Activation of 5HT2A receptors is on the whole bad.  The more receptors we have, the more likely they’ll activate, so it’s better to have fewer receptors.

Activation of the 5-HT2A receptor is necessary for the effects of the “classic” psychedelics like LSD, psilocin (‘shrooms’) and mescaline (peyote), which act as full or partial activators at this receptor (Activators acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity) (R).

5HT2A receptors are commonly found in platelets, the heart, joints, immune cells (monocytes), the vagus nerve (R) and brain (hypothalamus, brain stem, prefrontal) (R).

5HT2A receptors decrease with age (R).  This receptor exhibits a circadian rhythm (R).

I’ve already discussed a few other serotonin receptors:

There are more serotonin receptors that are likewise interesting.

What You Need to Know

5HT2A receptor activation is one of the contributing factors to CFS.  This receptor is important for people with the CIRS subgroup of CFS because this receptor increases TGF-beta (R).  This receptor also decreases glutathione (R).

When it comes to mold illness and CIRS, it’s interesting that some ergot alkaloids of fungi activate the 5-HT2A receptor (such as agroclavine, which is found in corn and Ergovaline (R))  (R).

LSD is the most famous ergot-like compound that activates the 5HT2A receptor, and the symptoms produced by LSD are similar to some symptoms produced by mold toxicity, including an altered sense of time, visuals disturbances and anxiety.  These ergot compounds that activate the 5HT2A receptor also restrict blood flow, which causes a variety of health problems because of low oxygen.

Activation of this receptor causes anxiety, OCD, depression, fatigue, lower heart rate, lower blood pressure, insomnia and less deep sleep.  5HT2A receptor activation probably contributes to fatigue and depression after orgasming, and maybe POIS.

These are a cluster of issues that are commonly experienced by people with chronic health issues and which can partially be explained by the 5HT2A receptor.

Even more interesting, 5-HT2A has sialic acid in it, which is bound to by lectins.  When I took sialic acid supplements, my reactions to lectins go down.  It could be that one of the negative effects of lectins are by binding to sialic acid, which are found on 5HT2A receptors and lectins could activate these receptors or change them in some way. Therefore, I wouldn’t be surprised if this receptor was implicated in lectin sensitivity to a degree, given all of its associated symptoms.

In addition, Inositol reduces 5HT2A receptor function (R), and it also seems to reduce lectin sensitivity and also OCD and anxiety related to lectin consumption (R).

Now a lot of the differences between people not only have to do with the genes of the 5HT2A receptors (scroll on), but also inflammation.  IL-1b increases the responsiveness of these receptors (at least in some cells) (R), which can exacerbate someone’s genetics.

Last, we know stress is even more significant to people with chronic health issues.  Stress can exacerbate health issues in part by 5HT2A receptor activation, which is the case in animals (R).

Normally the 5HT2A receptor can shut down the amygdala, but stress prevents the calming of the amygdala (R).

Cortisol can increase 5HT2A receptors in some animal models (R).

Th 5HT2A receptor is a nice piece of information that is able to connect all of the symptoms of people with chronic or nagging health issues that aren’t taken seriously by the medical establishment.  Now, even though 5HT2A receptors are important, it’s just one piece of the puzzle.

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)
    • Obesity (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 anti-psychotics and can help depression (R). This receptor may to some extent account for the difference in outcome of antidepressant/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 rs6311) (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-HT1A5-HT1B, 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.
  • Decreased sexual function (R).   5HT2A activation is part of the mechanism of SSRI-induced sexual dysfunction. 5HT2A/2C blockers helped people with SSRI-induced sexual dysfunction, in a small pilot trial (R).
  • Maybe helps skin repair from the sun. Blocking 5HT2A helps skin repair from UVdamage (R).

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).
  • Increase testosterone (R).

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).


Animal studies suggest that activation of 5-HT1A5-HT2C, 5HT1B, 5HT1D, 5HT5, 5HT7 receptors may counteract the effects of activating 5-HT2A receptors (R).

23andme SNPs

There are over 255 SNPs in this gene (R).  But here are the main ones.

SelfDecode has all these SNPs and many more.

rs6311 -1438 G/A

The “T” allele results in more receptors/increased gene expression and more active receptors (R,R2).

TT is associated with depression, panic disorder, and a higher stress response.

The T allele was associated with a reduction in general health, vitality, and social
function (p=0.0031-0.040) (R).

The T allele is associated with IBS (R) and CFS (R).

The C allele is associated with an extraverted personality, rheumatoid Arthritis and novelty seeking.

CC=3.6x increased risk of sexual dysfunction when taking SSRI Antidepressants (R).

This SNP correlates perfectly with rs6313, as in the T allele here will result in the A allele by rs6313 (R).

rs6313 T102C or C102T

The A allele was associated with lower general health and social function scores (p=0.0032–0.034) (R).

GG is more common in suicide attempters (R).

The allele has been associated with higher extraversion personality scores among borderline personality disorder patients and the presence of visual and auditory hallucinations in patients with late-onset Alzheimer’s Disease (R).

In schizophrenia, GG tends to do worse on working memory tasks than do individuals with an allele (R).

This SNP correlates perfectly with rs6311, as in the A allele here will result in the T allele by rs6311 (R).

rs6314 C1354T His452Tyr

~7% of the alleles in the global population are “A“. So GG is the common version.

The A allele had reduced ability to activate the receptor or cause downstream signals.  This means it causes a blunted signal after activation (R). (Technical: reduced ability to activate phospholipases C and D, suggesting that signaling through both G(q) and G(13) pathways is hindered) (R).

AA had significantly greater mental fatigue scores than the AG (and greater than GG)
(p=0.026)  (R).

AG is associated with ADHD, better response to antidepressants, worse memory (R).

AG was associated with better response to the SSRI paroxetine (Paxil) (R).

GG had a better memory (R).

Although common, GG or AG has higher rheumatoid arthritis risk (R).

(Tyr=A, His=G)

rs5443 C825T – GNB3

This SNP codes for GNB3, which in turn codes for a second messenger complex associated with 5HT2A receptor signaling (R).

47% of the alleles in a population are “T“.

The T allele is thought to increase the second messenger signaling (R).

TT responds better to viagra, more likely to be obese, hypertension, SSRI-induced sexual dysfunction, respond to triptans for migraines

T allele carriers are 2-3 fold more likely to be obese in Caucasian, Chinese, and African American populations (R).

T carriers are clearly at higher risk for hypertension (R).

TT women gain significantly more weight during pregnancy CT or CC women and had a significantly higher pre-pregnancy body mass index (R).

TT respond to Viagra better. 91% of them have a “positive erectile response” upon taking Viagra, whereas only around 50% of CT and CC individuals respond equivalently to the drug (OR=10, p = 0.01) (R).

TT patients receiving clozapine over a long term for the treatment of schizophrenia gain significantly more weight (16%) compared to patients carrying at least one C allele in a study of Chinese patients (R).

T carriers taking triptans for the treatment of migraines or cluster headaches were ~3 fold more likely to respond positively compared with CC (OR 2.96, p=0.0074) in a study of ~200 Caucasian patients (R).

CT genotypes are more prevalent in gastroesophageal reflux disease (GERD) patients relative to healthy controls (OR 1.43) (R).

CC individuals do not lose weight under sibutramine (weight loss drug) therapy whereas CT and TT individuals do, based on a study of 131 obese Taiwanese patients (R).


GG is the common genotype.

AA=18% more likely to respond to antidepressant-citalopram, which decreases 5-HTR2A. (R).


CC is the common genotype.

The C allele is associated with higher physical fatigue, less vitality, and CFS (R).

Although common, CC had significantly lower vitality than TT homozygotes (p=0.026) (R).


Number of A alleles is associated with panic disorder (R).

What Decreases 5HT2A Receptors


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.


  • Inositol – reduces 5HT2A receptor function (R).  Inositol and fluoxetine reduces 5HT2A receptor function at the receptor-G protein level (R).
  • Chromium – decreases sensitivity of 5-HT2A receptors in humans are rats (which is indicated by chromium lowering the cortisol response to challenge with 5-HTP) (R).
  • Feverfew (R)
  • Ginkgo (R)
  • Mangosteen is a 5HT2A antagonist (R)
  • St John’s Wort. Some studies show St John’s Wort decreases 5HT2A receptors (R). However, other studies report a 50-percent increase in 5-HT2A receptors after six months of use (R).
  • Sandalwood Essential Oil/Alpha-santalol (R)

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.

Other GSK-3 inhibitors include zinc, beryllium, mercury, and copper (R).

5-HT2A has sialic acid in it, which is bound to by lectins. I wouldn’t be very surprised if this receptor was implicated in lectin sensitivity to a degree, given all of its associated symptoms.


  • Risperidone (R)
  • Quetiapine – an antagonist of 5HT2A and to a lesser extent DRD2 (R).
  • SSRI’s
  • MDMA (R) -in recent MDMA users, post-synaptic 5-HT(2A) receptor densities were significantly lower in all cortical areas studied.
  • LSD, chronically. Even though LSD activates 5HT2A receptors, chronic usage causes a decrease in the number of receptors, which may explain part of the longer term happiness effects (R). Microdosing LSD is something to think about.

Lithium inhibits GSK3b (R), which can help fix this receptor, but it also decreases brain inositol (R).

Estrogen increases 5HT2A receptors, while progesterone seems to counteract it (R).

What Increases 5HT2A Receptors

  • Stress/CRH (CRHR1) (R)
  • Chronic activation of the CB2 cannabinoid receptor (R)
  • St John’s Wort increases the number of postsynaptic 5-HT2A receptors (R).
  • DMT –  agonist (R)
  • LSD – agonist. Even though LSD activates 5HT2A receptors, chronic usage causes a decrease in the number of receptors, which may explain part of the longer term happiness effects (R). Microdosing LSD is something to think about.
  • Agmatine supplements may activate the 5HT2A receptors (R).

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