Evidence Based
21

5-HT1A: The “Single” & “Self-Transcendent” Receptor?

Written by Puya Yazdi, MD | Last updated:
Nattha Wannissorn
Medically reviewed by
Nattha Wannissorn, PhD | Written by Puya Yazdi, MD | Last updated:

SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source.

We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic.

Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists.

All of our content is written by scientists and people with a strong science background.

Our science team is put through the strictest vetting process in the health industry and we often reject applicants who have written articles for many of the largest health websites that are deemed trustworthy. Our science team must pass long technical science tests, difficult logical reasoning and reading comprehension tests. They are continually monitored by our internal peer-review process and if we see anyone making material science errors, we don't let them write for us again.

Our goal is to not have a single piece of inaccurate information on this website. If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please leave a comment or contact us at [email protected]

Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Serotonin levels strongly influence mood and social behavior. Scientists think that the serotonin 5HT1A receptor is particularly important–it seems to be entangled in the science of romance, dating, happiness, and emotional self-awareness.

Serotonin Science

Beyond Mood

Serotonin is an important signaling molecule best known as the “happiness hormone.”

Scientists describe serotonin as both a hormone and a neurotransmitter. It plays an important role in the brain, where its main job is to transmit messages between nerve cells. According to some scientific theories, serotonin is involved in all aspects of human behavior [1, 2].

However, brain serotonin comprises less than 2% of the total serotonin found in our bodies. Most serotonin (over 90%) is actually made, stored, and released by the gut [1, 3, 4].

Research suggests that serotonin is implicated in all the following processes in the body [4, 1, 3, 5, 2]:

  • Mood and emotions
  • Movement (motor function)
  • Sleep-wake cycle
  • Body temperature
  • Appetite
  • Bowel movements & gut functions
  • Blood clotting
  • Constriction and relaxation of blood vessels
  • Immune responses
  • Bone health
  • Heart function
  • Reproductive function
  • Pain perception

Read more about serotonin in this article.

5HT1A Receptors

Interplay with Other Receptors

When we talk about serotonin-associated disorders, its important to know that these disorders are not necessarily due to serotonin levels or production as such.

They can stem from issues with serotonin reuptake or the availability of certain serotonin receptors. There are over 15 different receptor types discovered to date, including 5-HT1A, 5-HT2A, and 5-HT2C [6, 7, 8].

Autoreceptors vs Postsynaptic Receptors

The 5HT1A receptor is tricky in terms of its action, because its effects depend on where and how it’s activated [9, 10].

For a signal to be sent in the brain, two neurons are involved: one which sends the signal and one which receives it. The first is the presynaptic neuron; the second is the postsynaptic neuron [11, 10].

In serotonin signaling, both the presynaptic and postsynaptic neurons have 5HT1A receptors; the presynaptic receptors are also called autoreceptors since the same signal they release (serotonin) can bounce back to affect them in a sort of self or auto-regulation [11, 10].

Activating the postsynaptic receptors is linked with all the typical serotonin actions, such as anti-anxiety and mood-boosting properties. However, increased autoreceptor activity causes a reduction in serotonin, as this pathway is meant to prevent excessive signaling [10].

That’s why two targets are typically studied: desensitizing the autoreceptors or continuously increasing serotonin [10].

Avoiding Misinterpretation Pitfalls

Limited evidence suggests that the 5HT1A receptor plays a role in depression.

For example, one study found lower 5-HT1A receptor production in certain brain areas (the prefrontal cortex or DLPFC and hippocampus) in people with major depression. A decrease in 5-HT2A receptor production, on the other hand, was associated with bipolar disorder [12].

What can we conclude from this study?
To start with, let’s remember that the role of 5-HT1A receptors in mood disorders and depression is still highly speculative. It might have some influence, but we’re not sure how relevant this is.

Additionally, the above-mentioned study – as well as the majority of studies covered in this article – deal with associations only. In other words, a cause-and-effect relationship hasn’t been established.

Just because depression has been linked with low 5HT1A activity in certain brain areas doesn’t mean that depression is caused by low 5HT1A. Data are lacking to make such claims.

Also, even if a study did find that low 5HT1A activity contributes to depression, this receptor is highly unlikely to be the only cause. Complex disorders like depression always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Too Much of a Good Thing?

As you are probably aware by now, neuroscience is not as simple as basing effects off whether a certain compound – like serotonin – is simply “increased” or “decreased.”

Here’s one famous example: both antidepressants – like buspirone and SSRIs – and the street drug MDMA “increase” levels of serotonin, but their pharmacological effects are completely different. And let’s not forget about psychedelics like LSD, DMT, and psilocybin, perhaps even more famous for activating serotonin receptors in the brain [13, 14].

What we see with serotonin is not an exception in neuroscience, it’s the rule. As another example, let’s take a look at dopamine…

Dopamine seems to be great for increasing motivation and attention. Prescription stimulants can therapeutically target it to help people with ADHD. But too much dopamine is also involved in addiction. Various substances and behaviors (say, gambling) reinforce addiction by hijacking the dopamine system [15].

Plus, let’s not forget that no neurotransmitter acts alone. Monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine affect mood together [16].

An imbalance in serotonin, dopamine, and norepinephrine may play a role in bipolar disorder. It has been proposed that the combined low levels of these 3 neurotransmitters, and not serotonin alone, may contribute to mood disorders [17].

Lastly, excess serotonin may lead to serotonin syndrome, which can be fatal and results from drug interactions. MDMA, LSD, and other synthetic drugs may cause serotonin syndrome [18, 19].

Note: Both psychedelics like LSD and psilocybin as well as MDMA (“ecstasy”) are illegal drugs. They are classified as Schedule I drugs, which means that they have no medical uses and a high potential for abuse and harm. Having possession of these substances can result in criminal prosecution.

The FDA recently approved a trial with a psilocybin-based drug in people with depression under a Breakthrough Therapy Designation. Another trial was approved under the same procedure for MDMA in people with PTSD. However, until the results of these studies are published and carefully reviewed by regulatory bodies, both compounds remain classified as illegal drugs.

Potential Effects of 5HT1A Activation

List of Effects

Scientists are investigating whether 5-HT1A activation can [20]:

  • Stimulate the vagus nerve and reduce fight-or-flight activity [21]
  • Reduce fatigue; a link between CFS and fewer 5HT1A receptors has been suggested but remains unconfirmed [22].
  • Increase sociability, potentially via increasing oxytocin and endorphins based on studies in rats [23]
  • Increase sex drive and arousal [24, 25]
  • Improves some kinds of learning associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release [26]
  • Decrease aggression and impulsivity [27]
  • Soothe nausea [28]
  • Lower body temperature [29]
  • Suppress pain perception [30] and substance P (via 5-HT1A receptors in the dorsal raphe nucleus) based on experiments in rodents [31]. 5HT1A receptors are hypothesized to combine with mu-opioid receptors numb pain [30]. A link between depression, chronic pain, and serotonin dysregulation has been proposed but remains unproven [31].
  • Increase the time it takes to get to REM sleep since 5-HT1A activation increases wakefulness [32]
  • 5HT1A blockade increases erections and reversed the sexual side effects of SSRIs in animals; fluoxetine is an example of an SSRI antidepressant that can cause sexual dysfunction as a side effect [33]
  • Cause pupils to get smaller and constrict (interestingly, the opposite happens in rodents) [34]

Most of these proposed mechanisms are highly experimental and haven’t been confirmed in proper human studies.

Hormonal Balance

5-HT1A receptor activation is hypothesized to induce the secretion of the following hormones [35, 36, 37]:

The Circadian Rhythm

Some scientists believe that 5HT1A receptors have less of a powerful response depending on the time of the day. In rats, peak responses were observed in what would be our daytime while the weakest responses were observed in what would be our nighttime [38].

Other research groups suggest that the 5HT1A receptor might help set the circadian rhythm, though this also remains unconfirmed in humans. In hamsters, 5HT1A activators induce a significant phase advance, which makes the animals wake up earlier under constant light conditions [39].

The 5HT1A activators accelerated the rate of entrainment in hamsters that appeared to shift the circadian rhythm [39].

Another study found 5HT1A activators had an inhibitory effect on Per1 and Per2 mRNA levels in the SCN (which is induced by light). This occurred only during the hamster’s mid-day, but not during the time described as early day or night [40].

Human studies are needed to clarify these links.

5HT1A Genes/SNPs

SNPs

SNPs in the 5HT1A gene:

  1. RS1364043 (5-HT1A) GT
  2. RS6295 (5-HT1A) GG

“Single” and “Self-Transcendent”?

5-HT1A has been nicknamed the “single” receptor thanks to one highly-publicized Chinese study. In this study, researchers found a surprisingly robust link between 5HTR1A variants and relationship status [41].

Young Chinese adults with a ‘GG’ genotype had about a 50% chance of being in a relationship. Even a single copy of the ‘C’ allele resulted in a lower chance of being in a relationship (around 20% chance less likely to be in a relationship). That may not sound like much, but in the world of DNA research, it’s a huge effect for a single SNP to have [41].

More about how 5HT1A might affect romantic relationships in our personalized genetics blog at SelfDecode.

This brings us to the next association: why “self-transcendent”?

One famous PET imaging study suggested a link between 5-HT1A density in certain brain regions (the raphe nuclei, hippocampus, and neocortex) and self-reported tendencies to have spiritual experiences. It was published in 2003 and included 15 healthy men – a small and uniform sample it’s impossible to draw conclusions from [42].

Fast forward to 2018, and the authors of this study failed to replicate their findings on a larger sample. When they examined the same link – 5HT1A receptor density and measures of spirituality – in 50 healthy men, they stumbled upon a lack of correlation [43].

This implies that the speculated “self-transcendence” link simply doesn’t exist, based on the best evidence we have.

Experimental: Factors that May Affect 5HT1A Activity

When to See a Doctor

If your goal is to increase 5HT1A/serotonin to improve your mood-related issues – including those of depression or anxiety – it’s important to talk to your doctor, especially your mood is significantly impacting your daily life.

Your doctor should diagnose and treat the condition causing your symptoms.

Additionally, changes in brain chemistry are not something that people can change on their own with the approaches listed below.

Therefore, you may try the complementary approaches listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

Additional Precautions

Speak with your doctor before taking any supplements. Make sure to 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 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.

Research Limitations

We’re providing a summary of the existing research, which should guide further investigational efforts.

The studies listed below were mostly done in animals and should not be interpreted as supportive of any health benefit in humans.

What Might Decrease 5HT1A Autoreceptors or Increase Postsynaptic Receptors

Supplements

  • CBD is being researched for activating 5HT1A receptors CBD isn’t legal in all countries and states, so be sure to familiarize yourself with the regulations before considering CBD use [44].
  • St John’s Wort increases the number of postsynaptic 5-HT1A (and 5-HT2A) receptors in animals [45].
  • Ashwagandha may sensitize 5-HT1A based on animal experiments [46].
  • Zinc–may have mixed effects but adequate intake supports overall physical and mental health [47, 48].
  • Fish Oil; diets low in Omega-3s seem to decrease 5-HT1A receptors in animals, which reduced the effects of SSRIs like fluoxetine. This hasn’t been explored in humans [49].

Other Pathways

Scientists are investigating whether the following hormones or drugs affect 5HT1A signaling in animals and cells:

  • T3 is being researched for augmenting antidepressants in animals. It is hypothesized to reduce the sensitivity of 5-HT1A (and 5HT1B) auto-receptors in the hypothalamus [50].
  • Estradiol is similarly being studied for accelerating the effects of SSRIs in animals [51].
  • Cortisol. Chronic exposure to cortisol desensitizes 5-HT1A autoreceptors receptors. Excess cortisol and using corticosteroids over the long term has many detrimental health effects [52].
  • Prescription, high-dose lithium theorized to increase 5HT1A postsynaptic sensitivity without affecting autoreceptors. Some researchers think this might, in part, be responsible for its mood-stabilizing action [53].
  • Transcranial Magnetic Stimulation (rTMS) is hypothesized to reduce the sensitivity of postsynaptic 5-HT1A receptors in the hypothalamus. Some researchers think that this may partially underlie its antidepressant mechanism. rTMS is approved for certain forms of treatment-resistant depression in Canada [54, 55].

Hypothesized to Modulate the 5HT1A Receptor

Human data are lacking.

Remember that the factors listed in this section are theoretical or anecdotal. They aren’t backed up by solid research.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

Click here to subscribe

RATE THIS ARTICLE

1 Star2 Stars3 Stars4 Stars5 Stars
(No Ratings Yet)
Loading...

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.