What is the difference between Δ-8 THC and Δ-9 THC?
By: Info Korasana
The attention for the cannabinoid Δ-8-tetrahydrocannabidiol began in the 1980s, where its rapid action to cross the blood-brain barrier, passing from the blood to the brain, was proven, and studies focused on its pharmacological effects were then started (1, 2.10). According to the U.S. Cannabis Council, Δ-8THC is an isomer (chemical analog) of Δ-9THC, having lower psychotropic po- tency (approximately 75%). In recent years it has been widely commercialized in the United States. The National Cancer Institute (US) has defined Δ-8THC as “A tetrahydrocannabidiol (THC) analog with anti-emetic, anxiolytic, appetite-stimulating, analgesic and neuroprotective properties (1,3,7).
What is the difference between Δ-8 THC and Δ-9 THC?
The cannabinoid structures (THC) that have the potential to interact with the human organism are Δ-9THC, Δ-8THC, TH-C-V, and THC-A. In addition to small structural differences between these molecules (Figure 1), eventually and naturally in metabolization, Δ-8THC ends up being transformed into Δ-9THC (5,6,8). It is reported even described as “light marijuana” or “pain relief with less psychotropic activity”. Present at low levels in the cannabis plant, lower than Δ-9THC, it ends up being often synthesized from THC or even from CDB (3,7).
Due to this fact, it has milder effects and less adverse effects when comparing the action of Δ-9THC, for example, anxiety and other psychotropic effects such as cognitive deficit (4,7). The in vivo and in vitro stereochemical metabolism of both molecules are similar, and Δ-8THC is chemically more stable, does not undergo oxidation, and ends up preserving its original properties for longer than Δ-9THC (10).
In the Cannabis plant, concentrations vary a lot according to genetics, but normally we can say that approximately 20% of the plant weight corresponds to Δ-9THC and 0.3 to 0.5% to Δ-8THC (5). This information is not well described in the literature due to the wide variety of strains (8).
Mechanism of Action
A partial agonist of CB1 and CB2 binds to G protein, located in the CNS. Receptor binding and activation of the arachidonic acid cascade (8), including an Adenyl- -cyclase, increases the activity of activated mitogen protein kinases, modulates several potassium channel conductors, and inhibits calcium channels. This agent also exhibits psychotropic potency such as Δ-9 THC, a primary form of THC found in Cannabis, which is neuroprotective. Activation of CB1 in the CNS causes depolarization induced by suppression of inhibition and excitation, reported to modulate hippocampal signaling. It also binds to CB2 receptors, related to an anti-inflammatory and neuroprotective action (1,7).
Its structure differs from Δ-9THC by a double bond on carbon atoms 8 and 9, instead of carbons 9 and 10. Due to this structural change, Δ-8THC has an affini- ty for the CB1 receptor and a lower affinity, however significant, for CB2 receptor, with a potency lower than Δ-9THC (6.9), favorable for supplementation.
• It relieves the highly potent effects of Δ-9THC in daily maintenance doses.
• Rescue in crises, for example, and for use in pediatric and elderly public, and in patients with milder symptoms or sensi- tivity (7) and for daily use.
Δ-8THC acts with nociceptive action, suppressing the sensation of pain, through binding with CB1 receptors, unlike CBD, which, despite also acting by binding to CB1, has a greater affinity for CB2 (1,7,9), which may be an adjuvant therapeutic strategy or even a unique one. There is still a need to carry out studies evaluating in greater depth its action on another important receptor for pain relief and nociception: the vanilloid receptors, but as well as the Δ-9THC, probably has potent action on TRVP1 providing relief and analgesia.
In the chronic phase of Amyotrophic Lateral Sclerosis (ALS), in which symptoms such as neurodegeneration, inflammatory lesions, loss of neuronal function, in addition to tremors, altered spasticity, and paralysis can be observed. The endogenous production of cannabinoids is naturally increased, demonstrating the body’s autonomous response to defend itself, with neuroprotective action and improvement of these symptoms by binding to CB1 and increasing immunity by binding to CB2 (17).
Following ingestion, it is metabolized by cytochrome P450, including CYP2C9 and CYP3A4, first converted to Δ-8THC and then to 11-nor-8-tetrahydrocannabinol-9-carboxylic acid. Finally, it undergoes glucuronidation by the action of glucuronidase enzymes to form 11-nor-8-tetrahydrocannabinol-9 carboxylic acid glucuronide, excreted in human urine (14).
In a study performed by Mechoulam’s team, published in the journal Life Sciences (7), the therapeutic action of this cannabinoid was evaluated in a pediatric cancer group, aged between 3 and 12 years old, treated with several antineoplastic drugs for more than 8 months, where total prevention of emesis (vomiting) was observed after antineoplastic application, with no adverse effects.
In a model to reduce pain and inflammation in the cornea, the topical application of cannabinoids was effective, being an association of CBD and Δ- 8THC (1). Both 9 and Δ-8THC have been shown to decrease eye pressure both in oral and intraocular use in humans and animals, which demonstrates the interest in the treatment of glaucoma with cannabinoids (10,11,12). A double-blind comparative study with 42 individuals, demonstrated post-traumatic stress relief even with low doses of THC. When applied higher doses, adverse effects such as bad mood were observed (18). In an observational study, where opioids were removed from animals, relief was observed in the behavioral symptoms observed during weaning (15). Other analyzes demonstrated anticonvulsant potential (3). THC showed to inhibit aggregation of beta- -amyloid plaques and reduce levels of GSK3beta and p-GSK3beta (16), but the activity of this action still needs to be further evaluated.
Adverse Effects and Safety
Regarding toxicity, the use of cannabinoids is usually safe and presents lethal doses only in large amounts, which was proven in a study of administration of Δ-8THC in monkeys, with a single dosage of 9000 mg per kg of weight, which was not it was lethal (13).
In a bulletin released by the Virginia State University of Health (US, 2021), the substance’s adverse effects are the same as those seen with its Δ-9THC metabo- lite: vertigo, bradycardia, and hypotension, confusion, and anxiety. Even so, most reports refer to not having the common adverse effects of Δ-9THC of paranoia, anxiety, and sedation (4). Even so, increased eye redness, dizziness, dryness of the mouth and throat, as well as fatigue, may occur. This is interesting because it helps in adjusting the patient’s dosage, which must be monitored in its intro- duction and therapy. Even so, symptoms such as increased body perception, we- akness, tachycardia, reduced motor coordination, recent memory lapses, drow- siness, and altered perception of time may appear, remembering that we should always prioritize the lowest dosages (1,2).
• Pain reduction
• Nausea and vomiting
• Stress and anxiety reduction
• Insomnia treatment
• Appetite stimulation
• Smoother action compared to
• Decrease in intraocular pressure (oral and topical)
• Neuroprotective action
• Prevents and treats muscle tension
Indications for Use
• Preventive of nausea and vomiting in patients undergoing chemotherapy
• Withdrawal crises
• Parkinsonian and withdrawal tremor
• Adjuvant in the therapy for the treatment of multiple sclerosis
• Adjuvant in CBD treatments • Pain
• Fibromyalgia and neuropathic pain • Stress and Anxiety
• Posttraumatic Disorder
• Depression, anorexia and bulimia
• Pediatric treatments
• Neurodegenerative diseases
• Prevention of emesis and nausea after chemotherapy application: Take one dose (according to weight guidance and dosage strategy) 2 hours before each chemotherapy treatment, and thereafter 24 hours with dosages every 6 hours.
• As it is a highly lipophilic molecule (6), administration with food is recommended.
• It is suggested to divide into 2 or 3 daily shots, which can be used as a rescue to optimize its absorption in the event of a crisis. • The suggested dosages are from 5 to 25mg per day, may vary in larger dosages, which can be safe if there are no adverse effects, and the posological introduction should be carried out gradually, avoiding high and unnecessary doses, starting with the minimum dosage.
• In a study with pediatric patients and chemotherapy treatment (7), a range from 20 to 40 mg per day (2 to 4 gums a day) was suggested.
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