C receptors may also mediate the release of dopamine in response to certain common drugs, including caffeine, nicotine, amphetamines, morphine, cocaine, and others [4].

5-HT2C Receptors in Mood and Anxiety Disorders

According to some early research, (over-)activation of 5-HT2C receptors may be associated with certain psychiatric disorders, such as depression and anxiety [1, 10].

Some other research has reported that suicide victims sometimes show an abnormally high number of 5-HT2C receptors in the prefrontal cortex, which adds suggestive evidence that 5-HT2C activation may be somehow involved in depression and suicide [1].

Additionally, preliminary findings from some animal studies suggest that 5-HT2C activation may be related to OCD, although additional research in humans would be needed to fully confirm this [11, 12].

Due to these potential links, some researchers have proposed that some psychiatric disorders, such as schizophrenia, may potentially be treated by using 5-HT2C activation to reduce levels of dopamine in the mesolimbic pathway of the brain [4].

However, much more research is still needed to fully clarify all of these effects, and the potential mechanisms that might be involved.

5-HT2C Receptors and Fatigue

According to one early study, people with chronic fatigue syndrome (CFS) reported lower perceived levels of fatigue when given medications that block the 5-HT2C receptor [13].

Relatedly, studies in animals have reported that mice lacking 5-HT2C receptors show more wakefulness-related behaviors – however, they also exhibit abnormalities in REM sleep [14].

Conversely, activating 5-HT2C receptors in rats caused them to become less active overall, possibly indicating a fatigue-like effect [4].

Interestingly, because one of the factors that can activate 5-HT2C receptors are pro-inflammatory cytokines, some researchers have proposed that this may be one of the mechanisms that could explain some of the links between viral infections, chronic fatigue symptoms, and depression [1].

However, more research in humans will be needed to confirm these early findings.

5-HT2C Receptors and Inflammation-Related Pain

According to one early study, 5-HT2C receptor activation may increase (“potentiate”) the pain produced by inflammation [15].

5-HT2C Receptors and the Circadian Rhythm

The parts of the brain that are believed to be highly involved in regulating the circadian rhythm – such as the suprachiasmatic nucleus, or SCN for short – receive many serotonin-based signals from other parts of the brain, such as the raphe nuclei.

This has led some researchers to investigate the effects that 5-HT2C receptors might have on controlling the circadian rhythm, and therefore on sleep-related behavior in general.

According to one early animal study, the effects of 5-HT2C receptor activation may be similar to the effects of natural light signals on the SCN neurons in rats [16]. This finding suggests that these receptors may play a role in helping “set” the circadian rhythm.

Preliminary findings from a few other studies may back this up.

For example, giving animals drugs that activate 5-HT2C receptors during nighttime resulted in increased SCN activity, while giving the animals these same drugs during the day did not produce any detectable change [17].

Another study, this time in humans, reported that 5-HT2C activators increased SCN activity at midnight, but not noon [16].

In rats, 5-HT2C activators reportedly increase the same genes that are turned on from light (such as cFOS, PER1, and PER2 in the SCN) [18].

Altogether, this early evidence may suggest that 5-HT2C receptors may play a role in helping the brain use light cues from the environment to set or adjust the circadian rhythm – however, much more research will be needed to fully confirm this.

Nonetheless, These potential links have led some researchers to speculate that people with a relatively higher number of 5-HT2C receptors may be more susceptible to circadian rhythm disruption from stress.

Interestingly, agomelatine is an antidepressant medication that blocks 5-HT2C receptors, and activates melatonin receptors. This medication has been reported to be useful in helping to “re-set” the circadian rhythm, at least according to a few preliminary studies [19, 20].

5-HT2C Receptors and the HPA Axis

The HPA axis is one of the brain’s main systems involved in the stress response, and is known to be particularly sensitive to serotonin in particular.

(As a sidenote, this may be one of the reasons that some people report feeling “wired” when taking supplements that increase serotonin levels, such as 5-HTP.)

In particular, serotonin is believed to increase corticotropin-releasing hormone (CRH) via activation of the 5-HT2C receptors in the hypothalamus. For example, genetic inactivation of 5-HT2C receptors in animals has been reported to produce a “blunted” stress response, as measured in the amount of corticotropin-releasing hormone (CRH) and corticosterone (the animal version of cortisol) that was released after serotonin administration [21].

Mice without 5-HT2C receptors have also been reported to show a blunting of amygdala-induced HPA activation in response to anxiety-causing stimuli [22].

People who carry the ‘C’ allele for the SNP rs6318 (located in the 5HT2RC gene) have been reported to show faster and stronger HPA axis activation when 5-HT2C-activating drugs were given. This early finding might suggest that people with such an allele may have a relatively somewhat higher chance of experiencing adverse side-effects from serotonin-based medications [23]. Nonetheless, much more research will be needed to confirm this finding further, and to figure out just how significant this effect might actually be.

5-HT2C and Hormones

Stimulation of 5-HT2C receptors has been reported to lead to an increase in several different hormones including vasopressin, prolactin, adrenocorticotropic hormone (ACTH), and oxytocin [1].

Other Potential Effects

These receptors may also have other roles, although the following effects have only been reported by animal studies so far:

  • 5-HT2C activators have been reported to potentially reduce pain [24, 25]
  • 5-HT2C activators have been reported to increase body temperature in rats [26]
  • 5-HT2C receptors may be involved in susceptibility to seizures [27, 28]
  • 5-HT2C receptors (in the prefrontal cortex) may be involved in the “reward response” caused by the abuse of cocaine, and may, therefore, play some role in drug addiction [29]

What Decreases 5-HT2C Receptors?

There aren’t a lot of natural substances that have been reported to affect 5-HT2C receptors, specifically.

However, eating, social interaction, and sexual activity have all been reported to release dopamine, possibly via inhibition of 5-HT2C receptors [1].

According to one animal study in rats, the hormone estradiol may decrease the number of 5-HT2C receptors in the ventral hippocampus, while also increasing 5HT2A receptors [30].

In another animal study, Kudzu root (Puerarin) was reported to be a potential blocker of 5-HT2C activity [31].

Finally, some evidence suggests that fish oil – or, most likely, the DHA it contains – may be able to reduce (“down-regulate”) 5-HT2C receptors [2].

Nonetheless, much more research would still be needed in order to know for sure whether any of these dietary or supplement compounds have similar effects in healthy human users.

What Increases 5-HT2C Receptors?

Similarly, not too much is known about substances or factors that might increase 5-HT2C receptors, although preliminary research has identified a few potential possibilities so far:

  • Dehydration may cause the release oxytocin via 5-HT2C [1]
  • Increased stress, and/or increased levels of CRH (CRHR1) may contribute to increased 5-HT2C receptors [32]
  • Several common psychiatric medications: increased activation of 5-HT2C receptors by serotonin is believed to be responsible for several of the negative side-effects associated with the use of SSRI and SNRI medications (such as sertraline, paroxetine, venlafaxine, and others) [1]

What Other Factors Affect 5-HT2C Receptors?

According to one animal study, the purported “anti-depressant” effects of inositol may involve the 5-HT2C receptor, since selectively blocking these receptors prevents these effects.

Along similar lines, some preliminary evidence suggests that some of the purported effects of curcumin may also involve the 5-HT2C receptor somehow [33, 34].

The antidepressant and anti-anxiety effects of the medication agomelatine may also arise through 5-HT2C receptors [35].

Ginseng, Schisandra, Reishi, and Ziziphus also interact with the 5-HT2C receptor. These herbs have been reported to have sleep-promoting (“hypnotic”) effects, and one preliminary study suggests that these effects may be due, in part, to these herbs’ interactions with 5-HT2C receptors [36].

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine. Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers. Joe is a thriving entrepreneur, author and speaker. He is the CEO of SelfHacked, SelfDecode and LabTestAnalyzer. His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.
Joe has been studying health sciences for 17 years and has read over 30,000 PubMed articles. He's given consultations to over 1000 people who have sought his health advice. After completing the pre-med requirements at university, he founded SelfHacked because he wanted to make a big impact in improving global health. He's written hundreds of science posts, multiple books on improving health, and speaks at various health conferences. He's keen on building a brain-trust of top scientists who will improve the level of accuracy of health content on the web. He's also founded SelfDecode and LabTestAnalyzer, popular genetic and lab software tools to improve health.

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