The Connection Between CBD and Psychedelic Receptors in the Body

Key Points:

• Both CBD and LSD molecules interact with the same type of receptor, called 5-HT2A, which is associated with what is known as the “psychedelic experience.”
• Cannabinoid receptors can combine with serotonin receptors to form receptor complexes (so-called dimers) with unique properties not found in their individual components.
• Animal studies show that CB1 combined with 5-HT2A can modulate THC’s effects on pain perception and the cannabinoid’s influence on short-term memory formation.
• Scientists are just beginning to study the therapeutic effects of how THC and CBD interact with serotonin-releasing receptors.

Serotonin: More Than the “Happiness Neurotransmitter”

In scientific circles, serotonin is often called the “happiness and joy neurotransmitter.” However, this description has become somewhat outdated, as serotonin is involved in a wide range of emotional and physiological processes. Serotonin (also known as 5-HT, short for 5-hydroxytryptamine) regulates aggression, hunger, sleep cycles, learning and memory, cognitive processes, and the brain’s reward system. It is found in high concentrations in the human brain and gut, with about 90% of the body’s serotonin located in the intestines, where it regulates muscle contractions. Deficiencies can lead to mental health issues like depression and chronic digestive disorders.

Biochemist Maurice Rapport isolated serotonin and described its chemical structure in the late 1940s. By 1979, scientists discovered that serotonin interacts with two types of receptors, 5-HT1 and 5-HT2 (later renamed 5-HT1A and 5-HT2A). Later, it was found that CBD, a non-psychoactive cannabinoid, can also bind to these same receptors, suggesting a link between CBD’s effects and serotonin activity.

Unlike THC, CBD interacts only indirectly with endocannabinoid receptors CB1 and CB2, but it binds directly to 5-HT1A and 5-HT2A receptors. Notably, 5-HT2A is the receptor targeted by many psychedelics, including LSD and mescaline. However, CBD affects this receptor in a unique way, different from typical psychedelic effects.

Receptor Complexes or Dimers

The first scientific reports confirming CBD’s interaction with 5-HT receptors appeared in 2005. Since then, researchers have begun exploring the previously unknown connection between the endocannabinoid and serotonergic systems. Both serotonin and endogenous cannabinoids like anandamide are crucial for regulating biological systems in many living organisms. Both systems are linked to the family of G-protein-coupled receptors, which are found in the brain and peripheral nervous system and regulate similar processes such as pain, anxiety, nausea, headaches, and body temperature.

G-protein-coupled receptors are complex biochemical mechanisms, and their full function is still not completely understood. Over half of modern pharmaceuticals target these receptors to modulate cell activity and achieve therapeutic effects. It was once thought these receptors worked alone, but research has shown they can form dimer complexes, combining to create new receptors with unique functions. For example, a 2013 Spanish study found that a CB2/5-HT1A dimer in pigs was linked to increased risk of death from vascular constriction due to loss of neuroprotective functions.

Cross-Talk Between Receptors

The serotonergic and endocannabinoid receptor systems constantly interact, modulating each other’s activity. Anandamide, an endocannabinoid produced in the brain, naturally activates 5-HT1A, and CBD from plants can also bind to this receptor. In addition to activators, there are also molecules that block or suppress these receptors. For example, cannabidiolic acid (CBDA), a precursor to CBD, is used to suppress nausea during chemotherapy by activating 5-HT1A.

When CBD interacts with 5-HT1A, it sends signals throughout the body that lower blood pressure, reduce body temperature and heart rate, and significantly decrease pain. A 2013 study in the British Journal of Pharmacology reported that CBD’s interaction with serotonergic receptors reduced pain, stress, and improved liver healing in animal models.

CB1 receptors, directly activated by THC, are the most common G-protein-coupled receptors in the human nervous system, especially in the brain’s raphe nuclei and occipital lobe, where serotonergic receptors modulate emotional states. Animal studies show that stimulating neurons in this brain region can alleviate depression and anxiety, while suppressing them increases the risk of depressive disorders. Genetically modified mice lacking CB1 in this area are more likely to develop depression and anxiety than normal mice.

In 2006, Dr. Matthew Hill suggested that constant activation of 5-HT1A could disrupt its normal function, reducing the effectiveness of cannabinoids in regulating pain, inflammation, thermoregulation, metabolism, and memory. This was later confirmed by further mouse studies.

5-HT1A: The “Trip Generator” and Memory Forgetting Mechanism

CBD interacts with both 5-HT1A and 5-HT2A receptors. While CBD acts as an activator and signal enhancer for 5-HT1A, it serves as a suppressor for 5-HT2A. Recent research links 5-HT2A to various biological phenomena, from headaches to personality disorders and hallucinations. 5-HT2A binds even more strongly to psychedelics and hallucinogens than 5-HT1A.

Some users report that consuming large amounts of potent cannabis extracts can cause hallucinations similar to low doses of LSD. According to Dr. Ethan Russo, a leading U.S. cannabis medicine expert, THC affects 5-HT2A, producing such effects, while CBD acts as a receptor blocker, reducing hallucinations. Unlike CBD, THC cannot directly affect 5-HT2A but does so indirectly via CB1 activation. A 2015 study in PLoS Biology confirmed that CB1/5-HT2A dimers may be linked to THC’s psychedelic effects, providing unique pain relief and promoting the breakdown of short-term memories. Another study in Molecular Neurobiology found that increased numbers of these combined receptors are associated with frequent cannabis use.

While high doses of cannabis can impair short-term memory—a common side effect—this property could be beneficial, for example, as an alternative therapy for post-traumatic stress disorder (PTSD). Some experts also believe that interaction with serotonergic receptors may help cannabinoids enhance nervous tissue recovery and counteract the negative effects of fatigue and stress on cognitive abilities, though this hypothesis remains unproven.

5-HT3A, CBD, and THC

The 5-HT family also includes the 5-HT3A receptor, which differs from its relatives because it is not a G-protein-coupled receptor but an ion channel that regulates cell membrane permeability to electrical impulses. 5-HT3A is found at the ends of both central and peripheral nerve cells. Dysfunction of this receptor is linked to several diseases and mental disorders, and it plays a role in pain regulation. Blocking 5-HT3A suppresses nausea and vomiting.

Unlike other 5-HT receptors, 5-HT3A does not interact with CBD or THC, as these substances deform its structure and suppress its ability to bind serotonin. This is thought to be how phytocannabinoids and anandamide suppress pain and nausea signals related to this receptor.