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.
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 .
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 .
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 .
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 .
5-HT2C Causes Mood and Anxiety Disorders
Activation of the 5-HT2C receptor can help disorders like schizophrenia by reducing dopamine to the mesolimbic pathway .
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) .
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 .
5-HT2C Causes Fatigue
When given a blocker of the 5-HT2C receptor, people with CFS reported less perceived fatigue (8).
In rats, an activator of this receptor causes them to be less active ( a long-term indicator of fatigue) .
The 5-HT2C receptor is increased by inflammatory cytokines. This could possibly be the link between viral infections and depression (and CFS) .
5-HT2C Increases Pain From Inflammation
5-HT2C receptors potentiate pain that is produced from inflammation .
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 .
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 .
Another study showed that 5-HT2C activators increased SCN firing in human times at midnight, but not noon .
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 , which in turn works via the melanocortin-4 receptors .
5-HT2C Decreases Weight
Besides inhibiting appetite, these receptors cause lower insulin from the pancreas , 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.
5-HT2C Helps Libido
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 and The HPA Axis
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 .
Mice without 5-HT2C receptors show a blunting of an amygdala-induced HPA activation in response to anxiety stimuli .
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 .
5-HT2C and Hormones
- 5-HT2C activators lessen pain [24, 25].
- 5-HT2C activators increase body temperature in rats .
- 5-HT2C is decreased in epilepsy . Mice lacking serotonin 5-HT2C receptors are extremely susceptible to audio-induced seizures .
- 5-HT2C activators are being explored for frequent urination .
- 5-HT2C activators reduce alcohol addiction in animals.
- 5-HT2C receptors in your prefrontal cortex are the mediators of the reward from cocaine .
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 .
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 .
Kudzu root/Puerarin seems to be a 5-HT2C blocker .
What Increases 5-HT2C Receptors
- Stress/CRH (CRHR1) 
- Dehydration causes the release oxytocin via 5-HT2C , 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 .
- 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 . 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.
Agomelatine has anti-depressant properties and acts through the 5-HT2C receptors .
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 .
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