Cannabinoids’ Effects Beyond Cannabinoid Receptors

The human body contains receptors which detect change. Receptors are made up of specialized cells which not only monitor for change but respond to any changes they detect. Receptors are connected to our central nervous system and they help to keep our bodies in balance. There are millions of receptors in the human body, working away all day, every day. Some receptors respond to chemicals in cannabis called cannabinoids, often in similar ways to prescribed medications but in a more natural, healthier and sometimes even more powerful way.

Our bodies make their own chemicals to influence these receptors. This is the main function of our Endocannabinoid System. The ECS is made up of cannabinoid receptors, cannabinoids and enzymes which work together to keep our bodies in balance, alongside other receptors in our bodies. Cannabis affects ECS receptors because cannabis contains cannabinoids, similar to the cannabinoids our bodies produce naturally.

We know that cannabinoids like THC tend to bind to cannabinoid receptors 1 and 2 (CB1 & CB2). Some cannabinoids like CBD, however, do not have an effect on cannabinoid receptors. Instead, CBD has an effect on serotonin receptors, opioid receptors and so on. Here’s more on the molecular targets of the big six cannabinoids (less is known about the other minor cannabinoids), and a description of the receptors cannabinoids effect.

Key to Understanding Some Essential Biological Terms

We’ve tried to make this article as simple as possible but since we’re dealing with complex biological functions, some scientific words had to be included. This key will help you to understand the next part of the article. Our glossary can also help.

Ligand

A substance that forms a complex with a biomolecule to serve a biological purpose.

Agonist

An agonist is a chemical that promotes a biological response by binding to a receptor. A chemical or compound that binds to a receptor partially but not completely is known as “partial agonist”.

Antagonist

The opposite of an agonist. An antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. A chemical or compound that binds to a receptor partially is known as a “partial agonist”.

Inverse Agonist

An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.

Neutral Agonist

A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either by competing at the receptor site.

Allosteric Modulator

An allosteric modulator is like a volume control for a receptor. Allosteric modulators change the way in which a receptor processes a signal. Allosteric modulators do not bind to the main, active site, but a site away from the main receptor. Allosteric modulators can, however, change the way agonists interact with the receptor site.

There are three main types of allosteric modulator: positive, negative and neutral.

Positive allosteric modulators

Turn up the volume and increase agonist efficacy/affinity

Negative allosteric modulators

Turn down the volume and decrease agonist affinity/efficacy

Neutral allosteric modulators

Have no direct effect but can block other allosteric modulators.

Neurotransmitters that bind to the main, active site on a receptor are called “orthosteric modulators”.

Autoreceptor

An autoreceptor forms a part of a negative feedback loop in signal transduction. Autoreceptors help prevent further release of a neurotransmitter.

Some of the Receptors Cannabinoids Effect

Cannabinoid Receptor 1 (CBR1)

Found in the brain and spinal cord. CB1 receptor agonists are responsible for cannabis’s psychoactive effects, as well as increasing hunger or sleepiness.

Cannabinoid Receptor 2 (CBR2)

Found in the immune system, and responsible for inflammatory responses.

G Protein-Coupled Receptor (GPR or CPCR)

GPRs are a large group of evolutionary related proteins that have cell surface receptors that detect molecules outside the cell and activate cellular responses. GPR receptors are responsible for:

• Vision
• Taste
• Smell
• Behavior and mood regulation
• Immune system regulation and inflammatory responses
• Autonomic nervous system (ANS) transmission – responsible for blood pressure, heart rate, and digestive processes
• Detecting, sensing and regulating cell density
• Homeostasis (e.g. water balance)
• The growth and metastasis of some types of tumors
• Cellular responses and the building of some types of proteins

GPR6, GPR18 and GPR55 are considered by some to be endocannabinoid receptors, and are referred to as CB3 receptors by some.

Serotonin Receptor (5HT)

There are 15 types of serotonin receptor.

5-HT1A

• Addiction
• Aggression
• Anxiety
• Appetite
• Autoreceptor
• Blood Pressure
• Cardiovascular Function
• Emesis (vomiting)
• Heart Rate
• Impulsivity
• Memory
• Mood
• Nausea
• Nociception (pain detection)
• Penile Erection
• Pupil Dilation
• Respiration
• Sexual Behavior
• Sleep
• Sociability
• Thermoregulation (regulation of internal body temperature)
• Vasoconstriction (narrowing of blood vessels)

5-HT1B

• Addiction
• Aggression
• Anxiety
• Autoreceptor
• Learning
• Locomotion
• Memory
• Mood
• Penile Erection
• Sexual Behavior
• Vasoconstriction

5-HT1D

• Anxiety
• Autoreceptor
• Locomotion
• Vasoconstriction

5-HT1E

• Cannabinoids’ effect in this subtype of serotonin receptor is unknown.

5-HT1F

• Headache/Migraine

5-HT2A

• Addiction (potentially modulating)
• Anxiety
• Appetite
• Cognition
• Imagination
• Learning
• Memory
• Mood
• Perception
• Sexual Behavior
• Sleep
• Thermoregulation
• Vasoconstriction

5-HT2B

• Anxiety
• Appetite
• Cardiovascular Function
• GI Motility
• Sleep
• Vasoconstriction

5-HT2C

• Addiction. (potentially modulating)
• Anxiety
• Appetite
• GI Motility
• Heteroreceptor for norepinephrine and dopamine
• Locomotion
• Mood[
• Penile Erection
• Sexual Behavior
• Sleep
• Thermoregulation
• Vasoconstriction

5-HT3

• Addiction
• Anxiety
• Emesis
• GI Motility
• Learning
• Memory
• Nausea

5-HT4

• Anxiety
• Appetite
• GI Motility
• Learning
• Memory
• Mood
• Respiration

5-HT5A

• Autoreceptor
• Locomotion
• Sleep

5-HT5B

• 5-HT5B is a pseudogene in humans, meaning it is coded for but has no function that we know of.

5-HT6

• Anxiety
• Cognition
• Learning
• Memory
• Mood

5-HT7

• Anxiety
• Autoreceptor
• Memory
• Mood
• Respiration
• Sleep
• Thermoregulation
• Vasoconstriction

Opioid Receptors

There are five main kinds of opioid receptors: mu, delta, kappa, nociceptin (NOR) and zeta.

Mu

μ1

• Analgesia
• Physical Dependence

μ2

• Respiratory Depression
• Miosis
• Euphoria
• Reduced GI Motility
• Physical Dependence

μ3

• Possible Vasodilation

Delta

• Analgesia
• Antidepressant Effects
• Convulsant Effects
• Physical Dependence
• May modulate μ-opioid receptor-mediated respiratory depression

Kappa

• Analgesia
• Anticonvulsant Effects
• Depression
• Dissociative/Hallucinogenic Effects
• Diuresis
• Miosis
• Neuroprotection
• Sedation
• Stress

NOR

• Anxiety
• Depression
• Appetite
• Development of tolerance to μ-opioid agonists

Zeta

• Tissue Growth
• Embryonic Development
• Regulation of cancer cell proliferation

Dopamine Receptors

Dopamine receptors are implicated in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders, such as ADHD/ADD, schizophrenia and bipolar disorder.

There are 5 types of dopamine receptors: D1, D2, D3, D4 and D5.

Peroxisome Proliferator-Activated Receptor (PPAR)

PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. There are three main types of PPAR.

Alpha, expressed in the liver, kidney, heart, muscle and adipose tissue; beta/delta, expressed mainly in the brain, adipose tissue and skin; and gamma, of which there are three subtypes expressed in the heart, kidney, muscle, colon, pancreas, spleen, adipose tissue, macrophages (type of white blood cell), white adipose tissue and large intestine.

Glycine Receptor (GlyR)

Glycine is one of the most widely distributed inhibitory receptors in the central nervous system (CNS). Glycine has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brainstem.

Transient Receptor Potential (TRP) Channels

There are about 30 TRP channels that share some structural similarity to each other, but there are two broad groups. Group 1 includes TRPC ( “C” for canonical), TRPV (“V” for vanilloid), TRPM (“M” for melastatin), TRPN (“N” for no mechanoreceptor potential C) , and TRPA (“A” for ankyrin). In group 2, there are TRPP (“P” for polycystic) and TRPML (“ML” for mucolipin).

TRP channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. Some TRP channels are thought to behave like microscopic internal thermometers in animals that can sense hot or cold.

Norepinephrine

The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine is responsible for the flight or fight effect. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger.

Norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety.

Delta-9 Tetrahydrocannabinol (delta-9 THC)

• CB1 – Partial Agonist
• CB2 – Partial Agonist
• G Protein-Coupled Receptor 55 (GPR55) – Agonist; Lysophosphatidylinositol (LPI, lysoPI) Inhibitor
• GPR18 – Agonist
• 5HT3A – Antagonist
• Mu- and Delta- Opioid Receptors – Allosteric Modulator
• Peroxisome Proliferator-Activated Receptor-Gamma (PPARγ) – Agonist
• Glycine Receptor (GlyR) – Positive Allosteric Modulator at GlyR alpha-1 and alpha-3 receptors
• Transient Receptor Potential (TRP) Channels – TRPV 2, 3, 4 Agonist; TRPM8 Antagonist; TRPA1 Agonist
• Dopamine Receptor (D2) – Agonist
• Norepinephrine Receptor – Agonist

Delta-8 THC

• CB1 – Partial Agonist
• CB2 – Partial Agonist

Cannabinol (CBN)

• CB1 – Agonist
• CB2 – Agonist; Inverse Agonist
• TRP Channels – TRPA1 Agonist; TRPM8 Antagonist

Cannabidiol (CBD)

• CB1 – Antagonist; negative allosteric modulator
• CB2 – Antagonist
• Anandamide Uptake – Inhibitor
• GPR55 – Antagonist
• GPR18 – Antagonist
• GPR6 – Inverse Agonist
• 5-HT1A – Agonist
• 5-HT2A – Partial Agonist
• 5-HT3A – Antagonist
• Adrenergic-1A Receptor (A1A) – Agonist
• Mu- and Delta Opioid Receptors – Allosteric Modulator
• PPARγ – Agonist
• GlyR – GlyR alpha- 1 and 3 positive allosteric modulators
• GABAA – Positive Allosteric Modulator
• TRP Channels – TRPV1, 2 Agonist; TRPM8 Antagonist; TRPA1 Agonist
• Dopamine Receptor, D2 – Partial Agonist

Cannabichromene (CBC)

• CB1 Receptor – Agonist
• CB2 Receptor – Agonist
• Anandamide Uptake – Inhibitor
• TRP Channels – TRPV3, 4 Agonist; TRPM8 Antagonist; TRPA1 Agonist

Cannabigerol (CBG)

• CB1 – Partial Agonist
• CB2 – Partial Agonist
• Anandamide Uptake – Inhibitor
• GPR55 – LPI Inhibitor
• 5-HT1A – Antagonist
• Alpha-2 Adrenergic Receptor – Agonist

Delta-9 Tetrahydrocannabivarin (delta-9 THCV)

• CB1 Receptor – Antagonist
• CB2 Receptor – Partial Agonist
• GPR55 – Partial Agonist; LPI Inhibitor
• 5HT1A – Agonist
• TRP Channels – TRPV2 Agonist; TRPM8 Antagonist; TRPA1 Agonist

Cannabidivarin (CBDV)

• GPR55 – LPI Inhibitor
• TRP Channels – TRPV1, 2, 3 Agonist; TRPA1 Agonist