Cannabinoid and Terpenoid Receptors, Ion Channels, and Enzymes
Article by Justin L Scharton, Independent Researcher
Last updated 12/9/2024
Receptors are specialized proteins that act as molecular switches and channels that mediate different chemicals and signals within the body. There are numerous receptors, but here we focus on the ones that are pharmacological targets for different health problems. There are at least 24 different receptors, ion channels, and enzymes that cannabinoids and terpenes will interact with, going way beyond the CB1 and CB2 receptors.
These molecular targets and their associated receptor actions or influences include:
Transient receptor potential (TRP) channels: TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM7, TRPM8
Cannabinoid receptors: CB1, CB2
G protein-coupled receptor: GPR55
Opioid receptors: Mu opiate, Delta opiate
Ion channels: T-type calcium channel
Nuclear receptors: PPARγ
Serotonin receptors: 5HT1A, 5HT3
Enzymes and other modulators: Adenosine uptake inhibitors, COX-2, Phospholipase A2, mechanisms that suppress tryptophan degradation, Acetylcholinesterase inhibitors, α7 nAChR, Muscarinic Acetylcholine M3 receptors (CHRM3), and anticholinergic actions.
TRPA1
Transient receptor potential ankyrin 1
TRPA1 is a non-selective cation channel permeable to calcium, potassium and sodium ions.(5A)
In Mammals, TRPA1 is a sensor for chemical irritants, and sometimes referred to as the “wasabi receptor”. TRPA1 takes on a different role in infrared-sensing snakes and insects as a heat sensor, with mild sensitivity to chemical irritants.(6A)
TRPA1 receptors are on the plasma membranes of different cells, including sensory neurons and cerebral vascular endothelial cells. TRPA1 activation will cause neurogenic vasodilation through releasing the vasodilator, calcitonin gene-related peptide. TRPA1 activation in the cerebral vasculature causes endothelium-dependent vasodilation, starting with localized Ca2+ signals.(1A)
Cannabinoid agonists of TRPA1 in order of Potency EC50 (μM)( 2A,3A,4A)
Other TRPA1 agonists include: acetaldehyde (from ethanol metabolism),(7A) formaldehyde, iodoacetamide, 4-Hydroxynonenal,(8A) formalin,(9A) 4-oxononenal, mustard, cinnamaldehyde,(10A) hydrogen peroxide,(11A) allyl isothiocyanate (found in wasabi and mustard oils),(12A) ginger,(13A) and acrolein which is an irritant from gas and vehicle exhaust fumes.(14A)
Terpenes that interact with the TRPA1 receptor: eucalyptol is a TRPA1 antagonist,(33D) (-)-α-bisabolol is a TRPA1 antagonist,(53D) cedrol is a TRPA1 modulator,(3E) Carvacrol is a TRPA1 agonist,(15E) Thymol is an agonist of TRPA1,(25E) and eugenol acts as a TRPA1 agonist.(68C)
TRPA1 Antagonists: camphor, gadolinium and ruthenium red.(7A)
Important: some substances such as ruthenium red are for research purposes only, and is dangerous for people since it disrupts cell signals throughout the body and affects multiple receptors other than TRPA1.
Essential oils that activate TRPA1: cinnamon, wintergreen, clove, mustard,(13A) and bitter orange.(15A)
Many of these essential oils contain different terpenes, and some will activate more receptors than just TRPA1. For example, bitter orange contains linalyl acetate, geranyl acetate, osthole, geranyl propionate, neryl acetate, and other unlisted terpenes.(15A)
Alterations in TRPA1 include: Familial Episodic Pain Syndrome type 1, Cramp-Fasciculation Syndrome,(14A) Multi Chemical Sensitivity,(16A) Colorectal Cancer.(17A)
TRPV1
Transient receptor potential vanilloid 1
TRPV1 is a ligand-gated ion channels that facilitate transmembrane permeability to calcium and sodium ions.(18A)
TRPV1 are found on vascular smooth muscle and endothelial cells. Activation of TRPV1 with capsaicin can be either vasodilatory or vasoconstrictive depending on individual responses. Excessive TRPV1 activation through an unnecessary consumption of a large amount of capsaicin can result in vasospasm and heart attack in people with certain inflammatory conditions.(25A) Chronic use of TRPV1 agonists like capsaicin will desensitize neurons reducing pain such as diabetic peripheral neuropathy and arthritis.(24A)
Cannabinoid agonists of TRPV1 in order of Potency EC50 (μM)(3A,19A,20A,21A)
Other agonists include: Capsaicin13A, 4-oxononenal(22A), temperature above 42°C, intracellular acidosis (ph <6), 12-hydroperoxytetraenoic acid, and bradykinin(23A)
Antagonists: capsazepine, AMG-0347, AMG-517, AG-489, AG-505(24A)
Terpenes that interact with the TRPV1 receptor: b-myrcene,(68C) (-)-α-bisabolol is a TRPV1 antagonist,(52D) nerolidol is a TRPV1 agonist,(68C) geraniol is a TRPV1 putative modulator,(81D) and cedrol is a TRPV1 modulator.(3E)
TRPV1 activation with capsaicin is also anti-cancer and can reduce inflammation.(25A) Those receptors are on monocytes, macrophages, and dendritic cells. TRPV1 and other TRP receptors are required for T-cell receptor activation by mitogens.(26A)
Aside from being a heat receptor, hippocampal TRPV1 influences synaptic plasticity affecting memory and learning. Those TRPV1 receptors in the hippocampus affect the glutamatergic terminals.(28A)
TRPV1, along with CB1 activation can reduce excessive neuronal excitement and febrile seizures. They can also enhance neuronal plasticity.(27A 28A)
Alterations of TRPV1 include: Cystinosis, Nephropathic (kidney problems) and Pulpitis (tooth pulp decay/inflammation) and toothache,(29A,30A,31A) Multi Chemical Sensitivity.(16A)
TRPV2
Transient receptor potential vanilloid 2
TRPV2 is a non-selective cation channel permeable to calcium.(32A)
TRPV2 is located on neurons, neuroendocrine cells, immune cells, and some cancers.(33A)
TRPV2 is involved in immune system regulation and response. It plays a role in processes such as immune cell activation and cytokine release, making it a potential therapeutic target for enhancing immune function and treating various conditions linked to immune system activity.(80B)
Cannabinoid agonists of TRPV2 in order of Potency EC50 (μM)(3A,19A)
TRPV2 is activated by heat (≥52°C), probenecid, insulin-like growth factor 1 (IGF-1), insulin (INS), platelet-derived growth factor (PDGF), neurohypophysial hormone analogs (NHA), lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI), 2-aminoethoxydiphenyl borate (2-APB), and N-formylmethionine-leucyl-phenylalanine (fMLP).(34A)
Diseases associated with TRPV2 include: Kidney Pelvis Papillary Carcinoma and Renal Pelvis Transitional Cell Carcinoma.(32A)
TRPV2 traffickers
Interaction with certain receptors or through glycosylation can cause TRP receptors to move within the cytosol and surface at the cell membrane, where ligands can interact with them. This process is known as TRP trafficking.(81B) The exact mechanism behind this process is still not fully understood. CBD, as well as other molecules like IGF-1, insulin (INS), lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI), platelet-derived growth factor (PDGF), N-formylmethionine-leucyl-phenylalanine (fMLP), and neurohypophysial hormone analogs (NHA), appear to have this capability.(34A)
TRPV2 trafficking could benefit various disease processes and cancers by increasing the availability of TRPV2 receptors at the cell membrane, where they can be activated by cannabinoids, potentially enhancing immune system responses.
TRPV2 on immune cells
CD34+ hematopoietic stem cells - TRPV2 regulates stem/progenitor cell cycle progression, growth, and differentiation.(35A)
Granulocytes, macrophages, and monocytes - TRPV2 stimulates fMet-Leu-Phe migration, zymosan-, immunoglobulin G-, and complement-mediated phagocytosis. It also influences lipopolysaccharide-induced tumor necrosis factor-alpha and interleukin-6 production.(35A)
Mast cells - TRPV2 allows intracellular Ca2+ ions flux, stimulating protein kinase A-dependent degranulation.(35A)
CD56+ natural killer cells - TRPV2 is responsible for Ca2+ signal in T cell activation, proliferation, and effector functions.(35A)
CD4+ and CD8+ T lymphocytes - TRPV2 is located on messenger RNA.(35A)
CD19+ B lymphocytes - TRPV2 regulates Ca2+ release during B cell development and activation.(35A)
TRPV3
Transient receptor potential vanilloid 3
TRPV3 is a non-selective cation channel permeable to calcium.(36A)
TRPV3 is most abundant in keratinocytes and peripheral neurons. It is involved with signaling pathways of itch, dermatitis, hair growth, skin regeneration and physiology, temperature perception, pain transduction, inflammation, cancer and other diseases. TRPV3 is a potential pharmaceutical target for pain and itch.(36A,37A)
Cannabinoid agonists of TRPV3 in order of Potency EC50 (μM)(3A,19A)
Terpenes that are TRPV3 agonists: camphor, menthol, dihydrocarveol, 1,8-cineol,38A 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol, (+)-borneol,(39A) eugenol.(36A)
Other agonists: 2-aminoethoxydiphenyl borate (2-APB),(38A) TRPV3 is activated from temperatures 22 and 40 degrees C, and an increased response at noxious temperatures greater than 39 degrees C.(40A)
Terpenes that interact with the TRPV3 receptor: camphor is a TRPV3 agonist,(95D) carvacrol is a TRPV3 agonist,(15E) thymol is an agonist of TRPV3,(25E) and eugenol is a TRPV3 agonist.(36A)
Whole herbs that contain terpenes that are agonists to TRPV3: oregano, savory, clove and thyme.(41A)
A prolonged exposure for 5-15 minutes to TRPV3 agonist terpenes, such as camphor and 1,8-cineol will result in desensitization of TRPV3. Long-term exposure to those terpenes desensitized the currents in TRPV3 that express oocytes.(38A) This study focused on amphibian oocytes, specifically those from Xenopus laevis, so it is unclear how these findings would translate to mammalian oocytes and their potential physiological effects.
TRPV3 activation can cause vasodilation through triggering the release of Adenosine Triphosphate (ATP), calcitonin gene-related peptide (CGRP), nitric oxide (NO), and prostacyclin (PGI2).(42A,43A)
Diseases associated with TRPV3 include: Olmsted Syndrome 1 and Focal 2 Nonepidermolytic Palmoplantar Keratoderma.(43A)
TRPV4
Transient receptor potential vanilloid 4
TRPV4 is a non-selective calcium permanent cation channel involved in osmotic sensitivity and mechanosensitivity.(44A)
TRPV4 is in cardiomyocytes, endothelial cells, smooth muscle cells, lung, chondrocytes, neurons, astrocytes, and sperm.(45A,46A,47A,48A)
TRPV4 modulates mitochondrial activity, Ca2+ homeostasis, sperm motility and thermotaxis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction.(45A,47A)
Cannabinoid agonists of TRPV4 in order of Potency EC50 (μM)(3A,54A)
TRPV4 is activated by heat (27–34 °C), mechanical stimuli, hypo-osmolarity and arachidonic acid metabolites, P450-derived metabolites (epoxyeicosatrienoic acids), endocannabinoids (anandamide and 2-arachidonoylglycerol).(51A,52A)
TRPV4 becomes upregulated in cardiac fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarction and arrhythmia, cystic fibrosis, ciliary beat frequency, bronchoconstriction, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, acute respiratory distress syndrome and cough.(45A,46A)
Mutations of TRPV4 include brachyolmia and Koszlowski disease.(51A)
Diseases associated with TRPV4 include Metatropic Dysplasia and Hereditary Motor And Sensory Neuropathy, Type 2C.(44A)
TRPV4 activation in macrophages are required for effective phagocytosis, and secreting anti-inflammatory cytokines. TRPV4 was found to protect the lung from injury after pneumonia from an infection with P. aeruginosa through MAPK signaling.(53A)
In a rat study, TRPV4 was found to become upregulated in sterile pericarditis in rats with atrial fibrillation.(49A) TRPV4 inhibition reduces atrial remodeling and induction of atrial fibrillation.(50A)
TRPV4 channels are present in astrocytes in the brain. They regulate blood flow by controlling calcium ion flow in the endfeet, the branches of astrocytes that wrap around and interact with blood vessels.(48A)
TRPV4 channels are found in all vertebrate sperm cells, from fish to mammals. This receptor is important for sperm motility and thermotaxis, and its expression and location differ between swim-up and swim-down sperm cells. Activation of TRPV4 induces calcium influx, which regulates the movement of sperm, and may have implications for male fertility, contraception, and species conservation.(47A)
TRPM7
Transient receptor potential melastatin 7
Carvacrol is the only terpene to target TRPM7.(18E) Cannabinoids do not interact with this receptor.
TRPM7 is not a pharmacological target for medications yet, but carvacrol (from oregano) is a TRPM7 inhibitor.(18E)
Carvacrol is a TRPM7 inhibitor and anti liver cancer
Carvacrol, a TRPM7 inhibitor, shows promise in overcoming sorafenib (Sora) resistance and its associated cardiotoxicity in hepatocellular carcinoma (HCC). In a rat model of HCC, the combination of carvacrol and Sora improved survival rates, enhanced liver function, and reduced tumor progression compared to Sora alone. Carvacrol mitigated sorafenib-induced damage to cardiac and liver tissues and boosted its anti-cancer effects by promoting apoptosis and inhibiting proliferation, angiogenesis, and metastasis. The combination downregulated key markers of drug resistance and stemness, such as NOTCH1 and CD133, suggesting its potential as an effective and safer therapeutic strategy for advanced HCC.(18E)
There is limited research for TRPM7 compared to the other TRP receptors that are easily targeted by pharmaceuticals.
TRPM8
Transient receptor potential melastatin 8
TRPM8 is a receptor-activated non-selective cation channel permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium.(55A)
TRPM8 detects sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius.(55A)
Cannabinoid antagonists of TRPM8 in order of Potency IC50 (μM)(3A,19A,54A)
Tested against Icilin
Tested against Menthol
Cannabinoids act as antagonists to TRPM8, as opposed to TRPA1 and TRPV1-4 in which they act as agonists.
Terpenes that interact with the TRPM8 receptor: eucalyptol is a TRPM8 agonist.(33D)
Diseases associated with TRPM8 include Lichen Sclerosus Et Atrophicus and Dentin Sensitivity.(55A)
Cancers with TRPM8: colon, bone, breast, pancreatic, gastric, esophageal, oral squamous cell, uveal melanoma, malignant melanoma A-375 cells, bladder, glioblastoma, and prostate. (56A,57A,58A,59A,60A,61A,62A,63A,64A,65A)
TRPM8 is moderately expressed in normal prostate tissue, and becomes highly overexpressed in prostate cancer.(66A)
Mutations in TRPM8 gene expression are associated with dry eye disease (DED). Mice with severe DED were given installations of a TRPM8 antagonist, M8-B, which relieved the corneal pain associated with severe DED.(67A)
TRPM8 is abnormally expressed in non-melanoma skin cancers (NMSC). In basal cell carcinoma (BCC), TRPM8 expression is much lower compared to normal skin, while in squamous cell carcinoma (SCC), TRPM8 receptors are overexpressed.(68A)
There are two oral squamous cell carcinoma cell lines, HSC3 and HSC4, that can be worsened by TRPM8 agonists like menthol. TRPM8 antagonists are needed to reduce the invasion potential of these cancer types.(60A)
CB1 and CB2
Cannabinoid Receptor 1 and 2
CB1 and CB2 are class A G protein-coupled receptors (GPCRs)(69A)
CB1 Ligands
THC, Anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), THCV (antagonist), CBG (partial agonist), CBN (Weak agonist)(69A,70A,71A)
CB2 Ligands
2-arachidonoyl-glycerol (2-AG), Caryophyllene, CBD (Inverse agonist), CBC (agonist) CBG (partial agonist), THCV (Partial agonist), Anandamide (AEA) (low affinity compared to CB1)(69A,70A,72A,73A)
Terpenes that interact with the CB1 receptor: humulene(6D)
Terpenes that interact with the CB2 receptor: b-caryophyllene(72A)
CB1 and CB2 locations in the body
CB1 and CB2 receptors are expressed in 37 tissues in the human body, according to data from microarray and RNA sequencing analysis.(74A,75A) Previous research suggested that CB1 receptors were present in areas where CB2 receptors were not, particularly in the brain. However, newer studies indicate that both receptors are more widely distributed, including in overlapping areas.
Here are the tissues tested for CB1 and CB2 receptors: Adipocyte, Adrenal gland, Artery, Bladder, Bone marrow, Brain, Breast, Cerebellum, Colon, Cortex, Esophagus, Heart, Kidney, Liver, Lung, Lymph nodes, Ovary, Pancreas, Pituitary, Placenta, Prostate, Retina, Salivary gland, Spinal cord, Skeletal muscle, Skin, Small intestine, Smooth muscle, Spleen, Stomach, Testis, Thymus, Thyroid, Uterus, White blood cells, Tibial nerve, Whole blood.(74A,75A)
CB1 and CB2 on immune cells
CB1 is located on B-cells, T-cells, and innate cells.(77A) Innate cells include: granulocytes, monocytes, macrophages, dendritic cells, and natural Killer cells.(78A,79A)
CB2 location on the immune cells are B-cells, natural killer cells, monocytes, macrophages, polymorphonuclear neutrophil cells, T8 cells, T4 cells.(79A,80A,81A)
Synthetic CB1 agonist can be deadly
CB1 and CB2 receptors are more difficult to target with synthetic pharmaceuticals due to their widespread effects and complex signaling, but they are more easily influenced by natural cannabinoids. In 2016, a clinical trial involving a FAAH inhibitor called BIA 10-2474, which indirectly affects the CB1 receptor, resulted in one person being declared brain dead and five others in critical condition.(76A)
CB1 activation and seizure reduction
CB1 activation can reduce excitatory synaptic transmission and cause vasodilation.(74A) However, in seizure types related to issues with vasodilation, such as those triggered by hot showers, CB1 activation may lead to mixed results due to excessive cerebral vasodilation. In such cases, CBD might be a better option, as it can modulate CB1 activity or balance out the effects of CB1 activation when combined with THC.
How CBD stops you from getting high!
There is no available information on how CBD actually stops the “getting high” effect of THC when taken in a 1:1 ratio or other ratios with higher amounts of CBD. It is known that CB2 is on microglia, and neurons communicate with microglia.(42E) THC binding to brain CB1 receptors are responsible for people feeling high from marijuana.(82A) The above images are the possible representation on how CBD interacts with microglia, and how that microglia modulates the neuron with THC bound to it; reducing the excitatory calcium ions going from the presynaptic and postsynaptic neurons.
GPR55
G protein-coupled receptor 55
GPR55 are receptors that are highly expressed in large dorsal root ganglion neurons. Activation of GPR55 from some cannabinoids, like THC, will increase intracellular calcium in those neurons, and inhibit M-current.(83A) M-type current in neurons uses potassium to help regulate neuronal excitability, stabilizes membrane potential, and prevents excessive neuronal firing.(84A) M-type current is also inhibited by the activation of M1 muscarinic receptors that is activated by acetylcholine.(85A)
Delta 9 THC activates GPR55, while CBD inhibits GPR55.86A GPR55 inhibition could help with intestinal inflammation through reducing leukocyte migration and activation, particularly macrophages.(87A)
Delta 9 THC, the anandamide analog methanandamide, and JWH015 are confirmed to activate GPR55 receptors.(83A) CBD has some similar effects to GPR55 antagonists, but it is unclear if CBD directly interacts with the GPR55, or if its effect of GPR55 is from indirect interactions from other receptors.(89A) More research will need to be done to verify how CBD influences GPR55.
There are no current medications outside of research use to target the GPR55 receptor.
GPR55 and nicotine addiction
GPR55 inhibition disrupted the reward center of the brain in relation to nicotine addiction.(88A) It is possible that THC might worsen nicotine addiction since THC activates GPR55, and CBD might decrease nicotine addiction since CBD inhibits GPR55 based on that study, but more targeted research would need to be done on how THC or CBD would affect nicotine addiction. Since those cannabinoids affect more than just GPR55, it is not clear how those cannabinoids will affect the reward center of the brain with nicotine.
μ-Opiate and δ-Opiate
Mu-Opiate and Delta-Opiate receptors
Mu and Delta opiate receptors and different subtypes and effects as follows:
- Mu-1 receptor is responsible for analgesia and dependence.(90A)
- Mu-2 receptor will cause euphoria, dependence, respiratory depression, miosis, decreased digestive tract motility along with constipation.(90A)
- Mu-3 receptor is responsible for vasodilation.(90A)
- Delta receptors bind to enkephalins that play a role in analgesia and reduction in gastric motility.(90A)
CBD and Delta 9 THC are allosteric modulators of Mu and Delta opiate receptors, meaning they can change how those receptors will respond to other ligands, whether endogenous or from an external source like morphine.(91A) This could possibly help with increasing the effectiveness of the pain relief of opiates with a lower dose when combined with different levels of CBD and/or THC.
How Myrcene releases endogenous opiates
A 1990 study about myrcene showed that pain relief (antinociception) this terpene involves endogenous opioids and alpha-2 receptors. This action was reversed (antagonized) by Naloxone (Narcan),(92A,93A) which is used to reverse opioid overdose. A 2003 study further explained that mu-opioid receptors and alpha2A-adrenergic receptors can physically interact and modulate each other’s signaling pathways.(94A)
Myrcene can help with pain relief from interacting with the alpha2A-adrenergic receptor that releases endogenous opiates. Those opiates interact with the mu-opiate receptors, reducing pain. Narcan will reverse those endogenous opiates, which will increase pain. Other ligands, such as adrenaline (epinephrine), will interact with the alpha2A-adrenergic receptors.(95A) Myrcene along with THC or CBD can enhance the pain relief action of the opiate receptors with the entourage effect.
Delta-opioid receptors are targeted by a few medications
Eluxadoline is an agonist of both Mu and Delta opioid receptors and is used to treat irritable bowel syndrome with diarrhea (IBS-D).(97A)
Buprenorphine is a partial agonist at the Mu receptor and has mild interactions with the Delta opioid receptor. This medication is often used to treat opioid use disorders and manage pain. It is less likely to cause physical dependence compared to other opioids, making it a suitable option for replacement therapy in heroin addiction.(98A)
T-type Calcium Channel Modulation
T-type Ca2+ channels have a role in the development, maintenance, and repair of many tissues, including neuronal, cardiovascular, and endocrine. Dysregulation of T-type calcium channels can result in different diseases of those tissues. T-type Ca2+ channel blockers have been found to be neuroprotective, and help with age related hearing loss. They may even help with protecting auditory neurons against acoustic trauma.(99A)
Medications that interact with T-type calcium channels:
Ethosuximide is an anti-epileptic medication to treat absence seizures that is an inhibitor of the T-type calcium channel.(1B)
Zonisamide is a T-type calcium channel inhibitor used to treat partial onset seizures, infantile spasms, myoclonic, absence generalized tonic-clonic seizures and tonic/atonic seizures.(2B)
Mibefradil is a selective T-type calcium channel inhibitor that was used to treat high blood pressure.(3B) It was removed from the market in 1998 due to dangerous interactions with other medications.(4B)
Verapamil and Diltiazem are used to treat hypertension, cardiac arrhythmia, and coronary vasospasm, and are effective in the treatment of angina pectoris.(5B) Those medications are a combined T and L-type calcium channel inhibitor.(6B)
CBD and THC interacts differently from each other with the T-type calcium channel
THC acts as a T-Type calcium channel indirect agonist
THC prolongs the opening of T-type calcium channels, allowing increased calcium influx,(7B) which indirectly enhances calcium activity without directly binding to or fully activating the channel in the typical manner of an agonist.
CBD acts as a T-Type calcium channel modulator
CBD does not prolong the opening of T-type calcium channels,(7B) but it can still influence the channel’s behavior by regulating its function, making it a modulatory agent rather than a direct agonist or antagonist.
Keeping in mind their different actions can direct what cannabinoids to use for specific effects. This action with T-Type calcium channels can affect the cardiovascular system, and THC may cause problems with certain people with different heart conditions. Certain seizure disorders will also react differently to THC and CBD through these channels. THC may be better for other applications that benefit from the extra calcium ions entering the cells with the open channel, such as certain types of pain. Targeted research is needed to address the specifics of how THC and CBD should be used for different conditions that are affected by T-type calcium channels.
PPARy
Peroxisome proliferator-activated receptor gamma
Rosiglitazone (Avandia) and pioglitazone (Actos) are used to treat type 2 diabetes. Their blood sugar-lowering effect comes from increasing insulin sensitivity by activating the PPARγ receptor.(8B,9B)
CBD and Delta 9 THC activate PPARy (PPAR-gamma). The vasorelaxation effects of CBD may be partially due to the activation of PPARy, but is mostly from calcium channel inhibition.(10B) Activation of PPARy is known for causing insulin sensitization and enhances glucose metabolism.(11B)
Terpenes that interact with PPAR: geraniol and citronellol are PPARa and PPARy agonists.(77D)
When CBD interacts with the PPARy receptor, it modulates the insulin channel on the same cell to allow for glucose to enter the cell easier by increasing insulin sensitivity.
5HT1A
5HT1A receptors are a pharmacological target for depression, anxiety, and other psychiatric disorders.(12B)
CBD is an agonist of 5-HT1a, and was found to reduce the response to stress. This may be helpful for stress-coping mechanisms, such as depression and post-traumatic stress disorder.(13B)
Alterations in 5HT1A receptors
In conditions like schizophrenia, there is an increase of 5HT1A receptors in the prefrontal cortex. In Alzheimer’s Disease, there is a decrease in 5HT1A binding in the temporal cortex that is linked to aggressive behavior associated with that disorder. Other altered expressions of 5HT1A are observed in emotional and behavioral disorders.(14B)
Medication classifications of antidepressants and antipsychotics are classified into the following categories:
5HT1A agonist - Medications like buspirone and flesinoxan bind to the 5HT1A autoreceptors that stop the release of serotonin from the presynaptic terminal. The medication binds to the 5HT1A receptors on the postsynapse.(14B) Vilazodone is a partial 5HT1A agonist and a serotonin partial agonist reuptake inhibitor.15B Trazodone have partial agonist properties of 5HT1A, and an antagonist of the A1-adrenoceptor.(16B)
5HT1A antagonist - These medications are often used for depression, anxiety, drug- and nicotine-withdrawal, and cognitive dysfunction like Alzheimer’s Disease.(14B) Those medications affect other receptors and neurotransmitters, but also can antagonize the 5HT1A receptor. Risperidone and Chlorpromazine are a couple of examples of this class of drugs.(17B)
SSRI - These medications inhibit the protein SERT (Serotonin Transporter) that is located on the surface of the presynaptic neuron. Extra serotonin can remain in the synaptic cleft or gap in between the neurons since SERT has a reduced ability to absorb the serotonin.(18B) Medications in this class include: Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram, Vilazodone. They are often prescribed to treat Major depressive disorder, Generalized anxiety disorder, Bulimia nervosa, Bipolar depression, Obsessive-compulsive disorder, Panic disorder, Premenstrual dysphoric disorder, Treatment-resistant depression, Post-traumatic stress disorder, Social anxiety disorder.(19B)
MAOI - These are often used to treat atypical depression, panic, social anxiety disorders, treatment-resistant depression, and bipolar disorder. Monoamine oxidases (MAO) breakdown neurotransmitters like norepinephrine, epinephrine, dopamine, tryptamine, and tyramine, inhibiting those enzymes. Inhibition of MAO-A and MAO-B will increase those neurotransmitters.(20B)
Tricyclic antidepressants decrease the reuptake of norepinephrine and serotonin, making those neurotransmitters more available in the synaptic cleft. They often take weeks for the antidepressant action to start working. Medications in this class include: Imipramine, Trimipramine, Amitriptyline, Nortriptyline, Desipramine, Protriptyline, Doxepin, and Clomipramine.(21B)
Dangers of Combining CBD with Prescription Antidepressants
Combining CBD with antidepressants that increase serotonin levels can raise serotonin excessively, potentially causing harmful or even dangerous side effects.
Mild symptoms may include nervousness, insomnia, nausea, diarrhea, tremor, and dilated pupils. These can progress to moderate signs such as hyperreflexia (overactive reflexes), sweating, agitation, restlessness, clonus (rhythmic muscle spasms), and ocular clonus (side-to-side eye movements).(43E)
Severe symptoms of excessive serotonin include a body temperature exceeding 38.5°C (101.3°F), confusion, delirium, sustained clonus or muscle rigidity, and rhabdomyolysis (muscle breakdown).(43E)
5HT3
5HT3 receptor antagonists include dolasetron, granisetron, palonosetron, and ondansetron. These are used to treat nausea and vomiting. Gastric irritation or cellular damage triggers the intestinal release of 5-HT, which binds to 5-HT3 receptors in the GI tract. When 5-HT (serotonin) binds to 5-HT3 receptors, it will trigger nausea and vomiting.(41E)
The terpene alpha-phellandrene is also a 5-HT3 receptor antagonist.(40D) 5HT3 antagonists can be used to treat certain types of irritable bowel syndrome and relieve nausea and vomiting. It is a type of antiemetic. 5HT3 is also called 5-hydroxytryptamine 3 receptor or type 3 serotonin receptor.(41D)
Terpenes that interact with the 5-HT receptor: beta-pinene is a 5-HT3 receptor antagonist,(40D) a-phellandrene is a 5-HT3 receptor antagonist,(40D) fenchone is a 5 HT receptor modulator.(90D)
Adenosine
CBD is an adenosine uptake competitive inhibitor, which contributes to the anti-inflammatory effects of CBD. Mice treated with a low dose of CBD reduced TNF alpha production.(22B) It blocks the ENT1 transporter which is responsible for the reuptake of adenosine. The extra adenosine in the extracellular space is able to bind to adenosine A1 and A2A receptors. Activation of A1 provides antiarrhythmic benefits, while A2A has anti-inflammatory properties.(23B)
Terpenes that interact with the adenosine A2A receptor: +/- limonene,(89B) and humulene.(6D)
Medications that work with adenosine
Dipyridamole is an adenosine reuptake inhibitor, and a platelet phosphodiesterase inhibitor. This medication increases vasodilation, coronary blood flow, and decreases platelet aggregation. The increased adenosine is responsible for the vasodilation and increased blood flow, and partially responsible for the decreased platelet aggregation. The phosphodiesterase inhibition is also responsible for platelet aggregation.(24B,25B) Platelets have adenosine A2A and A2B receptors, and are considered as a pharmacological target for antiplatelet therapy.(26B)
Regadenoson is a selective A2A adenosine receptor agonist. It is used as a vasodilator to increase coronary blood flow during cardiac stress tests.(27B)
Istradefylline is a selective adenosine A2A receptor antagonist to treat the off episodes of Parkinson's patients while on levodopa/decarboxylase treatment.(28B)
COX-2
CBDA is a potent and selective COX-2 inhibitor with an IC(50) at around 2 microM. CBDA affects COX-2 with a nine-fold higher selectivity than COX-1 inhibition. THCA also is a COX-2 inhibitor, but is less potent than CBD with an IC(50) at over 100 microM.(29B)
Celecoxib (Celebrex) is a selective COX-2 inhibitor. That inhibition is responsible for reducing inflammation, fever, and pain. It mildly inhibits COX-1, which affects platelet aggregation less than that of aspirin.(30B)
Most other NSAIDS inhibit both COX-1 and COX-2. These include ibuprofen (Motrin), naproxen (Aleve, Naprosyn), and Ketorolac (Toradol). COX-1 is responsible for providing the protective mucous layer in the stomach. When COX-1 is inhibited, that mucous layer is compromised leading to ulcers.(31B)
CBDA is unstable, and will eventually decarboxylate into CBD over time.(51B)
Terpenes that interact with COX-2: (-)-α-bisabolol is a COX-2 modulator,(62D) geraniol is a COX-2 inhibitor,(77D) carvacrol is a COX-2 inhibitor,(18E) eugenol is a COX-2 modulator or expression inhibitor.(68E)
Suppression of Tryptophan Degradation
CBD and Delta 9 THC suppresses the breakdown of tryptophan and the formation of neopterin. This action is independent of CB1 or CB2 activation, and may lead to the increased availability of tryptophan which later could be used for biosynthesis into serotonin. The increased levels of tryptophan could improve mood,(32B) depression, sleep disorders, anxiety, neurodegenerative diseases, and help correct the functionality of the brain-gut axis and immunology. The increase in serotonin biosynthesis from tryptophan could have a role in helping with autism spectrum disorder, obesity, anorexia and bulimia nervosa; which all have an association with reduced levels of serotonin.(33B)
As mentioned in the first sentence, CBD and Delta 9 THC can reduce the formation of neopterin, and that is used as a marker for certain types of infection and inflammation. There is no current research to show what exactly happens if the formation of neopterin is reduced.
Phospholipase A2 Modulator
THC, CBD, CBN, and CBG modulates phospholipase A2 depending on the concentrations. CBD and CBG have specific EC and IC values that are found online, while THC and CBN don’t show their specific values. The original journal shows that THC, CBD, CBN, and CBG show activation with an EC(50) at a range of 6.0-20.0 X 10(-6) M and IC(50) values in the range 50.0-150.0 X 10(-6) M.(34B)
CBD - EC(50) at 6.4 mM; IC(50) at 134 mM(70A)
CBG - EC(50) at 9.5 mM; IC(50) at 55 mM(70A)
Phospholipase 2 (PLA 2) inhibition was shown to be neuroprotective in injuries related to cerebral ischemia and reperfusion.(35B) There was about a 4 times increase in PLA 2 in the brains of people with Alzheimer’s disease. There is a correlation between sPLA2-IIA in reactive astrocytes around the amyloid plaques in Alzheimer’s disease.(36B)
Acetylcholinesterase inhibitor
Acetylcholinesterase inhibitors are used in treating dementia, Alzheimer’s Disease, cholinergic poisoning, and Myasthenia Gravis. They block the normal breakdown of acetylcholine into acetate and choline and increase both the levels and duration of actions of acetylcholine found in the central and peripheral nervous system. These medications will increase the parasympathetic response from the extra acetylcholine, which affects the vagus nerve.(10C)
Overstimulation of the parasympathetic nervous system, such as increased hypermotility, hypersecretion, bradycardia, miosis, diarrhea, and hypotension. They should not be used in people with certain health problems such as bradycardia, and heart conditions like AV block.(10C) Donepezil, rivastigmine and galantamine are common prescription acetylcholinesterase inhibitors.(11C)
Terpenes that are Acetylcholinesterase inhibitors (37E,52C)
Cholinergic system - Acetylcholine Muscarinic receptors
Acetylcholine (ACh) binds to nicotinic and muscarinic receptors. ACh is synthesized in the cytoplasm of cells by the enzyme choline acetyltransferase (ChAT) from choline and acetyl-CoA. The vesicular acetylcholine transporter (VAChT) moves ACh into the synaptic vesicles. After depolarization, ACh leaves the vesicles into the synaptic cleft, and this is where it can bind to receptors. ACh in the synaptic cleft will be broken down by the enzyme, acetylcholinesterase (AChE), and turn ACh into choline and acetate; which are moved into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1) for recycling. In Alzheimer’s disease, cholinergic neurons are severely lost in the basal forebrain.(42C)
There are 5 subtypes of muscarinic receptors (M1-M5). (43C)
Brain - All five are in the brain, while the M1 receptor seems to be the one responsible for anticholinergic reactions such as delirium, cognitive impairment, dizziness, sedation, and confusion.(43C)
Eye - All five subtypes are in the eye, but the M3 is the most widely expressed. When ACh interacts with M3 in the eye, it will cause the pupil to constrict (Miosis). Anticholinergic activity and toxicity with this receptor can cause blurred vision and an improperly-times dilation of the pupils (Mydriasis). (43C)
Salivary glands - M1 and M3 are expressed in the salivary glands. ACh will increase salivation, while anticholinergic activity will cause dry mouth and difficulty swallowing from decreased salivation. (43C)
Sweat glands - M3 is the dominant muscarinic receptor of sweat glands. ACh will increase sweating, while anticholinergics decrease sweating which decreases our ability to dissipate heat. (43C)
Heart - M2 is widely expressed in the heart. ACh can slow down the heart rate, and heart contractility. Anticholinergics can increase the heart rate (sinus tachycardia), and increase contractility. (43C)
Lungs - M1-M4 are expressed throughout the lungs. They are not typically associated with anticholinergic reactions.(43C) Increased ACh in the lungs will cause bronchoconstriction. Anticholinergics like atropine, can prevent bronchoconstriction from cold air inhalation in a dose-dependent manner. (44C)
Gastrointestinal - M2 and M3 are expressed in the gastrointestinal system. Increased ACh will increase gastric motility. Anticholinergics will slow down gastric motility, and can lead to gastric stasis and constipation.(43C)
Bladder - M2 and M3 are found in the bladder. M3 is responsible for detrusor and bladder contractions. M2 may be involved with detrusor relaxation, but that role is still unclear. Anticholinergics can cause the bladder to be unable to contract leading to urinary stasis and retention.(43C) Increased ACh can cause an overactive bladder.(45C)
Skin - M3 is the main muscarinic receptor in the skin. The vascular endothelium reacts to ACh in opposite ways. ACh interacting with muscarinic receptors in the endothelium can cause vasodilation, while ACh binding to nicotinic receptors in the endothelium can cause vasoconstriction. This is also influenced by other factors like norepinephrine. Anticholinergic reactions often cause vasodilation, and reduce the body’s ability to dissipate heat.(43C)
Alpha7 subunit nicotinic acetylcholine receptor (α7 nAChR)
The Alpha7 subunit nicotinic acetylcholine receptor (α7 nAChR) is highly expressed in the hippocampus, hypothalamus, and the immune system. These receptors are activated by choline. There is a decreased expression of nAChRs in the brain with cognitive disorders like Alzheimer disease, Parkinson disease, Lewy-body dementia, and schizophrenia.(39E)
Agonists targeting α7 nAChRs have shown potential for treating the cognitive disorders mentioned above, as well as conditions like inflammation and sepsis. However, these agonists are primarily studied in research settings and are not yet available for clinical use.(40E)
Thymol (from thyme) and Carvacrol (from oregano) are α7 nAChR inhibitors.(17E) Based on research, agonists are beneficial for neurodegenerative disorders, but there is no research on inhibiting that receptor. People don’t normally ingest isolated forms of thymol and carvacrol, but that could potentially cause some problems if someone did that had neurodegeneration. Thyme and oregano are full of health benefits, but if someone with neurodegeneration feels weird or like their brain is turning off with eating too much of those herbs, then that would likely be due to the inhibition of α7 nAChR.
Muscarinic Acetylcholine M3 Receptor (CHRM3)
CHRM3 receptor acts on the protein kinase B (PKB/AKT)/mitogen-activated protein kinase (MAPK) pathway, which has neuroprotective benefits. The terpene geraniol acts on the CHRM3 receptor.(76D)
Anticholinergic
Alpha-Terpineol is an anticholinergic.(11D) Anticholinergic medications include Scopolamine for treating nausea and vomiting, Benztropine and trihexyphenidyl for reducing dopamine levels and relieve symptoms of Parkinson disease, and atropine for pupil dilation. Side effects or toxicity of anticholinergics include rapid heart rate, arrhythmias, urinary retention, blurred vision, constipation, reduced gut motility, hyperthermia, and inhibition of sweating.(35C)
Other cholinergic actions of terpenes
Linalool inhibits the release of Acetylcholine (ACh) at the neuromuscular junction. A local anesthetic reaction occurs due to the reduction of the channel open time.(55C) (See the linalool section for more detail)
Cannabinoid receptors on immune cells
These receptors are pharmacological targets that cannabinoids and some terpenes will modulate.
Below is an illustration to depict these receptors.
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NK-cells CB1 (77A), CB2 (80A), TRPV2 (35A)
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Macrophage CB1 (77A,78A), CB2 (80A), TRPA1 (91E), TRPV1 (92E), TRPV2 (35A), TRPV4 (93E)
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Dendritic - CB1 (77A,78A), CB2 (80A), TRPA1, TRPV1 (92E), TRPV2 (35A)
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CD4 T-cell - CB1 (77A), CB2 (80A), TRPA1 (94E), TRPV2 (35A), TRPM8 (95E)
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B-cells - CB1 (77A,78A), CB2 (80A), TRPV2 (35A)
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Monocytes - CB1 (77A,78A), CB2 (80A), TRPV1 (92E), TRPV2 (35A)
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Neutrophil - CB1 (77A,78A), CB2 (80A), TRPV2 (35A)
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Eosinophils - CB1 (77A,78A), CB2 (80A), TRPA1 (96E), TRPV2 (35A)
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Mast Cells - TRPA1 (96E), TRPV2 (35A)
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