The 5-HT2A receptor has been linked with anxiety, pain, insomnia, and psychedelic effects of hallucinogens in some studies. This post breaks down the science behind 5HT2A receptors.
What are 5HT2A Receptors?
Scientists believe that the activation of the 5-HT2A receptor may be responsible for some of the effects of “classic” psychedelics like LSD, psilocybin, and mescaline (peyote), which seem to act as full or partial activators at this receptor .
5HT2A receptors are commonly found in brain cells, as well as in other parts of the body including platelets, the heart, joints, immune cells (monocytes), and the vagus nerve [2, 3].
These serotonin receptors are found throughout the brain, but studies suggest that they are concentrated in the prefrontal cortex, amygdala, and hippocampus — areas implicated in learning, memory, and overall cognitive ability [4, 5, 6, 7, 8].
Some researchers hypothesize that 5HT2A receptors decrease with age . The activity of these receptors may also follow the circadian rhythm, becoming more or less active during certain parts of the sleep-wake cycle .
Other serotonin receptors:
Although we’ve structured this article around potential positives/negatives and activators/inhibitors, the details of how these receptors work and what they do can actually get quite complex when you drill down deeper.
5HT2A has an “active” binding site and multiple “allosteric” (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 for each specific compound.
So one form of activation or antagonism (blocking) can be completely different than another form, and it can result in different physiological effects.
More importantly, the majority of the scientific findings described in this article are from animal or cellular studies. These can’t be directly extrapolated to humans. We know little about factors that affect 2HT2A receptors in humans, with the exception of some drugs (certain atypical antipsychotics likely block these receptors and tryptamine hallucinogens activate them) [10, 11].
Therefore, the studies listed below should not be interpreted as indicative of any health effects in people.
Areas of Research
The CFS/CIRS Controversy
Most doctors do not accept that there is any causal connection between mold exposure and any health issue. In light of this, mold illness and CIRS (chronic inflammatory response syndrome) are considered to be highly controversial “pseudo-diagnoses” that may or may not be “real” illnesses .
Similarly, what people subjectively describe as CIRS has been linked to psychological disorders, including chronic fatigue syndrome (CFS), another controversial disorder [13, 14, 15].
Some scientists have suggested that the symptoms reported by people who claim to suffer from these conditions — such as tiredness, allergy-like symptoms, and increased vulnerability to infections — may simply be a psychological (“psycho-somatic”) response. For example, skeptics point to the fact that people who claim to suffer from mold illness often show no signs of fungal infection in the first place — meaning that whatever symptoms they might be experiencing could not possibly be due to mold or any other type of fungus .
Nonetheless, some scientists think that 5HT2A receptor activation may be involved in the reported symptoms of CFS. Ergot alkaloids of fungi might activate the 5-HT2A receptor (such as agroclavine, which is found in corn, and ergovaline), according to cell-based research. Additionally, 5HT2A is being studied for increasing TGF-beta, which may theoretically decrease glutathione [16, 17, 18, 19].
LSD is the most famous ergot-like compound that activates the 5HT2A receptor. Anecdotally, some effects produced by LSD are similar to some of the symptoms that people with mold toxicity claim to experience, such as an altered sense of time, visual disturbances, and anxiety.
However, other theories suggest that “mold toxicity” might just be a delusion, which would bring it closer to a psychosis-like state — which could suggest that over-activation of 5HT2A receptors might be involved somehow [20, 21].
Mood and Sleep
Researchers suggest that activation of this receptor may contribute to anxiety, OCD, depression, fatigue, lower heart rate, lower blood pressure, insomnia, and less deep sleep .
According to some hypotheses, stress might exacerbate health issues in part by 5HT2A receptor activation, which is the case in animals .
In animals, activation of 5-HTR2As during stress may mediate the down-regulation of BDNF that contributes to the negative effects of stress .
Scientists suggest that chronic stress may lead to the loss (“down-regulation”) of 5-HTR2As in the orbitofrontal cortex (OFC) (rat study). They proposed that, normally, the 5HT2A receptor can shut down the amygdala, but stress seems to prevent the calming of the amygdala [25, 26].
Cortisol increased 5HT2A receptors in some animal models .
Ultaimtely, though, the impact of stress on 5-HT2A receptors in humans is not well understood — and more research will definitely be needed to fully understand these potential links.
- Serotonin receptors are particularly prominent in brain regions involved in memory and learning .
- 5-HT2a receptors may play a role in glutamate [6, 4, 7], GABA , and dopamine release .
In rats, stimulation of 5-HTR2As enhances learning and memory .
Inhibition of these receptors might worsen cognitive function. Researchers are investigating whether:
- Loss (or “down-regulation”) of 5-HTR2As may play a role in the cognitive deficits observed in Alzheimer’s disease .
- 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 .
- Inhibiting 5-HTR2As impairs new learning (reversal learning) and increases impulsivity (perseverative responding to a previous reinforcer) (rat study) .
- Blocking 5-HTR2As impairs contextual memory (rat study) .
However, ketanserin, a selective antagonist (“blocker”) of HTR2a receptors, improves memory performance [34, 35].
Additional clinical trials will be needed to determine the role of these receptors in memory and overall cognitive function.
Inhibition of 5-HTR2As decreased impulsivity in one rat study .
Simimlarly, over-activation of 5-HTR2As increased impulsivity (premature responding / “response control”) in rats .
While these findings suggest that activation of these receptors might contribute to impulsivity, the data so far only comes from animal studies, and appropriate studies in humans are lacking.
Potentially Negative Effects Associated with 5HT2A Activation
Scientists hypothesize that the activation of 5HT2A receptors may contribute to:
- Anxiety and neuroticism. In particular, it increases glutamate release and neuronal excitation .
- Increased TGF-beta  – this effect is reversed by NAC and lipoic acid .
- Decreased glutathione 
- Obesity (38)
- Reduced BDNF. When activated, these receptors decrease BDNF production . This is the mechanism by which psychological stress reduces BDNF .
- Increased arachidonic acid, which can be inflammatory .
- Suicide and depression. Suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients . Blocking these receptors is a mechanism of antipsychotics and might help depression . This receptor may to some extent account for the difference in the outcome of antidepressant/SSRI treatment (minor alleles possibly more likely to benefit) . 5HT2A receptors are in high concentration in the default mode network [DMN], which may be overactive in depression . 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 . Some theories suggest 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, but this theory remains unproven .
- Insomnia and sleep problems .
- IBS. People with genes linked with more 5HT2A receptors were more likely to have IBS (T allele for rs6311) .
- 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) .
- OCD. Higher numbers of 5HT2A receptors in the caudate nuclei have been associated with OCD . 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), but large-scale trials are lacking .
- Pain. These receptors are found in the spinal cord regions that control pain . Activation of 5-HT2A receptors seems to potentiate pain produced by inflammatory mediators .
- Autism. These blockers may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders . Autistic people have more 5HT2A receptors in platelets, according to very limited data .
- Tourette’s  and head twitch response .
- Increased prolactin, cortisol and renin (activation of the 5-HT2A in the hypothalamus) .
- Decreased blood flow to the heart , skin  and other places. 5HT2A causes blood vessels to narrow (vasoconstriction of smooth muscle cells) .
- Increased platelet clumping , which can theoretically worsen blood flow and cause heart disease.
- Decreased sexual function . 5HT2A activation is proposed to be part of the mechanism of SSRI-induced sexual dysfunction. 5HT2A/2C blockers helped people with SSRI-induced sexual dysfunction, in a small pilot trial, but large trials are lacking .
- Blocking 5HT2A helps skin repair from UV damage in cell culture .
Keep in mind that the majority of the studies cited above either focused on associations in humans (not on a cause-and-effect relationship) or were done in animals or cells. Findings from animals and cells can’t be translated to humans.
Potentially Positive Effects Associated with 5HT2A Activation
Some researchers believe that the activation of 5HT2A receptors may contribute to :
- Lower heart rate and lower blood pressure (mediated by the vagus nerve) [2, 55].
- Reduced signs of inflammation in several tissues including the heart and gut (especially for TNF-induced inflammation).
- Enhanced dopamine in the areas responsible for a higher level of thinking (PFC), which theoretically enhances memory and plays a role in attention and learning.
- Reduced pressure in the eyes
- Increased oxytocin and ACTH (activation of the 5-HT2A in the hypothalamus).
- Increased testosterone .
However, these mechanisms remain unproven in humans.
According to one theory that remains to be validated, some of these effects could be as a result of lower orexin activation, as orexin neurons from the hypothalamus stimulate the RVLM (rostral ventrolateral medulla). 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, R).
In animals, the 5-HT2A receptors increase body heat by causing vasoconstriction in the skin (mediated by brainstem) .
There are over 255 SNPs in the 5-HT2A gene . The SelfDecode database has all the SNPs mentioned below and many more.
Keep in mind that these findings are based on association studies suggesting that certain genetic variants are more common in people with certain conditions or traits. However, more research will be needed to know what role, if any, these variants play in actually causing these conditions or traits.
Therefore, just because you have one of these genotypes does not necessarily mean you are more likely to have a certain trait of condition.
It’s important to note that just because certain genotypes are associated with a disease, it doesn’t necessarily mean that everyone with that genotype will actually develop the disease! Many different factors, including other genetic and environmental factors, can influence the risk of diseases.
Certain HTR2A genotypes have been associated with:
Risk alleles are associated with a decreased number  and sensitivity [63, 64] of 5-HT2a receptors, as well as a reduced ability of serotonin to bind to its receptors .
Risk alleles have also been associated with reduced grey matter volume in the cortex and the hippocampus [66, 64].
Scientists suspect that serotonin activity is required for the formation and storage of new memories ; hence a possible link to 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 [64, 67, 68].
Conversely, acutely decreasing serotonin levels impairs memory in both animals and humans .
Also, loss of 5-HT2a receptors over the lifespan may be a contributor to normal age-related cognitive decline in humans, according to some scientists .
Therefore, risk alleles likely involve under-activity of the HTR2A gene, which in turn might imply impaired activity or reduced levels of serotonin in general. Nonetheless, much more research will still be needed to figure out the exact mechanisms and effects of these genetic variants in human health.
Limited research suggests that risk alleles in the HTR2A gene may contribute to mood problems by increasing the activation of HTR2a receptors [69, 70].
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 [69, 70].
rs6311 – 1438 G/A
The ‘T’ allele has been associated with more receptors/increased gene expression and more active receptors. The ‘TT’ genotype has been associated with depression, panic disorder, and higher stress response. [71, 72].
The ‘T’ allele was associated with significant reductions in general health, vitality, and social function . The ‘T’ allele has also been associated with irritable bowel syndrome (IBS)  and chronic fatigue syndrome (CFS) .
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 with rs6313, as in the T allele here will result in the A allele by rs6313 .
rs6313 T102C or C102T
The ‘A’ allele was associated with significantly lower general health and social function scores .
According to one study, the ‘GG’ genotype was more common in suicide attempters .
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 .
In schizophrenia, people with ‘GG’ tend to do worse on working memory tasks than do individuals with an ‘A’ allele .
This SNP correlates with rs6311, as in the ‘A’ allele here will result in the ‘T’ allele by rs6311 .
rs6314 C1354T His452Tyr
~7% of the alleles in the global population are ‘A’. The ‘GG’ genotype is the more common variant.
The ‘A’ allele was linked with reduced ability to activate the receptor or cause downstream signals. This means it causes a blunted signal after activation . (Technical: reduced ability to activate phospholipases C and D, suggesting that signaling through both G(q) and G(13) pathways is hindered) .
In one study, carriers of the ‘AA’ genotype for this SNP had significantly greater mental fatigue scores than people with the ‘AG’ and ‘GG’ genotypes .
The ‘AG’ genotype has been associated with ADHD, better response to antidepressants, worse memory .
‘AG’ has also been associated with better responses to treatment with the SSRI paroxetine (Paxil) .
Carriers of the ‘GG’ genotype have been reported to have better memory .
Although common, the ‘GG’ and ‘AG’ genotypes have been linked with rheumatoid arthritis risk .
rs5443 C825T – GNB3
This SNP codes for GNB3, which in turn codes for a second-messenger complex associated with 5HT2A receptor signaling .
47% of the alleles in a population are ‘T’. The ‘T’ allele is hypothesized to increase the second-messenger signaling .
Limited studies suggest that the ‘TT’ genotype may be associated with a better response to viagra, as well as an increased likelihood of being obese, having hypertension, experiencing SSRI-induced sexual dysfunction, and a better response to triptans for migraines. ‘T’ allele carriers are 2-3 fold more likely to be obese in Caucasian, Chinese, and African American populations .
The ‘T’ allele has been linked with a risk for hypertension .
In one association study, women with the ‘TT’ genotype gained more weight during pregnancy than ‘CT’ or ‘CC’ women, and also had higher pre-pregnancy body mass index (BMI) .
Another study suggests that ‘TT’ carriers may respond to Viagra better. 91% of them have a “positive erectile response” upon taking Viagra, whereas only around 50% of ‘CT’ and ‘CC’ individuals responded equally strongly to the drug (OR=10, p = 0.01) .
‘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 .
‘T’ allele carriers taking triptans for the treatment of migraines or cluster headaches were ~3x more likely to respond positively compared with ‘CC’ carriers (OR 2.96, p=0.0074) in a study of ~200 Caucasian patients .
‘CT’ genotypes are more prevalent in gastroesophageal reflux disease (GERD) patients relative to healthy controls (OR 1.43) .
‘CC’ individuals do not lose weight under sibutramine (a weight loss drug) therapy whereas ‘CT’ and ‘TT’ carriers did, based on a study of 131 obese Taiwanese patients. Large-scale studies in more diverse populations are lacking .
‘GG’ is the more common genotype for this SNP. See the SelfDecode entry on this SNP here.
One study reported that carriers of the ‘AA’ genotype were more likely to respond to the antidepressant citalopram (Celexa), which decreases 5-HTR2A .
More research is needed, as the clinical significance of this study remains unclear.
‘CC’ is the more common genotype for this SNP. You can see the SelfDecode entry on this SNP here.
The ‘C’ allele has been associated with greater physical fatigue, less vitality, and chronic fatigue syndrome (CFS) .
The number of ‘A’ alleles was associated with panic disorder in one study .
Factors that May Decrease or Inhibit 5HT2A Receptors
No valid clinical evidence supports the approaches listed below to reduce 5HT2A activity.
The best way to balance your mood is to live a healthy lifestyle, decrease stress, address underlying health problems by seeing a doctor, and get a good night’s sleep.
If you believe that you are already ticking all of those boxes and you still struggle with mood or other mental health problems, talk to your doctor about any complementary strategies that could be right for you.
You may try the approaches listed below if you and your doctor determine that they could be appropriate for your health. Do not make any major changes to your lifestyle or supplements regimen before speaking to a doctor.
Additionally, remember that none of the approaches listed below should ever be used to replace whatever your doctor has recommended or prescribed.
5HT2A receptors are in high concentration in the “default mode network” (DMN). This brain network is implicated in self-related thinking and mind wandering, and has been reported to be over-active in people with depression . Studies suggest that meditation may help reduce activity in the default mode network , which could theoretically help some of the negative effects of the 5HT2A receptors on depression. Nonetheless, more clinical studies in human patients will be needed to fully confirm these early findings.
Make sure to speak with your doctor before taking any supplements. Let them know about any prescription or over-the-counter medication you may be taking, including vitamins and herbal supplements.
This is particularly important if you are already taking medications (such as antidepressants) or supplements that may increase serotonin levels. Interactions or incorrect dosing may cause serotonin syndrome, a serious condition that results from too much serotonin in the brain and body.
If you and your doctor agree that supplementing is a good idea, choose products made by a trusted and reliable manufacturer.
Remember that dietary supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them, but don’t guarantee that they’re safe or effective.
The effects of the following factors on serotonin / 5HT2A activity in humans is unknown. Clinical evidence is completely lacking to support any of them.
Scientists are currently investigating whether:
- St John’s Wort increases the number of postsynaptic 5-HT2A receptors. However, other studies report a 50-percent increase in 5-HT2A receptors after six months of use. Nonetheless, the results of studies on the effectiveness of St. John’s wort for depression are mixed [93, 94, 95].
- Inositol reduces 5HT2A receptor function . Inositol and fluoxetine might reduce 5HT2A receptor function at the receptor-G protein level .
- Chromium decreases the sensitivity of 5-HT2A receptors in rats (which may be indicated by chromium lowering the cortisol response to a challenge with 5-HTP) .
- Feverfew 
- Ginkgo 
- Mangosteen 
- Sandalwood Essential Oil / Alpha-santalol 
According to some theories, the negative effects of the 5HT2A receptors seem to work through activating GSK3  and stimulating calcium release inside cells. Research is looking to identify GSK-3 inhibitors by researching lithium, zinc, beryllium, mercury, and copper .
Risperidone and quetiapine are antipsychotics, and SSRIs are antidepressants — therefore, these drugs should only be used with a doctor’s prescription.
This section summarizes experimental research about the effects of psychedelics, such as LSD and MDMA, on mood and serotonin in the brain. Our aim is to discuss research findings. We strictly advise against taking these substances under any circumstances.
Some scientists are investigating the ways in which the following illegal drugs affect serotonin pathways:
- MDMA  – 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 (“down-regulation”) in the number of these receptors .
Both LSD and MDMA (“ecstasy”) are illegal drugs. They are classified as Schedule I drugs, which means that they are illegal, have no legitimate medical uses, and a high potential for abuse and harm. Having possession of these substances can result in criminal prosecution, and ingesting them can be highly dangerous.
Factors that May Increase 5HT2A Receptors
The best way to balance your mood is to live a healthy lifestyle, decrease stress, address underlying health problems by seeing a doctor, and get a good night’s sleep.
If you struggle with mood or other mental health problems, talk to your doctor to get an accurate diagnosis and adequate treatment.
Medically speaking, there is no valid reason to want to increase 5HT2A activity in the body. There are no known health benefits to 5HT2A receptor activation in humans.
Increased 5HT2A activity is likely detrimental. Relatedly, many illegal and dangerous substances — such as DMT and LSD — activate 5HT2A receptors, which may be part of the reason these drugs can have major negative and dangerous effects [108, 107].
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 [28, 25, 109, 33, 32, 30].
Therefore, we don’t recommend trying to affect the activity of these receptors directly. Fortunately, several studies have concluded that raising overall serotonin levels might normalize 5-HT2A receptor activity (by using prescribed antidepressants like SSRIs, for example) [25, 110, 67, 30].
An important first step to keeping your serotonin levels in balance is to avoid or reduce stress. Stress triggers the release of cortisol, a major stress hormone that might reduce overall serotonin levels (by increasing its removal, or re-uptake, from neural synapses) .
Scientists suspect that cortisol might also specifically affect how 5-HT2 receptors function, which might further worsen any negative cognitive effects [112, 24].
Therefore, it would be a good idea to adopt a proven stress-busting hobby. Meditation [113, 114, 115] and yoga [116, 117, 118] can help you to keep your cortisol levels down.
Additionally, consuming the basic ingredients (metabolic precursors) the body needs to make serotonin might be helpful in some cases. Although both tryptophan and 5-HTP act as precursors, limited data suggest that 5-HTP may be safer and more effective than tryptophan [119, 120, 121, 122].
According to some theories, 5-HTP may be better for supplementation than tryptophan because:
- Tryptophan is not as able to cross the blood-brain barrier (BBB) as 5-HTP is 
- 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 
- 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 
- Some of the metabolic products of tryptophan can have negative effects, whereas 5-HTP has much less risk of side-effects [119, 122]
Nonetheless, 5-HTP can interact with medications and its long-term safety is unknown. Remember to speak with a doctor before supplementing.