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5-HT2C Helps Explain Anxiety, Depression, Weight Gain

Written by Joe Cohen, BS | Last updated:

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This receptor can explain why people are anxious, depressed, lacking an appetite, thin and tired.

Executive Summary

The 5-HT2C receptors have some good and bad properties. Overall, they’re bad.

Activation is responsible for fatigue, low dopamine/being unmotivated, OCD, anxiety, an overactive nervous system and HPA axis, weight loss and low insulin. This is a common phenotype among my clients.

Inflammatory cytokines are the main driver of increasing these receptors and their associated effects, which might be playing a role in CFS. Chronic activation will disturb your circadian rhythm.

You can inhibit 5-HT2C receptors by social interaction, sexual activity, making sure you’re well-hydrated, Fish/Fish oil and Curcumin.

Intro

The 5-HT2C receptors are restricted to the brain, where they can be found in several locations, including the choroid plexus (highest density), the nucleus of the solitary tract, dorsomedial hypothalamus, PVN and the amygdala [1].

The choroid plexus is responsible for cerebrospinal fluid production and it acts as a filtration system, removing metabolic waste, foreign substances, and excess neurotransmitters from the CSF [2].

Given their locations, it’s no surprise that this receptor is integral to eating, anxiety, temperature regulation, wakefulness, sexual behavior and the occurrence of seizures [1].

As opposed to most receptors, 5-HT2C receptors appear to decrease in response to both chronic activators and blockers (however, chronic SSRI treatment may increase 5-HT2C in the choroid plexus). It’s also somewhat unique because it can be always active, even without any serotonin or drugs binding to it [1].

The Bad

5-HT2C Causes Mood and Anxiety Disorders

Activation of the 5-HT2C receptor causes depression and anxiety [3, 4].

In animal models, 5-HT2C activation is implicated in OCD [5, 6].

Activation of the 5-HT2C receptor can help disorders like schizophrenia by reducing dopamine to the mesolimbic pathway [1].

Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex (which means it will activate more) [3].

Dieting in women causes a supersensitivity of 5-HT2C receptors, probably in response to lowered levels of brain serotonin. It’s thought that is could play a part in dieting-induced dysregulation of eating and the development of eating disorders in predisposed individuals [7].

5-HT2C Causes Fatigue

When given a blocker of the 5-HT2C receptor, people with CFS reported less perceived fatigue (8).

Mice without 5-HT2C receptors had more wakefulness (and abnormalities in REM sleep) [9].

In rats, an activator of this receptor causes them to be less active ( a long-term indicator of fatigue) [1].

The 5-HT2C receptor is increased by inflammatory cytokines. This could possibly be the link between viral infections and depression (and CFS) [3].

5-HT2C Increases Pain From Inflammation

5-HT2C receptors potentiate pain that is produced from inflammation [10].

5-HT2C Can Increase the Risk of Circadian Issues

People who have more receptors are probably more susceptible to circadian disruption from stress.

The circadian centers (SCN) receive a signal from the serotoninergic raphe nuclei in order to regulate stress responses and the brain immune system.

5-HT2C activators act like light on circadian rhythms and activate SCN neurons in the rat [11].

5-HT2C activators given during what we would consider night resulted in activation of the SCN, but did not cause SCN activation during the induction at the time of expected lights on [12].

Another study showed that 5-HT2C activators increased SCN firing in human times at midnight, but not noon [11].

In rats, 5-HT2C activators increased the same genes that are turned on from light (cFOS, Per1, and Per2 in the SCN) [13].

Agomelatine is a drug that blocks 5-HT2C and can be useful in resetting circadian rhythms (also activates melatonin receptors) [14, 15].

The Good

5-HT2C Decreases Appetite

Serotonin drugs reduce food intake in rodents by increasing satiety. In humans, they have been shown to reduce caloric intake, an effect associated with reduced hunger. These effects appear to be mediated, at least in part, by the 5-HT2C receptor [16], which in turn works via the melanocortin-4 receptors [17].

5-HT2C Decreases Weight

Besides inhibiting appetite, these receptors cause lower insulin from the pancreas [18], which is a common feature in the chronic fatigue people I deal with.
Antipsychotics often block the 5-HT2C receptor, which is one mechanism by which they cause weight gain.

Interestingly, some 5-HT2C SNPs appear to determine levels of circulating leptin, providing a potential mechanism underlying the genetic association of the 5-HT2C receptor with weight gain [19].

5-HT2C Helps Libido

Activation of the 5-HT2C receptor helps men ejaculate and get hard [20, 1].

I wouldn’t be surprised if this receptor is part of long-term sexual dysfunction in men who take SSRIs (chronic SSRIs reduce these receptors).

5-HT2C and Neurotransmitters

Activation of the 5-HT2C receptor inhibits dopamine and norepinephrine release in certain areas of the brain. 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.

5-HT2C receptors mediate the release of dopamine in response to many drugs, including caffeine, nicotine, amphetamine, morphine, cocaine, and others [1].

5-HT2C and The HPA Axis

Serotonin can actually activate your HPA axis, which is one reason why some people feel more wired from 5-HTP.

In particular, serotonin increases CRH via activation of the 5-HT2C receptors in the PVN of the hypothalamus. Genetic inactivation of 5-HT2C receptors produced a blunted CRH and corticosterone (animal version of cortisol) release after serotonin was given to animals [21].

Mice without 5-HT2C receptors show a blunting of an amygdala-induced HPA activation in response to anxiety stimuli [22].

Note: The prefrontal cortex is connected to your amygdala, which is connected to your hypothalamus or HPA axis. Through trying to control, exert your will, over-planning or if you’re just stuck in your head (which is in large part a function of your PFC), you can activate your stress response via the amygdala.

The C allele of SNP called rs6318 results in a faster and stronger HPA activation when a 5-HT2C activator is given, which means that people with such an allele will do worse with serotonin [23].

5-HT2C and Hormones

Stimulation of 5-HT2C receptors leads to an increase in vasopressin, prolactin, ACTH, and oxytocin. Dehydration or hemorrhage causes the release oxytocin via 5-HT2C [3].

Other

  • 5-HT2C activators lessen pain [24, 25].
  • 5-HT2C activators increase body temperature in rats [26].
  • 5-HT2C is decreased in epilepsy [27]. Mice lacking serotonin 5-HT2C receptors are extremely susceptible to audio-induced seizures [28].
  • 5-HT2C activators are being explored for frequent urination [29].
  • 5-HT2C activators reduce alcohol addiction in animals.
  • 5-HT2C receptors in your prefrontal cortex are the mediators of the reward from cocaine [30].

What Decreases the 5-HT2C Receptors

There isn’t a lot of natural substances that I’ve been able to find that affect these receptors.

Eating, social interaction, and sexual activity all release dopamine via inhibition of 5-HT2C [3].

Estradiol decreases these receptors in the ventral hippocampus (while increasing the 5HT2A receptors) [31].

Many SSRIs (but not fluoxetine, which is a 5-HT2C antagonist) indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse. After a few weeks, when people’s mood starts to improve, the 5-HT2C receptors decrease.

It seems like Fish oil (probably DHA) is able to reduce the 5-HT2C receptors, which has the effect of blunting the reduced appetite from 5-HT2C activation. But fish oil causes a decrease in appetite via other means [32].

Kudzu root/Puerarin seems to be a 5-HT2C blocker [33].

What Increases 5-HT2C Receptors

  • Stress/CRH (CRHR1) [34]
  • Dehydration causes the release oxytocin via 5-HT2C [3], so make sure you’re well hydrated to prevent activation of this receptor.
  • DMT, the main psychoactive chemical in ayahuasca, is a partial agonist of 5-HT2C [35].
  • Serotonin. Activation of 5-HT2C by serotonin is responsible for many of the negative side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine, and others [3]. Many SSRIs (but not fluoxetine, which is a 5-HT2C antagonist) indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse. After a few weeks, when people’s mood starts to improve, the 5-HT2C receptors decrease.

What Modulates the 5-HT2C Receptor

Inositol‘s antidepressant effects work with the 5-HT2C receptor since its antidepressant effects are blocked by a 5-HT2C blocker.

In animal seizure models, Bacopa increases 5-HT2C receptors in epileptic rats (reverses downregulation) [27].

Curcumin’s anti-depressant effect may work in part via the 5-HT2C receptor [36].

Agomelatine has anti-depressant properties and acts through the 5-HT2C receptors [37].

Ginseng, Schisandra, Reishi, and Ziziphus also interact with the 5-HT2C receptor. These herbs have somewhat of a hypnotic effect, and the study suggests that this may be due, in part, to the 5-HT2C receptor [38].

Want Better Ways to Improve Your Mood?

If you’re interested in natural and targeted ways of improving your mood, we recommend checking out SelfDecode’s Mood DNA Wellness Report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.

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About the Author

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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