Classical psychedelics—LSD, psilocybin, mescaline, and DMT—are a group of powerful mind-altering drugs. They work by activating your brain’s 5HT2A receptors—a special network of serotonin receptors that can influence your mood, visual perception, and sense of self, among other things.
5HT2A receptors are behind many of psychedelics’ best-known effects, including hallucinations and mystical experiences. Recent research suggests that 5HT2A receptors may also be the reason psychedelics show promise as a breakthrough therapy for treatment-resistant depression.
Here’s a look at what 5HT2A receptors do in your brain, and how psychedelics activate them to change the way you experience the world.
What are 5HT2A Receptors and What Do They Do?
Your brain is made up of billions of brain cells, all of which are connected to one another through sprawling networks. Those networks communicate using neurotransmitters—chemicals that send messages across your brain, driving your thoughts and behavior.
Serotonin is one of your primary neurotransmitters. It controls brain pathways that influence your mood, vision, memory, attention, and sense of self, among other things. 1
There are several types of serotonin receptors in your brain. Each type controls different aspects of your brain function and behavior. Psychedelics bind to one specific variety: the 5HT2A receptor.
Your 5HT2A receptors have a particular influence over your senses (vision, hearing, smell, and so on), as well as memory, attention, and higher-level abstract thinking.
That makes sense when you consider what psychedelics do:
- Cause sensory hallucinations (especially visual and auditory ones)
- Alter your attention processes so that you notice things you normally wouldn’t
- Shift your abstract thinking, allowing you to explore ideas and your sense of self in new ways
Where Are 5HT2A Receptors Located?
- Prefrontal cortex. The prefrontal cortex is the most recently evolved part of your brain and the part that sets humans apart from other animals. Your prefrontal cortex governs planning, consciousness, self-aware thought, and abstract thinking.
- Parietal cortex. One of the main sensory areas of your brain. The parietal cortex organizes sensory information from touch, vision, and spatial sense and navigation.
- Somatosensory cortex. The somatosensory cortex is the main area of your brain that controls your perception of touch and of your body moving through space. It is closely connected to your parietal cortex.
- Olfactory tubercle. The olfactory tubercle is a tiny part of your brain just behind your ear that processes sensory information. The olfactory tubercle also influences your attention and physical movement, especially in the context of social interactions.
How Do Psychedelics Work on 5HT2A Receptors?
Psychedelics exert most of their mind-altering effects through 5HT2A receptors.
Psychedelics are 5HT2A agonists, which means they increase serotonin activity in your brain. They work by binding directly to 5HT2A receptors like a key fits into a lock, mimicking serotonin and tricking your brain into strongly activating serotonin pathways. 4
When real serotonin reaches your serotonin receptors, it binds to them and briefly activates them, sending a quick impulse. Most hallucinogens are different. They lock into the receptor for a long time—multiple hours, in the case of LSD and psilocybin—and continuously activate it at a high level, causing intense changes to your consciousness.
5HT2A receptors also trigger a domino effect when you take psychedelics, causing your brain to release glutamate, another neurotransmitter. Glutamate powers down your default mode network, which can lead to ego death (loss of sense of self, a feeling of being one with everything around you). 5
Can you get the therapeutic benefits of psychedelics without hallucinations?
Researchers have found that if you block 5HT2A receptors and then give someone a psychedelic, that person won’t experience hallucinations—implying that 5HT2A receptor activation is what causes you to hallucinate when you take a psychedelic. 4
Other research suggests that 5HT2A receptors are also responsible for the mental health benefits of psychedelics.
Psilocybin, the active compound in psychedelic mushrooms, was recently granted Breakthrough Therapy status by the FDA for treating major depression, as well as treatment-resistant depression. 6 Studies have found that 5HT2A receptor activation is the reason psilocybin helps relieve depression. 7
Now researchers are looking into making drugs that provide the therapeutic benefits of psychedelics, without the hallucinations.
Psychedelics bind to 5HT2A receptors through biased agonism, which means that they only turn on part of the receptor’s full response.
4,8Researchers believe that they may be able to create replica drugs based on psychedelics that bind slightly differently and activate a different part of the receptor response, allowing drug producers to pick and choose the effects they want—for example, a drug that provides psilocybin’s antidepressant benefits without hallucinations.
However, this research is still in its infancy. For now, the only way to get the benefits of psychedelics is to take the psychedelics themselves—hallucinations and all.
Effects of Activating 5HT2A Receptors
- Visual and auditory hallucinations
- Out-of-body experiences
- Enhanced color perception
- Distorted proprioception (changes how you perceive your body’s location in physical space, which could result in you feeling like the world around you is stretching or shrinking)
- Altered consciousness
- Changes to mood
- Ego death (loss of sense of self, feeling connected to the world around you)
- Increased creativity
- Increased openness
- Antidepressant effects
5HT2A Receptor Frequently Asked Questions
What are 5HT2A receptors?
5HT2A receptors are a type of serotonin receptor. They’re the main target for the psychedelic drugs LSD, psilocybin, DMT, and mescaline. You have 5HT2A receptors all across your brain. They’re involved in a variety of processes, including sensory perception, mood, consciousness, attention, and self-aware thought.
Where are 5HT2A receptors in your brain?
You have 5HT2A receptors across most of your brain. However, they’re especially concentrated in the following brain regions:
- Prefrontal cortex, which governs planning, consciousness, and abstract thinking
- Parietal cortex, which influences sensory input
- Olfactory tubercle, which also affects sensory input, as well as attention and physical movement
Do all psychedelics activate 5HT2A receptors?
All classical psychedelics work by turning on your 5HT2A receptors. Classical psychedelics include LSD, DMT, psilocybin, and mescaline. 5HT2A receptors are less involved in some drugs with psychedelic-like effects, like MDMA and ketamine, which work mainly through other pathways in your brain.
Psychedelics’ most famous effects—hallucinations, ego death, out-of-body experiences, and so on—happen because of 5HT2A receptors. Recent studies suggest that 5HT2A receptors may also be the reason psychedelics seem to be so effective at treating depression.
There are still many things researchers don’t know about how psychedelic drugs affect your brain. What is clear is that 5HT2A receptors have influence over your consciousness—and that activating them with psychedelics can change your perception of both the world and yourself.
2. Aghajanian GK, Marek GJ. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res. 1999;825(1-2):161-171. doi:10.1016/s0006-8993(99)01224-x
3. Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 2005;95(6):1597-1607. doi:10.1111/j.1471-4159.2005.03485.x
5. Mason NL, Kuypers KPC, Müller F, et al. Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology. 2020;45(12):2003-2011. doi:10.1038/s41386-020-0718-8
6. Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285
7. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019;44(7):1328-1334. doi:10.1038/s41386-019-0324-9