Accurate Education – Marijuana (Cannabis): Cannabinoids

Cannabiniods

Δ-9 THC (Tetrahydrocannabinol)

Δ-9 Tetrahydrocannabinolic Acid (Δ-9 THCa)

Δ-9 Tetrahydrocannabinolic acid (Δ-9 THCa or 2-COOH-THC) is a precursor of tetrahydrocannabinol (Δ-9 THC), the major active component of cannabis. Δ-9 THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated and converted to Δ-9 THC with drying or with exposure to intense heat, although slow decarboxylation of ∆9-THC occurs at room temperature during aging.

Proposed benefits of THCa include:

• Immunomodulatory;
• Anti-inflammatory;
• Neuroprotective;
• Antineoplastic

More than 90% of the THC in cannabis plants grown in Europe is present as Δ-9 THCa, while cannabis grown in hot climates of Africa and Asia contain considerable more Δ-9 THC. The ratio of ∆9-THCa to ∆9-THC in leaves and flowers of Cannabis sativa has been reported to range from 2:1 in Africa to > 20:1 in Switzerland. In samples of cannabis resin (hashish) the Δ-9 THCa/Δ-9 THC ratio is reported to range between 6.1:1 and 0.5:1.

For Δ-9 THCa to become activated and converted to Δ-9 THC for therapeutic use, it generally must be exposed to intense heat such as when cannabis is smoked or cooked into cannabis edibles. Δ-9 THCa is often the main constituent in cannabis resin concentrates, such as hashish and hash oil comprising 50% – 90% by weight.

It has been reported that five minutes of heating to 200-210°C is optimal for this conversion, a few seconds in a burning cannabis cigarette is sufficient. Cannabis products with a high content of Δ-9 THC (e.g., hashish) may be very potent without heating, but usually the potency and medicinal efficacy of cannabis products is significantly increased with smoking the dried plant matter, or by cooking and baking.

Δ-9 THCa ‘s potential benefits include reducing inflammation associated with arthritis and autoimmune diseases. It may also help reduce symptoms of neurological conditions such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Δ-9 THCa is not psychoactive like Δ-9 THC but it does have some immuno-modulating effects but they are not mediated by the cannabinoid CB1 and CB2 receptor pathways. Δ-9 THCa is a TRPA1 partial agonist, and a TRPM8 antagonist which may underlie a potential role in the analgesia, and anti-inflammatory and anti-nausea properties. 

Proposed benefits of THC include:

THC has analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, while CBD is non-euphoric but has anti-anxiety, anti-depressant, anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is a versatile anti-inflammatory analgesic through numerous distinct mechanisms.

The clinical benefits from marijuana are derived from the many constituents found in the plant, including more than 80 pharmacologically active cannabinoids. The two best understood and most common of these cannabinoids are THC (tetrahydrocannabinol) and CBD (cannabidiol). There is very limited scientific information on the pharmacology and toxicology of the other cannabinoids and pharmacologially active constituents found in cannabis. THC acts as a CB1 receptor partial agonist, while CBD is a negative allosteric modulator of the CB1 receptor.

See:

Δ-9 THC

Delta 8 Tetrahydrocannabinol (Δ-8 THC)

See: Δ-8 THC

CBD (Cannabidiol)

See: CBD (Cannabidiol)

Proposed benefits of CBD include:

• Anticonvulsive;
• Anti-inflammatory and immunosuppressive (psoriasis, atopic dermatitis, and abrasions);
• Neuroprotective and antioxidative;
• Antipsychotic;
• Counteracts the intoxicating effects of cannabis;
• Anxiolytic;
• Addiction treatment;
• Antimicrobial (Gram-positives bacterial cutaneous infections);
• Anti-tumor

Cannabadiolic Acid (CBDa)

Cannabidiolic acid (CBDa) is a phytocannabinoid found in raw cannabis, meaning fresh flowers and leaves that are unheated. CBDA is decarboxylated to CBD with heat and light exposure. CBDa is often ingested through consumption of raw cannabis juice. Like THCa, CBDa is a TRPA1 agonist, TRPV1 agonist, and TRPM8 antagonist which may underlie a potential role in the analgesia, and anti-inflammatory and anti-nausea properties. CBDa is a powerful anti-emetic and anti-anxiety agent (at least in rodents), and has anecdotal reports of benefit on skin and tumors.

Mechanism of Action of CBDa

In a 2020 study, CBDa was inactive at CB1 receptor (CB1R) and displayed only weak partial agonism at CB2 receptor (CB2R).  Apart from CB1R and CB2R activity, CBDa produces significant anxiolytic effects and is effective in reducing inflammatory pain, nausea and seizures in rodent models. Growing research suggests these effects of CBDa are mediated by 5HT1A.

The exact functions of CBDa and THCa physiologically suggest similar therapeutic benefits to CBD that may have the potential to work synergistically with CBD. These synergistic properties known as the “entourage effect” are currently thought to be the primary reason that lower CBD whole hemp extract dosing can be more therapeutic when compared to purified CBD.

THCa and CBDa concentrations depend on the species, strain, cultivation, and storage of the plant. The average concentrations in more than 30,000 cannabis preparations confiscated in the U.S. between 1980 and 1997 were 3.1% THCa and only 0.3% CBDaa. Various strains and marijuana-based products are now available that contain substantially higher contents of these constituents, especially THC.

CBD does not produce the mind-altering “high” effects like euphoria but it does reduce anxiety and enhance sleep. It has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. CBD is also thought to reduce nausea, particularly related to chemotherapy. CBD, in combination with THC, modulates some of the side effects of THC, including reducing THC-induced anxiety.

See: CBD (Cannabidiol)

CBDV (Cannabidivarin)

CBC (Cannabichromone)

Proposed benefits of CBC include:

• Analgesic;
• Anti-inflammatory

CBG (Cannabigerol)

CBGa (Cannabigerol Acid)

CBGa is not intoxicating and is a weak antagonist to the CB1 receptor. It has been shown to have antioxidant actions and animal studies suggest they may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer, and skin disorders.

Cannabigerol acid (CBGa) is notable among all other cannabinoids as being the precursor to each one of them as noted above, lending to its nickname: “The Mother All Cannabinoids.” The cannabis plant produces CBGa which in turn is converted to either CBDa, CBCa or THCa In particular, it has a direct link to the three most significant and abundant cannabinoids: THC, CBD and CBC. Therefore, the more THC a cannabis plant contains, the less CBG and vice-versa.

CBG is non-psychoactive and is found in the fresh cannabis plant. CBG is made by the decarboxylation of cannabigerolic acid (CBGa). CBG is a highly potent agonist for α2-adrenoceptor and a blocker of serotonin 5-HT1A receptor. This activity can decrease anxiety and muscle tension.

CBN (Cannabinol)

The third most common constituent of marijuana is cannabinol (CBN). Cannabinol (CBN) is a non-psychoactive cannabinoid found in fresh cannabis plant, usually in low amounts.  Unlike other cannabinoids, CBN does not stem from cannabigerol (CBG/CBGa) but is the nonenzymatic oxidative breakdown product of tetrahydrocannabinol (THC), seen in aged cannabis, and has about 25% of the potency of THC. In the evaluation of the freshness of a dried cannabis product levels of CBN, coupled with levels of THCa can potentially identify if the cannabis product has been stored properly. CBN is also formed by decarboxylation of CBNa but it is not yet (?) commercially available as an isolated compound.

CBN likely plays a small role in the pharmacologic effects of plant based cannabis products, but does show similar therapeutic properties to other phytocannabinoids, including pain relief as well as insomnia, anticonvulsant, anti-inflammatory, and antibacterial activity. 

Combined THC, CBD and CBN

A crossover, placebo controlled study published in 2021 assessed the use of a multi-cannabinoid medication  containing THC, CBD and CBN for insomnia. The test medication contained THC 20 mg/mL, CBN 2 mg/mL, CBD 1 mg/ mL and naturally occurring terpenes, extracted from a cannabis plant.  The placebo contained the same terpenes, but no cannabinoids, extracted from the same cannabis plant. Participants were given 0.5-1 ml sublingually for the study  (up to 20 mg THC, 2 mg CBN and 1 mg CBD).

The average total time spent asleep each night increased by 33.5 minutes and sleep efficiency increased by 2.9%–84.8%. The mean total time spent asleep across the 2-week period was over 7 hours while taking the medication (the recommended minimum sleep duration for adults, and above average for individuals of comparable age without insomnia).

Their data also suggested that for patients with sleep onset insomnia dosing 2–4 hours before desired bedtime might be optimal, while those with sleep maintenance insomnia should dose 1 hour before desired bedtime. It was concluded that nightly sublingual use of this cannabinoid formulation for 2 weeks improved insomnia symptoms without significant adverse events.

Based on preclinical and animal studies, cannabinol (CBN) is purported to be possibly helpful for treating:

• Neurological conditions including seizures
• Severe muscle stiffness
• Inflammatory conditions
• Neuropathic pain
  
• Insomnia
• Glaucoma
• ADD
• Loss of appetite
• Antibiotic (with anti-MRSA activity)