Serotonin 2A receptor variants: psychedelics, brain aging, and Alzheimer’s disease

What do Alzheimer’s disease and LSD have in common?

The serotonin 2A receptor…

Clinical trials are underway for using low-dose LSD or psilocybin, two psychedelic drugs that bind to the serotonin 2A receptor, to treat Alzheimer’s disease.

This article digs into the current research on the serotonin 2A receptor, psychedelics, and genetic variants — with a focus on brain aging and dementia.

Serotonin and the Serotonin 2A Receptor

Serotonin is a neurotransmitter created from the amino acid tryptophan. Most of the body’s serotonin is found in the intestines, where it acts as a neurotransmitter controlling intestinal peristalsis.

In the brain, serotonin helps to transmit signals between neurons. It is involved in learning, mood, memory, and emotions. Only about 1 – 2% of the body’s serotonin is found in the brain.[ref]

Serotonin cannot cross the blood-brain barrier, so it has to be synthesized in the brain from tryptophan. The body tightly regulates serotonin levels and it breaks down in the brain by the MAO (monoamine oxidase) enzyme. MAO inhibitors are a class of anti-depressant medications.

Recent research also elucidates the role of serotonin in immune function.[ref] This ties in with the role of serotonin in mood disorders as well as the role of inflammation in aging and dementia. (Read more about inflammation, genetics, anxiety, and depression.)

Serotonin Receptors

For serotonin to send a signal between neurons, the end of one neuron releases it to bind to a serotonin receptor of the next neuron. Activating the receptor then causes an action to occur in the next neuron.

Serotonin is produced and released in the axon terminal of a neuron. The neighboring neuron’s dendrites contain serotonin receptors to receive the serotonin.

Serotonin is present in all animals and acts as either a hormone or a neurotransmitter.

There are seven different families of receptors for serotonin in the human body, causing different actions to occur via binding to serotonin. The receptors are known as 5-HT or 5-hydroxytryptamine receptors.

The serotonin 2A receptor (5-HT2A) is found throughout the body, including in the brain. It is important in regulating memory, mood, cognition, appetite, anxiety, perception, sleep, thermoregulation, and vasoconstriction.

When activated, the effect of the serotonin 2A receptor is to increase the excitability of the neuron. The activation of this receptor causes:

  • In neurons that are excitatory, activation of the serotonin 2A receptor causes the neuron to increase firing.
  • In neurons that are inhibitory, such as GABAergic neurons, activation of the serotonin 2A receptor results in inhibiting neighboring neurons.
  • Some neurons have more than one type of serotonin receptor, with different effects.

In other words, this isn’t a straight forward equation of serotonin 2A = excitation in the brain.[ref]

So why do we care about serotonin 2A? It causes some unique effects in the brain, which could be important for mood, cognition, and preventing dementia.

Psychoactive chemicals and serotonin 2A

Humans have been using psychoactive chemicals in various forms throughout history. From Native Americans using peyote (mescaline) to Mazatec priests using psilocybin mushrooms, many historical uses of natural psychedelics have been recorded.

While serotonin is the naturally produced ligand that binds to the serotonin 2A receptor, certain drugs and natural substances also can bind to this receptor, causing interesting effects.

Drugs that bind to the serotonin 2A receptor include LSD (lysergic diethylamide), mescaline, DMT, and psilocybin.[ref]

Hallucinogens at higher levels cause altered states of consciousness – change in mood, perception, and thinking. Animal experiments show that binding with the serotonin 2A receptor, also known as the 5-HT2A receptor, is necessary for the hallucinogenic effects of certain drugs.

Interestingly, there are a few drugs that bind to the serotonin 2A receptor that do not cause hallucinations or altered cognitive states. These include lisuride (Parkinson’s medication) and ergotamine (migraine med).[ref] It seems to depend on how strongly different parts of the receptor are activated. Ergotamine is derived from ergot, which is a fungal growth on rye plants that can cause hallucinations.

What else does the serotonin 2A receptor impact?

To determine the function of the receptor, researchers use low doses of LSD as a serotonin 2A receptor agonist (something that binds to and activates the receptor). In comparison, many studies also use a placebo control group as well as a drug that inactivates the serotonin 2A receptor. This allows the investigators to determine the exact effect on the serotonin 2A receptor.

  • Social cognition: Another study shows the serotonin 2A receptor’s importance in social cognition and the sense of self in relation to others.[ref]
  • Adaptation to a group: A 2020 study shows the serotonin 2A receptor increases “social adaptation but only if the opinions of others are similar to the individual’s own.”[ref]
  • Relevance of stimuli: Researchers found that the serotonin 2A receptor alters the way people find meaning from stimuli.[ref]
  • Active coping: Researchers theorize that the serotonin 2A receptor is important for brain plasticity and the ability to actively cope with a stressor.[ref]
  • Music: A recent study investigated the role of the serotonin 2A receptor in people who were listening to music. The researchers found that the serotonin 2A receptor is critical in a person’s response to music such as the emotions, connections, and meaningfulness of the music.[ref]

The laws on testing psychedelics have just been changed in the past couple of years, allowing research on their efficacy in treating mood disorders. Prior to this, laws put into place in the 1970s during the ‘war on drugs’ in the US kept these compounds from being available for research.

The Aging Brain: why psychedelics and the serotonin 2A receptor may be important

Studies over the last decade have investigated the effects of serotonin 2A receptor agonists for depression and anxiety. Specifically, researchers have found:

  • one high, single dose of psilocybin produced a large decrease in depression and anxiety in cancer patients[ref]
  • various doses of LSD along with psychotherapy decrease anxiety in people with life-threatening illnesses[ref]
  • in a small trial, a single dose of ayahuasca alleviated depression in patients with recurrent depression[ref]

As we age, the number of serotonin 2A receptors in the brain decrease significantly.[ref]

Importantly, these receptors are located in the part of the brain impacted by dementia including the prefrontal cortex and the hippocampus.[ref]

The plasticity of the brain is the ability of the brain to change and grow.

Psilocybin and LSD increase neurogenesis – the growth of neurons – and induce brain plasticity.[ref]

Importantly, psychedelics can increase brain plasticity at very low doses (microdoses) which do not impair functioning or cause hallucinations.[ref]

Additionally, safety studies on microdoses of LSD and of ayahuasca show no detrimental side effects.[ref][ref] Most of the studies are rather small, though, so larger and more rigorous studies are needed here.

Alzheimer’s and serotonin 2A receptors:

Alzheimer’s disease remains the primary cause of dementia and affects about 10% of people over the age of 65. This creates a huge economic burden, as well as greatly impacting family members who act as caregivers. While mortality rates for stroke, heart disease, and certain cancers are decreasing, the number of deaths for Alzheimer’s increased by 71% between 2000 and 2013.[ref] Current numbers are even worse.

In Alzheimer’s patients, the expression of the serotonin 2A receptors is significantly decreased in the brain when compared to people their age without cognitive dysfunction. One study estimated a 33% decrease in receptor expression, which is a large change compared to age-matched controls. Other studies show the reduction in serotonin 2A receptors occurs early in Alzheimer’s when cognitive dysfunction is mild.[ref][ref][ref][ref][ref]

Research shows reduced serotonin in the cortex of people who had psychosis with Alzheimer’s disease (postmortem study).

The study also shows a genetic variant in the serotonin 2A receptor gene has associations with an increased risk of psychosis in Alzheimer’s disease. Psychosis in Alzheimer’s may not be entirely genetic, though. In addition to the serotonin 2A receptor variants, it is likely that psychosis in Alzheimer’s also involves environmental factors such as medication side-effects, angry caregivers, or stressful changes.[ref][ref]

Additionally, MAO-A levels are also decreased in Alzheimer’s. MAO-A (monoamine oxidase) is the enzyme that breaks down serotonin, regulating the amount of serotonin available.[ref]

I mentioned above that serotonin also impacts the immune system, which is integral to the formation of amyloid-beta plaque in the brain (increased in Alzheimer’s patients). Along with elevated cytokines such as TNF-alpha, the reduction of serotonin has shown to impact the formation of amyloid-beta plaques as well as increasing depression in Alzheimer’s patients.[ref][ref][ref]

Will increasing serotonin help to reverse Alzheimer’s?  Probably not.

While animal studies on SSRIs were initially exciting, SSRI studies for Alzheimer’s patients show mixed results. SSRI’s increase the amount of time that serotonin hangs out in the synapses of the neurons, but it doesn’t seem to reverse or stop Alzheimer’s pathology in humans, at least in the short term.[ref][ref][ref][ref]

On the other hand, long-term prior use of SSRI’s for depression may delay the progression of Alzheimer’s dementia.[ref][ref] While most of the antidepressant effects of SSRIs are thought to come from the serotonin 1A receptor, recent genetic studies point to a role of the serotonin 2A receptor in long-term effects of SSRIs.[ref]

So why would a serotonin 2A agonist, such as LSD, reduce Alzheimer’s pathology?  Increasing the amount of time that serotonin hangs out in the synapse in the brain doesn’t necessarily increase the serotonin 2A receptors in the aging brain.

On the other hand, psychedelic drugs increase the outgrowths of the serotonergic neurons, thus increasing the number of serotonin 2A receptors.[ref]

Increasing neurogenesis, plasticity, and brain connectedness – rather than a focus on serotonin – seems to be the key here.[ref][ref]

Activating the serotonin 2A receptor also increases mitochondria biogenesis (formation of new mitochondria).[ref] Alzheimer’s disease is also linked to decreased mitochondrial function in the brain.

Repeated microdoses of LSD are in clinical trials in older adults to determine safety and efficacy for Alzheimer’s prevention. Initial, phase I clinical trial results show that low doses of LSD are well tolerated without adverse events.[ref]


Genetic variants:

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HTR2A gene: encodes the serotonin 2A receptor

Check your genetic data for rs6313 T102C (23andMe v4, v5; AncestryDNA):

  • A/A: typical risk
  • A/G: increased risk of Alzheimer’s in people without the APOE E4 allele; increased risk of psychosis in Alzheimer’s disease
  • G/G: increased risk of Alzheimer’s in people without the APOE E4 allele[ref]; increased risk of psychosis in Alzheimer’s disease[ref][ref][ref] possible interaction with citalopram (Celexa) and agitation in Alzheimer’s[ref] Alzheimer’s patients more likely to respond to antipsychotics[ref]

Members: Your genotype for rs6313 is .

This is a really well studied genetic variant. Other studies on rs6313 (unrelated to Alzheimer’s/brain aging) show:

  • Increased risk of sexual dysfunction with citalopram (SSRI) for A allele carriers.[ref]
  • Moderate interaction with response to MDMA.[ref]
  • Increased suicide risk in people with the G/G genotype and stressful life events.[ref]

Check your genetic data for rs6314 C1354T or His452Tyr (23andMe v4, v5; AncestryDNA):

  • A/A: for everyone: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal, diminished hippocampal response to novel stimuli[ref][ref][ref];
    specifically for Alzheimer’s patients: poorer memory performance and decreased recognition task scores[ref]
  • A/G: reduced serotonin 2A receptors in the prefrontal cortex, increased risk of social withdrawal, diminished hippocampal response to novel stimuli
  • G/G: typical

Members: Your genotype for rs6314 is .

Other studies on rs6314 (unrelated to Alzheimer’s/brain aging) show:

  • Much better paroxetine (Paxil) therapy response in people with A/A or A/G (>7-fold increase in the odds that Paxil will work).[ref]
  • An association between the rs6314 A allele and susceptibility towards food reinforcement.[ref]
  • A study found  those with the A/A or A/G genotypes may not improve as much on olanzapine (an antipsychotic).[ref]

 

MAO-A variants:

The MAOA gene encodes the monoamine oxidase enzyme, which breaks down serotonin, tyramine, dopamine, epinephrine, and norepinephrine. In conjunction with certain psychedelics such as ayahuasca, substances inhibiting MAO-A are often consumed. Additionally, some mushrooms containing psilocybin also contain natural MAO-A inhibitors.

A common genetic variant in MAOA causes a decrease in the amount of MAOA produced. The MAOA gene is found on the X chromosome, so males only have one copy of the gene.  You may be wondering about the effects of inhibiting MAOA with psychedelics in a person that already has impaired MAOA enzyme function…While it seems like this could be a bad combination, I can’t find any research on this yet.

(Read about the cheese effect – genes involved in breaking down tyramine)

Check your genetic data for rs6323 (23andMe v4 only):

  • G/G or G: typical
  • G/T: somewhat reduced MAOA activity
  • T/T or T (males): reduced MAOA activity[ref][ref]

Members: Your genotype for rs6323 is .

 

If you want to know more about your genetic risk of Alzheimer’s disease, you can check your APOE type.


Lifehacks:

Please note that I’m not advocating that you microdose LSD, psilocybin, or do anything illegal. The information on the research studies is presented for informational purposes, and it truly is preliminary.

A lot more research needs to be done on this topic before psychedelics can be used for Alzheimer’s, but how exciting to see this avenue of research being pursued. John’s Hopkins University is currently conducting clinical trials using psilocybin in Alzheimer’s patients.[ref]

So what can you do to alter serotonin and the serotonin 2A receptors in the brain if you live in a place where psychedelics are illegal?

Tryptophan is the precursor amino acid for serotonin. It can cross the blood-brain barrier (unlike serotonin). While not a cure for Alzheimer’s, having sufficient tryptophan available for serotonin and melatonin production is part of overall brain health. Does everyone need to supplement with tryptophan? Probably not. Tryptophan is abundant in diets that contain enough protein. But if you think you are lacking tryptophan, it is readily available as a supplement.

Keep an eye on the current research and studies coming out on this topic. Many times, research and clinical trials will show efficacy for years (decades!) before a treatment is widely accepted.

Talk with your doctor about your options if you are experiencing the first stages of memory loss. While there isn’t yet an approved medication for reversing cognitive decline, there are current medications that slow the progress of Alzheimer’s.

Finally, here is a video interview of researcher discussing the mechanism of psychedelics for Alzheimer’s:

 


Related Articles and Genes:

Lithium Orotate: Mood, Alzheimer’s Prevention, and Telomeres
Lithium is a naturally occurring mineral that we consume in small amounts each day. Research now shows that low doses of lithium may impact mood, Alzheimer’s disease, and telomere length.

Serotonin: How your genes affect this neurotransmitter
Serotonin… a word that brings to mind a commercial that might show our happy brain neurons bouncing serotonin between them. There is a lot more to this molecule than most of us realize! This article covers how the body makes and transports serotonin and the needed receptors to complete its pathway.

Boosting NAD+ levels to fight the diseases of aging
Explore the research about how nicotinamide riboside (NR) and NMN are being used to reverse aging. Learn about how your genes naturally affect your NAD+ levels, and how this interacts with the aging process.

 

 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.