The HTR2A gene codes for 5-hydroxytryptamine receptor 2A (5-HT2A). 5-HT2A is a serotonin receptor [R].

Medications for schizophrenia and related conditions work by blocking 5-HT2A and altering the function of certain brain circuits. Blocking 5-HT2A also seems to improve the effects of some antidepressants [R].

Interestingly, the activation of 5-HT2A may be responsible for some of the effects of psychedelics like LSD, psilocybin, and mescaline [R].

HTR2A variants have been linked to many conditions, including [R]:

• Schizophrenia
• Depression
• Suicide
• Anxiety
• OCD
• ADHD
• Eating disorders
• Alzheimer's disease

G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.

(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.

Read: 5HT2A Receptors: A Root Cause of Anxiety, Fatigue, Sleep Problems and CIRS

The Bad

Activation of 5HT2A receptors contributes to:

• Anxiety and neuroticism.  In particular, it increases glutamate release and neuronal excitation (R).
• Increased TGF-beta (R) – this effect is reversed by NAC and lipoic acid (R).
• Decreased glutathione (R)
• Reduced BDNF. When activated, these receptors decrease BDNF production (R).  This is the mechanism by which psychological stress reduces BDNF (R).
• Increased arachidonic acid, which can be inflammatory (R).
• Suicide and depression. Suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients (R). Blocking these receptors is a mechanism of antipsychotics and can help depression (R). This receptor may to some extent account for the difference in the outcome of anti-depressant/SSRI treatment (minor alleles generally more likely to benefit) (R). 5HT2A receptors are in high concentration in the default mode network [DMN], which is overactive in depression (R).  This brain network is implicated in self-related thinking and mind wandering.
• Chronic Fatigue Syndrome. One study has linked abnormal 5-HT2A polymorphisms which may enhance receptor activity with Chronic Fatigue Syndrome (R).  It's possible that by activating the 5HT2A receptors, fatigue occurs because orexin neurons are shut off.  Antipsychotics that block 5HT2A receptors were found to activate orexin neurons (R).
• Insomnia and sleep problems (R).
• IBS. People with genes who produced more 5HT2A receptors were more likely to have IBS (T allele for ) (R).  When I took LSD (strong 5HT2A activator), it caused serious GI issues, which fits with this.
• Decreases Slow Wave Sleep (along with 5HT6….. 5-HT_1A, 5-HT_1B, and 5-HT₇ MAOA and serotonin transporters have been implicated in the control of REM sleep) (R).
• OCD. Higher numbers of 5HT2A receptors in the caudate nuclei are associated with OCD (R). Blocking the 5-HT₂ receptor has been shown to enhance therapeutic responses to SSRIs in patients with major depression and treatment-refractory obsessive“compulsive disorder (OCD) (R).
• Pain. These receptors are found in the spinal cord regions that control pain (R). Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators (R).
• Autism. These blockers may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (R).  Autistic people have more 5HT2A receptors (in platelets) (R).
• Tourette's (R) and head twitch response (R).
• Increased prolactin, cortisol and renin (activation of the 5-HT2A in the hypothalamus) (R).
• Decreased blood flow to the heart (R), skin (R) and other places.  5HT2A causes your blood vessels to narrow (vasoconstriction of smooth muscle cells) (R). Decreased blood flow can contribute to people feeling colder.
• Increased platelet clumping (R), which can worsen blood flow and cause heart disease.

The Good

Activators of 5HT2A (R):

• Lower heart rate and lower blood pressure (mediated by the vagus nerve) (R, R2).
• Reduce inflammatory effects in several tissues including the heart and gut (especially against TNF-induced inflammation).
• Enhance dopamine in the areas responsible for a higher level of thinking (PFC), which enhances memory and plays a role in attention and learning.
• Reduce pressure in the eye,
• Increase oxytocin and ACTH (activation of the 5-HT2A in the hypothalamus).

The lower heart rate and blood pressure are produced via the inhibition of Rostral Ventrolateral Medulla (RVLM) in the brain stem, which controls the baroreflex (R).

The baroreflex controls blood pressure and people with chronic fatigue often have low blood pressure.  These effects could, in part, be mediated by the 5HT2A receptors. Other effects could be as a result of lower orexin activation, as orexin neurons from the hypothalamus stimulate the RVLM (R).

The RVLM is the primary regulator of the fight or flight nervous system, sending excitatory signals to the sympathetic preganglionic neurons in the spinal cord, via reticulospinal tract (R).

In animals, the 5-HT2A receptors increase body heat by causing vasoconstriction in skin (mediated by brainstem) (R).

Technical

Animal studies suggest that activation of 5-HT1A, 5-HT2C, 5HT1B, 5HT1D, 5HT5, 5HT7 receptors may counteract the effects of activating 5-HT_2A receptors (R).

• Inositol – reduces 5HT2A receptor function (R),
• Meditation,
• Zinc (R),
• Lectin avoidance?
• Feverfew (R)
• Ginkgo (R)

Inositol and fluoxetine reduce 5HT2A receptor function at the receptor-G protein level.  In addition mI, and at high concentrations fluoxetine and imipramine, also reduces muscarinic acetylcholine receptors (R).

5HT2A receptors are in high concentration in the default mode network [DMN], which is overactive in depression (R).  

This brain network is implicated in self-related thinking and mind wandering. Meditation leads to a reduced activity in the default mode network (R), which can help some of the negative effects of the 5HT2A receptors on depression.

The negative effects of the 5HT2A receptors seem to work through activating GSK3 (R) and stimulating calcium release inside cells. Therefore, GSK3 inhibitors such as lithium might help.  

For the calcium release, magnesium may help. 5-HT2A has sialic acid in it, which is bound to by lectins.  I wouldn't be surprised if this receptor was implicated in lectin sensitivity to a degree, given all of its associated symptoms.  Lectins probably modify the receptor in some negative way in people who are susceptible.