Cannabis plants contain atleast 65 different, naturally occurring, active compounds called Cannabinoids. Cannabinoids, also known as phytocannabinoids, are concentrated in a sticky resin produced in the protruding structures on the surface of the plant known as glandular trichomes. Cannabidiol (CBD) is the most medicinal cannabinoid found in hemp cannabis.
Unlike Tetrahydrocannabinol (THC), the most well known cannabinoid, CBD does NOT get you "high" like smoking marijuana would. Cannabidiol (CBD) is a non-intoxicating compound, which means it does not cause psychedelic or disorienting effects. Since CBD does not cause intoxication, it is very useful for treating ailments & diseases, without having to worry about feeling dysphoric or lethargic.
Unlike Tetrahydrocannabinol (THC), the most well known cannabinoid, CBD does NOT get you "high" like smoking marijuana would. Cannabidiol (CBD) is a non-intoxicating compound, which means it does not cause psychedelic or disorienting effects. Since CBD does not cause intoxication, it is very useful for treating ailments & diseases, without having to worry about feeling dysphoric or lethargic.
Cannabidiol (CBD) slightly binds to the main cannabinoid receptors (CB1 & CB2), but mainly functions by modulating several non-cannabinoid receptors and ion channels. CBD boosts the levels of naturally produced neurotransmitters (endocannabinoids), but also acts on receptor-independent pathways by enhancing or inhibiting the binding actions of certain G-protein-coupled receptors (GPCRs).
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and our bodies. These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars, and proteins.
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and our bodies. These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars, and proteins.
What Receptors Does CBD Act on or Effect?
CBD has a complex pharmacology, affecting several receptors in the central nervous system, including GPR55, TRPV1, and 5-HT1A. The main function of CBD is boosting the levels of endocannabinoids (neurotransmitters) that activate receptors naturally, but also inhibits and modifies various other non-cannabinoid receptors.
Direct Site Activations
GPR55 receptor
Located all over the brain, especially in the cerebellum, the GPR55 is involved in modulating blood pressure and bone cell function, among other physiological processes.
CBD is an antagonist of the GPCR 55 (GPR55), which is modulated by phyto- and endo-cannabinoids as well as L-α-lysophosphatidylinositol (LPI), its primary nuerotransmitter. GPR55 has been associated with cancer, obesity, diabetes as well as inflammatory and neuropathic pain. This receptor appears to be a promising target for the treatment of epileptic disorders because epilepsy causes a disruption in these receptors. This means CBDs effects on dysfunctional GPR55 signaling is associated with its anticonvulsant effects.
Benefits of GPR55 inhibition:
CBD is an antagonist of the GPCR 55 (GPR55), which is modulated by phyto- and endo-cannabinoids as well as L-α-lysophosphatidylinositol (LPI), its primary nuerotransmitter. GPR55 has been associated with cancer, obesity, diabetes as well as inflammatory and neuropathic pain. This receptor appears to be a promising target for the treatment of epileptic disorders because epilepsy causes a disruption in these receptors. This means CBDs effects on dysfunctional GPR55 signaling is associated with its anticonvulsant effects.
Benefits of GPR55 inhibition:
- GPR55 promotes osteoclast cell function, which facilitates bone resorption
- Overactive GPR55 receptor signaling is linked to osteoporosis
- Decreaeses cancer cell proliferation
Vanilloid Receptors (TRPV1)
a.k.a. transient receptor potential cation channel subfamily V.
Named after the Vanilla Bean which contains eugenol, an essential oil that has antiseptic and painkilling properties. Traditionally, the vanilla bean has been used for headaches and blood clots.
The TRPV1 receptor is one of the several ion channels that Cannabidiol (CBD) binds to. TRPV1 is a non-selective cation channel that may be activated by a wide variety of exogenous (external) and endogenous (internal) physical and chemical stimuli. Its main functions include mediating pain perception, inflammation, and body temperature.
As CBD binds to TRPV1 receptors, like capsaicin, it leads to desensitisation of TRPV1 receptors, in which the previously excited neurons no longer respond to painful stimuli thus relieving pain. The TRPV1 is another important site that the endocannabinoid anandamide acts on. CBD being a full, although weak, agonist of the TRPV1 could activate cannabinoid receptors indirectly too, by increasing the amount of anandamide in the blood for a longer period of time. Conditions, such as neuropathy and rheumatoid arthritis, in which TRPV1 receptor sensitivity and expression are increased, can be treated with CBD, making it a useful alternative in the treatment of chronic pain.
Other well known activators of the TRPV1 receptor:
Named after the Vanilla Bean which contains eugenol, an essential oil that has antiseptic and painkilling properties. Traditionally, the vanilla bean has been used for headaches and blood clots.
The TRPV1 receptor is one of the several ion channels that Cannabidiol (CBD) binds to. TRPV1 is a non-selective cation channel that may be activated by a wide variety of exogenous (external) and endogenous (internal) physical and chemical stimuli. Its main functions include mediating pain perception, inflammation, and body temperature.
As CBD binds to TRPV1 receptors, like capsaicin, it leads to desensitisation of TRPV1 receptors, in which the previously excited neurons no longer respond to painful stimuli thus relieving pain. The TRPV1 is another important site that the endocannabinoid anandamide acts on. CBD being a full, although weak, agonist of the TRPV1 could activate cannabinoid receptors indirectly too, by increasing the amount of anandamide in the blood for a longer period of time. Conditions, such as neuropathy and rheumatoid arthritis, in which TRPV1 receptor sensitivity and expression are increased, can be treated with CBD, making it a useful alternative in the treatment of chronic pain.
Other well known activators of the TRPV1 receptor:
- temperatures greater than 43 °C (109 °F)
- acidic conditions
- capsaicin, the irritating spicy compound in hot chili peppers
- allyl isothiocyanate, the pungent compound in mustard and wasabi
Serotonin Receptors (5-HT1A)
At high concentrations, CBD activates the 5-HT1A serotonin receptor, which is the primary function of its anti-anxiety effect. This GPCR is involved in a large number of brain and bodily functions, including (but not limited to):
Further studies examining central control of cardiovascular function have also shown CBD and 5-HT1A interactions
- anxiety
- appetite
- addiction
- pain perception
- nausea and vomiting.
Further studies examining central control of cardiovascular function have also shown CBD and 5-HT1A interactions
Glycine Receptor (Alpha-1 & Alpha-1-Beta)
The glycine receptor (abbreviated as GlyR) is the receptor of the neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride currents. It is one of the most widely distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brainstem. The glycine receptor is made up of five subunits: two α1 subunits and three beta (β) subunits.
Receptor proteins have specific sites into which certain other molecules, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. The ligand for the glycine receptor is the protein building block (amino acid) glycine. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system.
Cannabidiol showed positive allosteric modulating effects at alpha(1) and alpha(1)beta receptors which are embedded in the membrane of nerve cells (neurons), in the spinal cord, and the brainstem. Direct activation of glycine receptors was also observed at higher concentrations. Glycine receptors may be a target for CBD mediating some of its anti-inflammatory and neuroprotective properties.
When glycine attaches (binds) to the glycine receptor, the receptor opens to allow negatively charged chlorine atoms (chloride ions) to enter the neuron. This influx of chloride ions reduces the neurons's ability to transmit signals to other neurons. Because they stop signaling (inhibiting), glycine receptors are known as inhibitory receptors.
Loss of inhibitory synaptic transmission within the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. This means non-cannabinoid receptor mechanisms of CBD might contribute to its anti-inflammatory and neuroprotective effects.
The receptor can also be activated by a range of simple amino acids including: GlyR is known to co-localize with the GABAA receptor on some hippocampal neurons.
Receptor proteins have specific sites into which certain other molecules, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. The ligand for the glycine receptor is the protein building block (amino acid) glycine. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system.
Cannabidiol showed positive allosteric modulating effects at alpha(1) and alpha(1)beta receptors which are embedded in the membrane of nerve cells (neurons), in the spinal cord, and the brainstem. Direct activation of glycine receptors was also observed at higher concentrations. Glycine receptors may be a target for CBD mediating some of its anti-inflammatory and neuroprotective properties.
When glycine attaches (binds) to the glycine receptor, the receptor opens to allow negatively charged chlorine atoms (chloride ions) to enter the neuron. This influx of chloride ions reduces the neurons's ability to transmit signals to other neurons. Because they stop signaling (inhibiting), glycine receptors are known as inhibitory receptors.
Loss of inhibitory synaptic transmission within the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. This means non-cannabinoid receptor mechanisms of CBD might contribute to its anti-inflammatory and neuroprotective effects.
The receptor can also be activated by a range of simple amino acids including: GlyR is known to co-localize with the GABAA receptor on some hippocampal neurons.
Reuptake Inhibitors
(indirect functions/activations)
CBD functions as an anandamide and adenosine reuptake and breakdown inhibitor, which raises endocannabinoid levels and extends the amount of time they circulates in the blood and brain. By preventing the breakdown of endocannabinoids in the blood, CBD intensifies and prolongs their effects.
CB1 Receptors
The Cannabinoid type 1 (CB1) receptor is a GPCR primarily, but not exclusively expressed in the central nervous system and is activated by the endocannabinoid neurotransmitters anandamide and 2-arachidonoylglycerol (2-AG). CB1 receptors are also found in the pituitary adrenal and thyroid glands, immune cells, reproductive tissues, gastrointestinal tissues, superior cervical ganglion, heart, blood vessels, muscles, fat cells (adipose), lung, bladder, liver, kidney, and central & peripheral nerve terminals. CB1 is also present on Leydig cells and human sperms. In females, CB1 is located on the ovaries, oviducts myometrium, decidua, placenta, and has been implicated in the proper development of the embryo.
Cannabidiol CBD acts as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulators of CB1 receptors have the potential to treat central nervous system and peripheral disorders while avoiding the negative effects associated with orthosteric agonism or direct antagonism (blocking) of these receptors. This means CBD can treat diseases that benefit from CB1 modification while avoiding the side effects that directly inactivating the receptors would cause.
CBD inhibits the anandamide hydrolyzing enzyme FAAH (which breaks down anandamide), indirectly facilitating endocannabinoid-mediated neurotransmission. CBD activates the CB1 receptors indirectly by increasing the amount and duration of circulating anandamide.This means that CBD can boost levels of the endocannabinoid anandamide in the blood and prevent it from breaking down, making its effects stronger and last longer. Increasing the brain's anandamide levels can help treat anxiety and depression.
Anandamide (N -arachidonoyl-ethanolamine, AEA) was the first endogenous ligand (endocannabinoid) of cannabinoid receptors to be discovered. It's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system. These cannabinoid receptors are also sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is one of the primary psychoactive cannabinoids found in cannabis.
Although, Anandamide (AEA) also appeared to exhibit some effects that were not mediated by CB1 & CB2. AEA exerts some behavioral actions in mice with genetically disrupted CB1 receptors, whereas it is usually an agonist of these receptors and a weak activator of CB2 receptors. Several pharmacological effects of AEA are mediated by CB1 receptors, which, by being coupled to G-proteins, can be seen as AEA "metabotropic" receptors. Meaning, at least two different, and as yet uncharacterized, G-protein-coupled AEA receptors have been suggested to exist in the brain and vascular endothelium. AEA is also capable of directly inhibiting ion currents mediated by L-type Ca(2+) channels and TASK-1 K(+) channels. However, to date the only reasonably well characterized, non-cannabinoid site of action for AEA is the vanilloid receptor TRPV1.
The extended presence of anandamide in the blood also prevents THC from interacting with cannabinoid receptors. CB1 modulation has been shown to play a role in preventing side effects like short-term memory loss and paranoia associated with THC.
Cannabidiol CBD acts as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulators of CB1 receptors have the potential to treat central nervous system and peripheral disorders while avoiding the negative effects associated with orthosteric agonism or direct antagonism (blocking) of these receptors. This means CBD can treat diseases that benefit from CB1 modification while avoiding the side effects that directly inactivating the receptors would cause.
CBD inhibits the anandamide hydrolyzing enzyme FAAH (which breaks down anandamide), indirectly facilitating endocannabinoid-mediated neurotransmission. CBD activates the CB1 receptors indirectly by increasing the amount and duration of circulating anandamide.This means that CBD can boost levels of the endocannabinoid anandamide in the blood and prevent it from breaking down, making its effects stronger and last longer. Increasing the brain's anandamide levels can help treat anxiety and depression.
Anandamide (N -arachidonoyl-ethanolamine, AEA) was the first endogenous ligand (endocannabinoid) of cannabinoid receptors to be discovered. It's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system. These cannabinoid receptors are also sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is one of the primary psychoactive cannabinoids found in cannabis.
Although, Anandamide (AEA) also appeared to exhibit some effects that were not mediated by CB1 & CB2. AEA exerts some behavioral actions in mice with genetically disrupted CB1 receptors, whereas it is usually an agonist of these receptors and a weak activator of CB2 receptors. Several pharmacological effects of AEA are mediated by CB1 receptors, which, by being coupled to G-proteins, can be seen as AEA "metabotropic" receptors. Meaning, at least two different, and as yet uncharacterized, G-protein-coupled AEA receptors have been suggested to exist in the brain and vascular endothelium. AEA is also capable of directly inhibiting ion currents mediated by L-type Ca(2+) channels and TASK-1 K(+) channels. However, to date the only reasonably well characterized, non-cannabinoid site of action for AEA is the vanilloid receptor TRPV1.
The extended presence of anandamide in the blood also prevents THC from interacting with cannabinoid receptors. CB1 modulation has been shown to play a role in preventing side effects like short-term memory loss and paranoia associated with THC.
Adenosine Receptors (A1A & A2A)
The adenosine receptors are a class of GPCR with adenosine as its endogenous ligand (endocannabinoid.) There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene. The adenosine receptors are commonly known for their antagonist chemicals caffeine and theophylline, whose action on the receptors produces the stimulating effects of coffee, tea, and chocolate.
CBD inhibits the reuptake of adenosine which causes anti-anxiety and anti-inflammatory effects. By delaying the binding and breakdown of this neurotransmitter, CBD boosts adenosine levels in the blood for a longer period of time.
Not only does CBD have effects within the central nervous system, but also within the cardiovascular system. Adenosine receptors have been implicated in regulating coronary blood flow and oxygen consumption by cardiac muscles and are present in the brain, most notably in the forebrain. CBD was found to inhibit the ventricular tachycardia following coronary artery blockage.)
CBD can exert an antiarrhythmic effect, possibly controlled by the adenosine A1 receptor. A2 receptor-mediated effects of CBD have also been reported and claimed to mediate some anti-inflammatory effects of CBD. Studies have suggested that neuroprotective effects of CBD are mediated via adenosine A2 receptor modulation. However, this has also been contested where species differences and animal developmental stages in the methodology of these conflicting studies may underlie the different conclusions drawn. Therefore, a clear link between the neuroprotective effects of CBD and adenosine A2 receptors has not yet been proven in humans.
CBD inhibits the reuptake of adenosine which causes anti-anxiety and anti-inflammatory effects. By delaying the binding and breakdown of this neurotransmitter, CBD boosts adenosine levels in the blood for a longer period of time.
Not only does CBD have effects within the central nervous system, but also within the cardiovascular system. Adenosine receptors have been implicated in regulating coronary blood flow and oxygen consumption by cardiac muscles and are present in the brain, most notably in the forebrain. CBD was found to inhibit the ventricular tachycardia following coronary artery blockage.)
CBD can exert an antiarrhythmic effect, possibly controlled by the adenosine A1 receptor. A2 receptor-mediated effects of CBD have also been reported and claimed to mediate some anti-inflammatory effects of CBD. Studies have suggested that neuroprotective effects of CBD are mediated via adenosine A2 receptor modulation. However, this has also been contested where species differences and animal developmental stages in the methodology of these conflicting studies may underlie the different conclusions drawn. Therefore, a clear link between the neuroprotective effects of CBD and adenosine A2 receptors has not yet been proven in humans.
GABA Receptors
A GABA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous (natural) ligand (neurotransmitter) is gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system.
CBD is a Positive Allosteric Modulator (PAM) at α1-6βγ2 GABA(A) receptors. PAMs of the GABA(A) receptor do not cause it to activate more frequently-they cause it's action (the opening of the chloride channel) to last for longer. This means that CBD increases the duration and efficiency of these receptor's functions.
The maximal level of enhancement seen with CBD was on α2-containing GABA(A) receptor subtypes. The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site like most PAMs at the GABA(A) site do.
Exploration of extrasynaptic α4β2δ receptors revealed that CBD enhanced GABA EC5 evoked currents. This means that CBD acts on specifically configured GABA(A) receptors that may be responsible for some of its anticonvulsant and anxiolytic effects.
Other Positive allosteric modulators of GABA:
(suggesting CBD may help with the withdrawal of some of the following drugs):
CBD is a Positive Allosteric Modulator (PAM) at α1-6βγ2 GABA(A) receptors. PAMs of the GABA(A) receptor do not cause it to activate more frequently-they cause it's action (the opening of the chloride channel) to last for longer. This means that CBD increases the duration and efficiency of these receptor's functions.
The maximal level of enhancement seen with CBD was on α2-containing GABA(A) receptor subtypes. The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site like most PAMs at the GABA(A) site do.
Exploration of extrasynaptic α4β2δ receptors revealed that CBD enhanced GABA EC5 evoked currents. This means that CBD acts on specifically configured GABA(A) receptors that may be responsible for some of its anticonvulsant and anxiolytic effects.
Other Positive allosteric modulators of GABA:
(suggesting CBD may help with the withdrawal of some of the following drugs):
Opioid Receptors
Opioid receptors (ORs) are GPCR subtypes called Gi/o protein-coupled receptors that opiate drugs bind to and activate.
CBD may serve as an allosteric modulator at the μ OR and the δ OR. In rat cortical membranes, the dissociation of OR agonist DAMGO (a synthetic opiate) from μ ORs was seen following the application of CBD. A similar effect was observed for δ ORs. For both receptors, half maximal inhibition was produced. This means that CBD reduced a synthetic opiates response (or binding) by half suggesting a treatment for opiate addiction and withdrawal.
Anatomical evidence suggests that GABA and Opioid systems are closely linked and activity of the same neuron may be regulated directly by both GABA and opioids.
CBD may serve as an allosteric modulator at the μ OR and the δ OR. In rat cortical membranes, the dissociation of OR agonist DAMGO (a synthetic opiate) from μ ORs was seen following the application of CBD. A similar effect was observed for δ ORs. For both receptors, half maximal inhibition was produced. This means that CBD reduced a synthetic opiates response (or binding) by half suggesting a treatment for opiate addiction and withdrawal.
Anatomical evidence suggests that GABA and Opioid systems are closely linked and activity of the same neuron may be regulated directly by both GABA and opioids.
Nicotine Receptors (nAChRs)
Nicotinic acetylcholine receptors, or nAChRs, are receptor proteins that respond to the neurotransmitter acetylcholine. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors, and they are directly linked to ion channels.
Nicotinic receptors also respond to drugs, including the nicotinic receptor agonist nicotine. They are found in the central and peripheral nervous system, muscles, and many other tissues.
Evidence shows that CBD modulates nicotinic acetylcholine receptor (nAchRs) function.
Concentration-dependent inhibition of (nAchRs) was shown in the presence of CBD. This means that CBD was shown to block the binding of these receptors which may be beneficial for treating nicotine and tobacco addictions.
Also, CBD inhibited acetylcholine-induced ion currents, and complementary biochemical evidence highlighted a noncompetitive binding to the α-7-nAChR.
Nicotinic receptors also respond to drugs, including the nicotinic receptor agonist nicotine. They are found in the central and peripheral nervous system, muscles, and many other tissues.
Evidence shows that CBD modulates nicotinic acetylcholine receptor (nAchRs) function.
Concentration-dependent inhibition of (nAchRs) was shown in the presence of CBD. This means that CBD was shown to block the binding of these receptors which may be beneficial for treating nicotine and tobacco addictions.
Also, CBD inhibited acetylcholine-induced ion currents, and complementary biochemical evidence highlighted a noncompetitive binding to the α-7-nAChR.
PPARs Nuclear Receptors
The peroxisome proliferator-activated receptors (PPARs), located on the surface of a cell's nucleus, are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. They also regulate genes that are involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions.
- Anti-cancer by activating PPAR-gamma
- Activation degrades amyloid-beta plaque, a chemical linked to the development of Alzheimer’s disease.
- May regulate DNA transcription or prevent genetic mutations
- May play a role in diabetes
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