Cannabinoids
Article by Justin L Scharton, Independent Researcher
Last updated 12/19/2024
Cannabinoids are a diverse group of naturally occurring compounds with tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most recognized. There are at least 150 different cannabinoids, and each has unique properties and benefits. These compounds interact with various receptors and signaling pathways in the human body, influencing processes related to pain, inflammation, mood, appetite, and more.
Most of the cannabinoids do not have much research that investigated their benefits. Nine of them have the most research that show a lot of health benefits to them. We will go over:
CBC - Cannabichromene
CBD - Cannabidiol
CBDA - Cannabidiolic Acid
CBDV - Cannabidivarin
CBG - Cannabigerol
CBN - Cannabinol
THC - Tetrahydrocannabinol
THCA - Tetrahydrocannabinolic Acid
THCV - Tetrahydrocannabivarin
CBC
Cannabichromene
CBC is a TRPA1 agonist and an anandamide reuptake inhibitor(70A)
Cannabichromene (CBC) is one of the lesser-researched cannabinoids, with limited information available compared to more widely studied compounds like THC and CBD. CBC is a trace cannabinoid that is in small concentrations in cannabis plants. Despite the limited research, CBC has shown potential in a few areas.
CBC as an anti-inflammatory
CBC is an anti-inflammatory through targeting the NLRP3 inflammasome and IL-6/STAT-3, reducing inflammation without affecting NF-κB. It may also influence RNA editing.(69B)
CBC as a treatment for neurodegeneration
CBC inhibits amyloid β aggregation, making it a possible treatment for neurodegeneration like Alzheimer’s Disease.(56B)
CBC oxidizes into the cannabinoid CBL (cannabicyclol)(77B)
CBC as an anticonvulsant CBC has anticonvulsant properties at a low dose.(55B)
CBD
Cannabidiol
TRP receptors CBD interacts with: TRPA1, TRPV1, TRPV2, TRPV3, TRPM8 (2A,3A,4A,19A,54A)
CBD has many benefits including being an analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic, neuroprotective, anti-inflammatory, and antioxidant activity.(37B)
Other actions of CBD: Suppression of Tryptophan Degradation,(32B) adenosine uptake competitive inhibitor,(22B) 5HT1A agonist,(3B) PPARy agonist,(10B) T-type calcium channel modulator,(7B) allosteric modulator of Mu and Delta opiate receptors,(91A) GPR55 inhibitor,(86A) CB2 inverse agonist, Phospholipase A2 Modulator.(70A)
CBD is a CB2 inverse agonist
CBD is a CB2 inverse agonist (70A) - Inverse agonists act like regular agonists in how they bind to receptors, but have the opposite pharmacological effect as a regular agonist.
CBD is an anticonvulsant and neuroprotectant
CBD acts as an anticonvulsant and neuroprotectant through calcium homeostasis in neuronal cells. CBD will cause a subtle increase of calcium in hippocampal cells under normal conditions. Under hyper excitability conditions, CBD reduced the calcium release, and prevented calcium oscillations. CBD regulates the calcium homeostasis in neurons by directing the mitochondria to either take in the extra calcium from the cytosol (known as a “sink”), or releasing extra calcium when needed (known as a “source”).(38B)
Vasodilation through calcitonin gene-related peptide (CGRP) release
CBD can release calcitonin gene-related peptide (CGRP) in a dose dependent manner from DRG neurons. This action is not from interacting with cannabinoid or TRPV1 receptors. CBD induced CGRP release is partially mediated from TRPV2 activation.(39B) CGRP is a highly potent vasodilator that is involved in the cardiovascular system and wound healing. It is known that CGRP antagonists can relieve migraines.(40B)
Does CBD cause migraines from CGRP release?
People will react to cannabinoids differently, but since CBD can affect other receptors and actions, the vasodilation effects of CGRP might be more regulated with small doses of CBD. Actual research will need to be done to assess the effects of different doses of CBD and migraines, especially how large doses of isolated CBD affect migraines. Also, the effects of CBD will be altered if using THC and certain terpenes that affect vasodilation or vasoconstriction. Some people with migraines could respond better to a Sativa THC strain, or a humulene rich strain that can be combined with CBD to keep the vasodilation to a minimum. Research so far typically says that CBD may help with migraines, leaving the questions still unanswered.
CBDA
Cannabidiolic acid
TRP receptors CBDA interacts with: TRPA1 partial agonist, TRPV1 agonist, TRPM8 antagonist(3A,19A)
Other actions of CBDA: COX-2 inhibitor(29B)
CBDA is unstable
CBDA will eventually decarboxylate into CBD over time.(51B) This will make it difficult to purchase CBDA, and people would need to grow this themselves to have a frequent fresh supply to utilize that cannabinoid. The easiest way to administer CBDA is to stuff dried CBDA buds into an empty capsule. Making tea by steeping the dried buds could work as well, but some of that resin will stick to the cup. Fresh leaves and buds can also work for tea making. Soaking the buds in some MCT oil is another option, but can make the cannabinoids prone to decarboxylation over time. I personally like the capsules, and I have a better effect with that method.
CBDA for obesity treatment
A study stabilized CBDA with CBDA-O-methyl ester (HU-580, EPM301) to prevent it from decarboxylating on its own. EPM301 at 40 mg/kg per day resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in diet-induced obese mice. EMP301 also prevented dietary induced hepatic dysfunction and steatosis. In preventative treatment, EPM301 inhibited weight gain and adiposity. That study did show that EMP301 reduced obesity and its metabolic abnormalities in both diet-induced obesity and genetic-induced obesity.(51B)
CBDA for Alzheimer’s Disease
CBDA was found to improve memory deficits, and reduce amyloid-beta and Tau pathology in mice with Alzheimer’s Disease.(50B)
CBDV
Cannabidivarin
TRP receptors CBDV interacts with: agonist and desensitizes TRPA1, TRPV1, and TRPV2(81B)
CBDV has anti-inflammatory, anti-nausea, anti-tumor, anti-convulsant, anxiolytic, and neuroprotective properties.(82B)
Antiseizure properties
CBDV has antiseizure properties. It was used in a Phase 2a placebo-controlled study for focal seizure but did not reach the primary endpoints back in February 2018. CBDV inhibits diacylglycerol (DAG) lipase-α, which is the enzyme responsible for synthesizing 2-arachidonoylglycerol (2-AG). The clinical significance of that inhibition is not known.(81B)
Rett Syndrome and Autism
CBDV was shown to reduce motor impairments and cognitive deficits in rats with Rett syndrome which has a degree of overlap with autism. The rat study used valproic acid prenatally to induce those neurological problems in the rats, and used CBDV to alleviate the symptoms. CBDV restores hippocampal endocannabinoid signaling and neuroinflammation induced by prenatal VPA exposure.(83B)
Duchenne muscular dystrophy (DMD)
CBD, CBDV, and THCV promoted myotube formation through TRPA1 activation. CBD and CBDV differentiation of murine C2C12 myoblast cells into myotubes by increasing calcium ions mainly through TRPV1 activation.(84B)
Compulsive behavior
Chronic CBDV administration in rats at a dose of 20 mg/kg normalized repetitive behavior.(83B) Human doses and trials will need to be done to show how this can help people with compulsive problems like OCD.
CBDV Strains
So far, strains high in CBDV are only available in autoflowering varieties. We will have to wait and see if photoperiod versions will become available in the future. These are some CBDV strains that are currently available that people can grow themselves.
Auto CBD-Victory by Dutch Passion Seeds
This autoflowering strain was created by Dutch Passion Seeds rated at 75% Sativa and 25% Indica. CBD and CBDV are both at 4-6% each, and THC is below 0.3%. The terpene profile is described as hints of wood, pine and a slight sweet vinegar taste. These plants take about 10 weeks to harvest under 20 hours of light per day (indoor grow).
Auto CBDV 1:1 by Seedsman
Seedsman genetics created this autoflowering 1:1 CBD:CBDV strain that takes 9-10 weeks to be ready to harvest indoors, and suitable for outdoor growing as well. The THC level is less than 0.3%. It is 75% Sativa and 25% Indica with the aroma of pine and tree resin (balsam).
Royal CBDV Automatic by Royal Queen Seeds
Created by Royal Queen Seeds, this strain has the parents of Solomatic CBD with Durban Poison with a rating of 75% sativa genetics, 20% indica, and 5% ruderalis. These plants produce 5%, CBD levels of 5%, and THC levels of 0.3%. They have earthy and piney terpenes, and take as little as 8 weeks to be ready for harvesting after germination.
CBDV Auto by Kannabia Seeds
CBDV Auto has a cannabinoid content of CBDV and THC is 25:1 with the THC less than 0.2%. They take about 63-70 days to be ready for harvesting, and have an earthy and spicy aroma, with hints of pepper.
Sedativa CBDV by Elite Seeds
Sedativa is a 50/50 hybrid with a fresh and floral aroma reminiscent of lavender and jasmine, and a cannabinoid content of CBDV:CBD 7:8 ratio, and a THC level below 0.5%.
CBG
Cannabigerol
TRP receptors that CBG interacts with: TRPA1 and TRPV1 agonist, TRPM8 antagonist.(70A)
Other actions of CBG: CB1 and CB2 partial agonist, Anandamide reuptake inhibitor, PhospholipaseA2 modulator/inhibitor,(70A,56B) Inhibits COX-1, COX-2 and 12/15-LOX.(56B)
CBG is found in cannabis and Helichrysum umbraculigerum.(70B) Common names for Helichrysum umbraculigerum include woolly umbrella helichrysum or umbrella everlasting in English, and kerriekruie in Afrikaans, which refers to its curry-like aroma.(71B,72B)
CBG has a role as an appetite enhancer, an anti-inflammatory agent, an antibacterial agent, a neuroprotective agent and an antioxidant. It is a phytocannabinoid and a member of resorcinols.(70B)
CBG for anxiety, psoriasis, gastric protection, and more
CBG reduces anxiety and stress and may enhance memory without intoxication, impairment, or subjective drug effects.(73B)
CBG is an inhibitor of cPLA2, COX-1, COX-2, and 12/15-LOX.(74B) CBG also protects against gastric mucositis,(56B) so the COX-1 inhibition would likely not cause any problems with the gastric mucosa from CBG’s protective benefits.
CBG reduces skin inflammation,(75B) which could be helpful against conditions like psoriasis, eczema, or dermatitis.
CBG for neurodegeneration
CBG inhibits amyloid β aggregation, making it a possible treatment for neurodegeneration like Alzheimer’s Disease.(56B)
CBG for SARS-CoV-2 (COVID) treatment
CBG and CBL (cannabicyclol) are both effective against the Covid virus with an EC(50) of cannabigerol at 5.5 µM and for cannabicyclol at 10.8 µM. They block SARS-CoV-2 Cell Fusion.(76B) CBL is formed when CBC oxidizes.(77B)
CBG for Pancreatic ductal adenocarcinoma (PDAC) Treatment
CBG is an effective anti-cancer treatment for the PANC-1 and MIAPaCa-2 cell lines of Pancreatic ductal adenocarcinoma (PDAC) through modulating EGFR-RAS-associated pathways.(78B)
Is CBG bad for pregnancy?
CBG and CBDV can negatively impact pregnancy by upregulating TRPV1 expression, which may lead to altered angiogenesis and an increased risk of pregnancy complications, such as intrauterine growth restriction and preeclampsia.(79B)
CBG strains
CBG strains are available in photoperiods that are included below. Some autoflowering versions are also available. It is possible that the clear trichomes would have more CBG than white trichomes, but that is not stated on any of the seed descriptions found online.
CBG-Force by Dutch Passion Seeds
CBG-Force is a photoperiod CBG strain with a THC percentage below 0.15%. This strain only takes about 7 weeks to be ready for harvesting. There is not a strong smell, or much terpenes in this strain.
CBG Zerodue by Seedstockers
CBG Zerodue is a cross between CBD Critical XXL and Italian Research Genetics. It can be expected to have THC levels below 0.2% and CBG levels as high as 9,18% and takes about 70 days to be ready for harvesting. This strain is a photoperiod.
Eboshi CBG by Medical Seeds
Eboshi CBG is a photoperiod that can reach up to 15% of CBG and both THC and CBD below 0.2%. It has the flavor and aroma of citric touches with fruity and wet earthy undertones.
CBG 1 by Seedsman
CBG 1 is a photoperiod with CBG levels are 16.9% while THC is at 0.25%. Flavours are tangy, from the terpene limonene, with berry notes, and takes about 12 weeks to be ready for harvesting.
Pure CBG by Philosopher Seeds
Pure CBG is a photoperiod with CBG levels of up to 12%, and a THC concentration below 0.3%. It takes about 55 days to be ready for harvesting, and has citric and sweet terpenes.
CBN
Cannabinol
TRP receptors that CBN interacts with: TRPA1 agonist, TRPM8 antagonist.(52B)
CBN is a CB1 and CB2 weak partial agonist.(70A)
Does CBN help with sleep?
A study showed that CBN at 10 mg/kg initially decreased REM sleep, but 4 hours after administration, REM was significantly increased. This could mean that CBN can reduce wake after sleep onset.(53B)
There was a clinical trial on the effectiveness of using CBN for sleep that was completed on 9-5-2023. This was a comparison of 30mg and 300mg of CBN. The results of that study are not available at the time of this writing (10-24-2024) which is over 1 year since the end of that study. We will need to wait until that is available at ClinicalTrials.gov ID NCT05344170.
CBN for pain relief
CBN inhibits voltage-dependent sodium (Nav1.7) channels and dorsal root ganglion (DRG) neurons, suggesting that CBN could be helpful in reducing neuropathic pain. Nav1.7 mutations are associated with painful disorders such as ophthalmic pain, and CBN could be useful in reducing that pain. CBN is slightly less potent in inhibiting Nav1.7 channels than either CBD or CBG.(52B)
CBN is an anti-inflammatory by inhibiting the NF-κB and NLRP3 inflammasome but works differently from THCV on specific pathways like STAT-3.(54B)
CBN for Neurodegeneration Treatment
CBN inhibits amyloid β aggregation, making it a possible treatment for neurodegeneration like Alzheimer’s Disease.(56B)
CBN has anticonvulsant properties at low doses.(55B)
How is CBN formed?
Research states that CBN is oxidized THC. CBN increases as THC degrades during storage.(70A) Marijuana growers tend to look at amber trichomes as a source of CBN. That can be achieved from letting the plant ripen longer before harvesting, and looking at the trichomes under magnification with a jewelers loupe. Amber trichomes also occur after water curing cannabis flowers. Water curing is soaking freshly harvested cannabis buds in water for 3-7 days, changing the water everyday. The image above is from a 3 day water cure of CBD Lemon Skunk. There is no lab testing available to show the conversion to CBN from water curing.
THC
Tetrahydrocannabinol
TRP Receptors THC interacts with: TRPA1 and TRPV2(2A,3A,4A,54A,19A)
Other actions of THC: Suppression of Tryptophan Degradation,(32B) PPARy agonist,(10B) T-type calcium channel indirect agonist,(7B) allosteric modulator of Mu and Delta opiate receptors,(91A) GPR55 agonist,(86A) Phospholipase A2 Modulator,(70A) CB1 and CB2 partial agonist.(41B)
Δ9-THC is the main psychoactive cannabinoid in the marijuana plant. It is commonly used for stimulating appetite to treat weight loss with patients with AIDS. It is also effective with reducing nausea and vomiting associated with chemotherapy cancer treatment.(41B)
Metabolites of Δ9-THC
11-Hydroxytetrahydrocannabinol (11-OH-THC)
This metabolite is often referred to as 11-hydroxy-THC. It is produced in the liver with the cytochrome CYP2C9 enzyme. It is mostly associated with the metabolism of the ingestion of THC edibles.(42B) 11-hydroxy-THC is several times more potent than Δ9-THC.(43B)
11-Nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH)
THC-COOH is the inactive metabolite that remains in the body for weeks, and is the target for drug testing.(42B)
Medication analog of THC
Marinol (Dronabinol) is a DEA Schedule 2 controlled substance that is a synthetic form of Δ9-THC. (41B)
Cognitive deficits from THC use
Chronic use of THC can lead to cognitive deficits, including: an impaired ability to focus attention and filter out irrelevant information.(44B) This impairment can persist for at least 7 days after stopping the use of THC, while some people could be affected for up to a month after they stopped THC use.(45B) It is possible that using enough CBD could prevent this cognitive impairment from the neuroprotective benefits of CBD, and how that cannabinoid modulates how THC acts on the CB1 receptor. The ratio of CBD to THC needed to prevent that might vary from person to person, and the type of terpenes being used. Chronic use of a-pinene strains would likely be more neuroprotective from that terpene acting as an acetylcholinesterase inhibitor. While decreased acetylcholine from linalool could have the opposite effect.
Delta 8 THC
Delta 8 THC is a CB1 agonist (44E)
Delta 8 THC has less research available compared to Delta 9 THC. It is less psychoactive than Delta 9 THC. The research so far shows that Delta 8 THC might have the benefits of being an antiemetic, anxiolytic, appetite-stimulating, analgesic, and neuroprotective activity.(46B)
Some adverse effects reported from Delta 8 THC include: hallucinations, vomiting, tremor, anxiety, dizziness, confusion, loss of consciousness, and even 1 pediatric death. Edibles like brownies and gummies infused with Delta 8 THC were responsible for 68% of the reported adverse effects.(47B)
THCA
Tetrahydrocannabiorcolic acid
TRP Receptors THCA interacts with: TRPA1 partial agonist, TRPV2 agonist, TRPM8 antagonist(3A19A)
Other actions of THCA: PPARy agonist(48B) Δ9-THCA activates PPARy stronger than THC.(49B)
THCA offers neuroprotection and is a possible treatment for Huntington’s Disease and Neurodegeneration
Δ9-THCA has potent neuroprotective effects through activating PPARγ, this improves mitochondrial function, prevents cytotoxicity, protects against striatal degeneration, and reduces neuroinflammation. These functions together suggest that Δ9-THCA could be a valuable treatment option for Huntington’s disease and other neurodegenerative conditions.(49B)
THCA was found to improve memory deficits, and reduce amyloid-beta and Tau pathology in mice with Alzheimer’s Disease.(50B)
THCA for TRPM8 Inhibition
THCA is more stable than CBDA during decarboxylation over time, making it a good option as a TRPM8 antagonist that is easy to obtain. Filling an empty capsule with dried cannabis flowers is an effective method of administering THCA. Grinding the buds first may expose the trichomes to oxidation, potentially converting some into CBN or triggering partial decarboxylation. From my experience, ground cannabis in a capsule feels more sedating compared to unground cannabis. Another option is to soak cannabis in MCT oil, but it will naturally decarboxylate over time. In my experience, the capsule method has been the best option for maintaining THCA content.
THCV
Tetrahydrocannabivarin
TRP receptors activated by THCV: TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, and antagonizes TRPM8.(3A,19A,20A,21A)
Other receptors and actions: CB1 antagonist, CB2 partial agonist.(69A,70A,71A) Small doses of THCV acts as a CB1 antagonist, while large doses of THCV acts as a CB1 agonist.(57B)
Areas that THCV can influence through TRPV4 activation include cardiomyocytes, endothelial cells, smooth muscle cells, lung, chondrocytes, neurons, astrocytes, and sperm.(58B,59B,60B,61B,62B)
THCV activation of TRPV4 in the immune system
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.(63B)
Can THCV cause breathing problems with COPD?
TRPV4 polymorphism is found with chronic obstructive pulmonary disease (COPD). TRPV4 agonists can cause bronchoconstriction, while TRPV4 antagonists will reverse that.(64B) There is a possibility that THCV could also cause airway constriction, particularly when smoked or inhaled, due to its possible TRPV4 agonism, which might exacerbate airway narrowing.
How can THCV act as a stimulant?
TRPV4 agonists increase the release of adenosine triphosphate (ATP).(64B) THCV’s potential to increase ATP release may contribute to its stimulant effects and potentially activate the sympathetic nervous system, leading to a stimulatory response.
Does THCV cause appetite suppression or an increase in appetite?
TRPV4 activation will increase the secretion of the hormone ghrelin. THCV is an agonist of TRPV4. That receptor is overexpressed in the stomachs of obese people, and an increase in ghrelin secretion occurs when the stomach is stretched.(65B)
THCV is a CB1 antagonist.(71A) When CB1 is activated with an agonist, appetite is increased. CB1 blockade with an antagonist decreases appetite.(66B) THCV is typically referred to as an appetite suppressant, but some people get hungry with THCV.
Does THCV cause palpitations?
TRPV4 is upregulated from conditions such as: cardiac fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarction, arrhythmia,(58B) cystic fibrosis, ciliary beat frequency, bronchoconstriction, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, acute respiratory distress syndrome and cough.(59B)
If TRPV4 is overexpressed in the heart, then TRPV4 activation could increase the excitability of the heart muscle and contribute to palpitations. The additional ATP release from THCV's action could further amplify the stimulatory effects on the heart, increasing the possibility of palpitations.
THCV also activates TRPV3. TRPV3 activation can cause vasodilation that could contribute to palpitations through reflex tachycardia. TRPV3 activation also increases ATP release.(42A,43A)
How extra ATP can affect the heart
A study showed that a 68 year old patient had an ATP infusion for a diagnostic test. She had a tachycardia and a wide QRS complex. After the ATP was infused, she went into ventricular fibrillation probably because of sympathetic overdrive secondary to the ATP infusion.(67B) THCV will cause the release of ATP. (64B)
Does THCV cause bladder contractions or increased urination?
TRPV4 in the bladder is responsible for giving a full bladder sensation through the activation of those receptors from the stretching of the bladder.(68B) THCV activating TRPV4 in the bladder could give people that sensation that the bladder is full when it really is not, and even lead to bladder contractions.
THCV as an anti-inflammatory
THCV reduces inflammation by inhibiting NF-κB and cytokine production pathways, including P2X7 and NLRP3 inflammasome assembly. It also blocks pathways that contribute to cytokine storms (excessive inflammation).(69B)
THCV lowers blood sugar in type 2 diabetics
THCV can increase insulin sensitivity and decrease plasma glucose through increasing pancreatic b-cell activity, adiponectin, and Apo A concentrations. THCV was more effective at lowering blood sugar than CBD.(57B)
Type 1 diabetics might notice blood sugar being lowered more with THCV and insulin administered together compared to insulin without THCV due to an increase of adiponectin, and Apo A concentrations.
THCV for reducing panic
There is no research available to explain why THCV can reduce panic. It could be from the stimulant effects of THCV that desensitizes the nervous system to our body’s response to adrenaline secretion.
Does THCV cause anxiety?
There is no research available to explain why this can happen to some people. Since THCV acts as a stimulant, people that get anxiety from stimulants like caffeine or adrenaline spikes in the body would likely get anxiety from THCV.
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