rs5443

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

Activation of 5HT2A receptors can contribute to many problems, including anxiety, depression, fatigue, OCD, sleep problems, etc. However, some good effects include lowered heart rate and blood pressure and reduced inflammatory effects.

Negative effects:

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-HT1A, 5-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.

Benefits

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 brainstem, 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).

A haplotype consisting of 4 SNPs in the HTR2A gene has been associated with risk for rheumatoid arthritis [PMID 18006541]; the 4 SNPs being:

• rs6311
• rs6313
• rs1328674
• rs6314

A SNP in the HTR2A gene, rs7997012 and another gene (GRIK4) may also influence the odds of success upon treatment with the antidepressant citalopram, potentially differently in patients of different ethnic backgrounds.[PMID 17671280]

Activation of 5HT2A receptors can contribute to many problems, including anxiety, depression, fatigue, OCD, sleep problems, etc. However, some good effects include lowered heart rate and blood pressure and reduced inflammatory effects.

• Inositol – reduces 5HT2A receptor function (R),
• Meditation,
• Zinc (R),
• 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.  

Magnesium can help with calcium release. 5-HT2A has sialic acid in it, which is bound to by lectins.  Lectins probably modify the receptor in some negative way in people who are susceptible.

• SSRIs,
• Sialic Acid?
• MDMA (R) -in recent MDMA users, post-synaptic 5-HT(2A) receptor densities were significantly lower in all cortical areas studied,

Lithium inhibits GSK3b (R), which can help regulate this gene, but it also decreases brain inositol (R). Some studies show St Johns Wort decreases 5HT2A receptors (R).

Other studies report a 50-percent increase in 5-HT2A receptors after six months of use of St. Johns Wort so it looks like to benefit is limited in time.(R).  

• Olanzapine (R)
• Sarpogrelate (R R)
• Aripiprazole (R)
• N,N-Dimethyltryptamine (R)
• Paliperidone Palmitate (R)
• Ritanserin (R)
• Tryptamine (R)
• Ziprasidone (R)
• Cyproheptadine (R)
• Spiperone (R)
• Norclozapine (R)
• Lithium Chloride
• (+)-JQ1 compound (R)
• Perphenazine GABA ester (R)
• Quetiapine Fumarate (R)
  

• Risperidone (R)
• Progesterone (R)
• Palmitic Acid (R)

Non human studies:

• Dopamine (R) ,(R), (R)
• Calcium (R) , (R) , (R)
• Cypermethrin (R) , (R)
• Estradiol 3-benzoate (R)
• Chlorpyrifos (R)
• Zalcitabine (R)
• Diazinon (R)
• Freund’s Adjuvant (R)
• Nanotubes, Carbon (R)
• Nitrofen (R)
• Ozone (R)
• Nicotine (R)
• Dietary Fats (R)
• Yohimbine (R)
• Dexamethasone (R)
• PCB 180 (R)
• Propylthiouracil (R)
  

Non human studies:

• Ketanserin (R)
• Corticosterone  (R)
• Tramadol  (R)
• Phencyclidine  (R)
• Tobacco Smoke Pollution (R)
• Pertussis Toxin (R)
• Iodopravadoline (R)
• Colforsin  (R)
• Streptozocin  (R)