What are 5HT2A Receptors?

Activation of the 5-HT2A receptor is necessary for the effects of the “classic” psychedelics like LSD, psilocybin (‘shrooms’) and mescaline (peyote), which act as full or partial activators at this receptor [1].

5HT2A receptors are commonly found in platelets, the heart, joints, immune cells (monocytes), and the vagus nerve [2, 3].

These serotonin receptors are found throughout the brain, but they are concentrated in the prefrontal cortex, amygdala, and hippocampus – all of which are key brain areas related to learning, memory, and overall cognitive ability [4, 5, 6, 7, 8].

5HT2A receptors decrease with age [1]. This receptor exhibits a circadian rhythm [9].

Other serotonin receptors:


Although we segment this article based on positives/negatives and activators/inhibitors, it can actually get quite complex when you drill down deeper.

5HT2A has an ‘active’ binding site and multiple ‘allosteric’ or less active binding sites. Each drug or substance interacts with the receptor differently, and we haven’t differentiated in this post exactly where the binding occurs

So one form of activation or antagonism (blocking) can be completely different than another form, and it can result in different physiological effects.

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 [10]. Activation of this receptor may also decrease glutathione [11].

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 [12]) [13].

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.

Mood and Sleep

Activation of this receptor contributes to 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 is that they bind to sialic acids, which are found on 5HT2A receptors. The presence of 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 [14], and it also seems to reduce lectin sensitivity and also OCD and anxiety related to lectin consumption [14].

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) [15], which can exacerbate someone’s genetics.


We know stress is significant to people with chronic health issues. Stress can exacerbate health issues in part by 5HT2A receptor activation, which is the case in animals [16].

Activation of 5-HTR2As during stress may mediate the down-regulation of BDNF that contributes to the negative effects of stress [17].

Chronic stress can lead to the loss (“down-regulation”) of 5-HTR2As in the orbitofrontal cortex (OFC) (rat study) [18].

Normally the 5HT2A receptor can shut down the amygdala, but stress prevents the calming of the amygdala [19].

Cortisol can increase 5HT2A receptors in some animal models [20].

Cognitive Function

  • Serotonin receptors are particularly prominent in brain regions involved in memory and learning [21].
  • 5-HT2a receptors may also play a role in stimulating the release of glutamate [6, 4, 7], GABA [5], and dopamine [22].

Inhibition of 5HT2A:

5-HTR2As play a key role in learning and memory; stimulation of 5-HTR2As enhances learning and memory (in rats) [23].

Inhibition of these receptors can worsen cognitive function:

  • Loss (or “down-regulation”) of 5-HTR2As may play a role in the cognitive deficits observed in Alzheimer’s disease [24].
  • Inhibiting 5-HTR2As causes learning and memory deficits in rats; conversely, SSRIs (here, citalopram) may up-regulate these receptors, which may be responsible for the alleviation of cognitive symptoms seen in depression patients treated with SSRIs [18].
  • Inhibiting 5-HTR2As impairs new learning (reversal learning) and increases impulsivity (perseverative responding to a previous reinforcer) (rat study) [25].
  • Blocking 5-HTR2As impairs contextual memory (rat study) [26].

However, ketanserin, a selective antagonist of HTR2a receptors, improves memory performance [27, 28].


  • Inhibition of 5-HTR2As decreased impulsivity in this rat study [29].
  • Over-activation of 5-HTR2As increases impulsivity (premature responding / “response control”) in rats [30].

The Bad

Activation of 5HT2A receptors contributes to:

  • Anxiety and neuroticism. In particular, it increases glutamate release and neuronal excitation [1].
  • Increased TGF-beta [10] – this effect is reversed by NAC and lipoic acid [10].
  • Decreased glutathione [11]
  • Obesity (31)
  • Reduced BDNF. When activated, these receptors decrease BDNF production [16]. This is the mechanism by which psychological stress reduces BDNF [16].
  • Increased arachidonic acid, which can be inflammatory [1].
  • Suicide and depression. Suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients [1]. Blocking these receptors is a mechanism of antipsychotics and can help depression [32]. This receptor may to some extent account for the difference in the outcome of antidepressant/SSRI treatment (minor alleles generally more likely to benefit) [1]. 5HT2A receptors are in high concentration in the default mode network [DMN], which is overactive in depression [33]. 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 [1]. 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 [34].
  • Insomnia and sleep problems [35].
  • IBS. People with genes who produced more 5HT2A receptors were more likely to have IBS (T allele for rs6311) [36]. When I took LSD (strong 5HT2A activator), it caused serious GI issues, which fits with this.
  • Decreases Slow Wave Sleep (along with 5HT6…. 5-HT1A, 5-HT1B, and 5-HT7, MAOA, and serotonin transporters have been implicated in the control of REM sleep) [35].
  • OCD. Higher numbers of 5HT2A receptors in the caudate nuclei are associated with OCD [1]. 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) [37].
  • Pain. These receptors are found in the spinal cord regions that control pain [38]. Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators [39].
  • Autism. These blockers may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders [37]. Autistic people have more 5HT2A receptors (in platelets) [40].
  • Tourette’s [1] and head twitch response [41].
  • Increased prolactin, cortisol and renin (activation of the 5-HT2A in the hypothalamus) [1].
  • Decreased blood flow to the heart [42], skin [43] and other places. 5HT2A causes your blood vessels to narrow (vasoconstriction of smooth muscle cells) [42]. Decreased blood flow can contribute to people feeling colder.
  • Increased platelet clumping [44], which can worsen blood flow and cause heart disease.
  • Decreased sexual function [37]. 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 [45].
  • Maybe helps skin repair from the sun. Blocking 5HT2A helps skin repair from UV damage [46].

The Good

Activators of 5HT2A [1]:

  • Lower heart rate and lower blood pressure (mediated by the vagus nerve) [2, 47].
  • 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 [48].

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 [47].

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 [49].

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 [49].

In animals, the 5-HT2A receptors increase body heat by causing vasoconstriction in the skin (mediated by brainstem) [43].


There are over 255 SNPs in this gene [3]. SelfDecode has all the SNPs mentioned below and many more.

Cognitive Function

HTR2A genotypes have been associated with:

  • General Cognitive Function, Learning, and Memory [50, 51, 52, 53, 54]

Risk alleles are associated with a decreased number [55] and sensitivity [56, 57] of 5-HT2a receptors, as well as a reduced ability of serotonin to bind to its receptors [58].

Risk alleles also associated with reduced grey matter volume in the cortex and the hippocampus [59, 57].

Serotonin activity is required for the formation and storage of new memories [57]; hence the association of this gene with cognitive functions such as memory and recall ability.

Increasing serotonin levels (e.g. with serotonergic drugs like SSRIs) improves memory and learning abilities in both humans and animals [57, 60, 61].

Conversely, acutely decreasing serotonin levels impairs memory in both animals and humans [57].

Also, loss of 5-HT2a receptors over the lifespan may be a contributor to normal age-related cognitive decline in humans [55].

Therefore, risk alleles likely involve under-activity of the HTR2A gene, which in turn means impaired/reduced serotonin activity/levels.


Risk alleles in the HTR2A gene may contribute to mood problems by increasing the activation of HTR2a receptors. Many common antidepressants, such as SSRIs, may have beneficial effects on mood by reducing (“down-regulating”) the numbers of HTR2a receptors, which leads to lower activity of these receptors [62, 63]. Therefore, you may be able to counteract your risk by reducing the activity of HTR2a receptors.

rs6311 – 1438 G/A

The “T” allele results in more receptors/increased gene expression and more active receptors [64, 65].

TT is associated with depression, panic disorder, and higher stress response.
The T allele was associated with a reduction in general health, vitality, and social function (p=0.0031 – 0.040) [66]. The T allele is associated with IBS [36] and CFS [66].
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.

This SNP correlates perfectly with rs6313, as in the T allele here will result in the A allele by rs6313 [66].

rs6313 T102C or C102T

The A allele was associated with lower general health and social function scores (p=0.0032–0.034) [67].
GG is more common in suicide attempters [68].

The G 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 [69].

In schizophrenia, GG tends to do worse on working memory tasks than do individuals with an A allele [69].

This SNP correlates perfectly with rs6311, as in the A allele here will result in the T allele by rs6311 [66].

rs6314 C1354T His452Tyr

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

The A allele had reduced the ability to activate the receptor or cause downstream signals. This means it causes a blunted signal after activation [70]. (Technical: reduced ability to activate phospholipases C and D, suggesting that signaling through both G(q) and G(13) pathways is hindered) [71].
AA had significantly greater mental fatigue scores than the AG (and greater than GG)
(p=0.026) [66].
AG is associated with ADHD, better response to antidepressants, worse memory [70].

AG was associated with better response to the SSRI paroxetine (Paxil) [72].

GG had a better memory [73].

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

(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 [74].

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

The T allele is thought to increase the second messenger signaling [74].

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 [75].

T carriers are clearly at higher risk for hypertension [76].

TT women gain significantly more weight during pregnancy CT or CC women and had a significantly higher pre-pregnancy body mass index [77].

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) [78].

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 [79].

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 [80].

CT genotypes are more prevalent in gastroesophageal reflux disease (GERD) patients relative to healthy controls (OR 1.43) [81].

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 [82].


GG is the common genotype. See the SelfDecode entry on this SNP here.

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


CC is the common genotype. See the SelfDecode entry on this SNP here.

The C allele is associated with higher physical fatigue, less vitality, and CFS [66].
Although common, CC had significantly lower vitality than TT homozygotes (p=0.026) [66].


The number of A alleles is associated with panic disorder [83].

What Decreases 5HT2A Receptors


5HT2A receptors are in high concentration in the default mode network [DMN], which is overactive in depression [33]. This brain network is implicated in self-related thinking and mind wandering. Meditation leads to reduced activity in the default mode network [84], which can help some of the negative effects of the 5HT2A receptors on depression.


  • Inositol – reduces 5HT2A receptor function [14]. Inositol and fluoxetine reduce 5HT2A receptor function at the receptor-G protein level [14].
  • Chromium – decreases the sensitivity of 5-HT2A receptors in humans are rats (which is indicated by chromium lowering the cortisol response to challenge with 5-HTP) [85].
  • Feverfew [86]
  • Ginkgo [87]
  • Mangosteen is a 5HT2A antagonist [88]
  • St John’s Wort. Some studies show St John’s Wort decreases 5HT2A receptors [89]. However, other studies report a 50-percent increase in 5-HT2A receptors after six months of use [90].
  • Sandalwood Essential Oil/Alpha-santalol [91]

The negative effects of the 5HT2A receptors seem to work through activating GSK3 [92] 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 [93].

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 [94]
  • Quetiapine – an antagonist of 5HT2A and to a lesser extent DRD2 [95].
  • SSRI’s
  • MDMA [96] – 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 [97]. Microdosing LSD is something to think about.

Lithium inhibits GSK3b [93], which can help fix this receptor, but it also decreases brain inositol [98].

Estrogen increases 5HT2A receptors, while progesterone seems to counteract it [99].

Animal studies suggest that activation of 5-HT1A, 5-HT2C, 5HT1B, 5HT1D, 5HT5, 5HT7 receptors may counteract the effects of activating 5-HT2A receptors [37].

What Increases 5HT2A Receptors

  • Stress/CRH (CRHR1) [100]
  • Chronic activation of the CB2 cannabinoid receptor [101]
  • St John’s Wort increases the number of postsynaptic 5-HT2A receptors [102].
  • DMT – agonist [103]
  • 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 [97]. Microdosing LSD is something to think about.
  • Agmatine supplements may activate the 5HT2A receptors [104].

SelfHacked Recommendations for 5HT2A Receptors

5-HT2A receptors play a very complex role in the brain’s serotonin system, and scientists don’t yet fully understand exactly how they affect cognition. For example, some studies claim that increased activity of these receptors is beneficial, while others claim that decreased activity is better [21, 18, 105, 26, 25, 23].

Therefore, we don’t recommend trying to affect the activity of these receptors directly. Fortunately, several studies have concluded that raising overall serotonin levels can normalize 5-HT2A receptor activity (by using antidepressants like SSRIs, for example) [18, 106, 60, 23].

This suggests that you may be able to further boost your cognitive ability by boosting your brain’s overall level of serotonin.

An important first step to keeping your serotonin levels high is to avoid or reduce stress. Stress triggers the release of cortisol, a major stress hormone that reduces overall serotonin levels (by increasing its removal, or re-uptake, from neural synapses) [107].

Cortisol can also specifically affect how 5-HT2 receptors function, which could further worsen any negative cognitive effects you might have from this genotype [108, 17].

Therefore, it would be a good idea to adopt a proven stress-busting hobby. Meditation [109, 110, 111] and yoga [112, 113, 114] can help you to keep your cortisol levels down.

One of the simplest ways to boost your levels of serotonin is to consume the basic ingredients (metabolic precursors) your brain needs to make serotonin. Although both tryptophan and 5-HTP can do this, we recommend supplementing with 5-HTP, as it is generally safer and more effective than tryptophan [115, 116, 117, 118].

Reasons 5-HTP is better for supplementation than tryptophan:

  • Tryptophan is not as able to cross the BBB as 5-HTP is [117]
  • Tryptophan requires certain genes to be present in order to be made into serotonin, whereas 5-HTP can be converted into serotonin much more directly [115]
  • 5-HTP can only be converted exclusively into serotonin, whereas tryptophan may have a variety of end products that could dilute its effects on overall serotonin levels [115]
  • Some of the metabolic products of tryptophan can have negative effects, whereas 5-HTP has much less risk of side-effects [115, 118]

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