Cannabidiol

Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from Cannabis sativa that has recently attracted considerable attention from the scientific community due to its claimed beneficial properties and therapeutic potential (Casiraghi A et al. 2020). Cannabidiol, like all cannabinoids, is predominantly present in the plant as an acid(CBD carboxylic acid).

Medical cannabis is currently legalized in Canada, 31 states in America and 19 countries in Europe (Sheriff Tet al. 2020). In Germany, cannabidiol has been subject to prescription for several years. In contrast to tetrahydrocannabinol, cannabidiol is not subject to the provisions of the Narcotics Act in Germany.

Products containing cannabidiol can be soldas food supplements or cosmetics as long as the THC content in the products is below 0.2 percent.

CBD has been attributed anti-proliferative, pro-apoptotic, cytotoxic, anti-invasive, anti-antiangiogenic, anti-inflammatory, antipruritic, and immunomodulatory properties (Kis B et al. 2019; Sheriff Tet al. 2020).

The exact mechanism of action of cannabidiol is not yet well understood.

Cannabidiol binds agonistically to the cannabinoid receptors CB1 and CB2, among others. However, it can also block the activity of these receptors. Furthermore, cannabidiol acts as an antagonist at the G-protein coupled receptor GPR55. It is suspected to act on the voltage-dependent anion-selective channel protein 1 (VDAC1), which is expressed on mitochondria. These channels play a role in calcium transport in cells (transmission of electrical signals in nerve cells).

CBD is used worldwide for numerous conditionsfor which there is no scientific evidence of the drug's efficacy (Huestis MA et al. 2019). Larger surveys of CBD users found that take the drug to manage self-perceived anxiety, stress, sleep disturbances, and other symptoms, often in low doses, and these patterns vary by demographic characteristics (Moltke J et al 2021).Fundamentally, the effects of the products depend on the purity, preparation, and concentration of CBD and other ingredients. However, there is a lack of consensus regarding their preparation, composition, use and efficacy. Thus, comparisons regarding efficacy and side effects are also possible only with limitations (Arzimanoglou A et al. 2020).

Approved indications for systemic applications:

• Multiple sclerosis (Nabiximols): CBD is a component of the medicinal hemp extract Nabiximols (alcoholic cannabis extract as a subligual spray), which is used as a spasmolytic in multiple sclerosis. It has been available for this indication since 2011.
• Refractory epileptic syndromes in childhood (Huestis MA et al. 2019): Cannabidiol has been approved for rare forms of epilepsy since October 2019 (commercial preparation: Epidyolex). Cannabidiol is used, together with clobazam, in patients aged 2 years and older for the adjunctive treatment of seizures, associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS). Cannabidiol is used in patients 2 years of age and older for the adjuvant treatment of seizures associated with tuberous sclerosis (TSC). The recommended starting dose of cannabidiol for this indication is 2.5 mg/kg (5 mg/kg/day) twice daily for one week. After one week, the dose should be increased to a maintenance dose of 5 mg/kg (10 mg/kg/day) twice daily. Depending on individual clinical response and tolerability, each dose may be increased in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day) up to a maximum recommended dose of 10 mg/kg twice daily (20 mg/kg/day). Discontinuation of the preparation: If cannabidiol is discontinued, the dose should be gradually decreased. In clinical trials, cannabidiol discontinuation has been accomplished by decreasing the dose by approximately 10% per day for 10 days. Slower or faster titration may be clinically necessary at the discretion of the treating physician.

Non-approved indications for systemic applications: In addition to those approved, there is insufficient or no evidence of efficacy for other indications. This applies to the following conditions:

• Other forms of epilepsy: Reported significant improvement in primary endpoints e.g. psychotic symptoms, anxiety, seizures. Doses ranged from <1 to 50 mg/kg/d. CBD was reported to be well tolerated.
• Miscellaneous conditions: Small randomized controlled trials (n = 6-62; doses average 2.4 mg/kg/d)) have investigated the following conditions: diabetes mellitus, Crohn's disease, ocular hypertension, fatty liver, chronic pain. However, the results of these studies require corresponding evidence from verifiable clinical study results.
• SARS-CoV2: Cannabis sativa extracts with high cannabidiol content are able to down-regulate the expression of the two key SARS-CoV2 receptors. Cannabidiol exerts a wide range of immunomodulatory and anti-inflammatory effects and may attenuate uncontrolled cytokine production in SARS-CoV2 infection (Esposito G et al 2020).

Topical applications: Cannabidiol is available in products such as oils, creams and sprays. These CBD products are not approved medications. Their clinical efficacy is uncertain. Animal experiments showed that CBD was absorbed within 10 minutes after intranasal application with a bioavailability of 34-46%. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 +/- 2.1 ng/ml, which was reached after 15.5 +/- 11.7 hours. The achievement of a significant steady-state plasma concentration suggests that CBD is adequately absorbed transdermally (Paudel KS et al.2010).

Unapproved dermatological indications:

• In reviewing the current literature, it crystallizes that cannabinoid products have been used for a variety of skin conditions. These include: pruritus, acne, allergic contact dermatitis, asteatotic dermatitis, atopic dermatitis, hidradenitis suppurativa, Kaposi's sarcoma, psoriasis, carcinomas of the skin, and the cutaneous manifestations of systemic sclerosis. However, most studies are poorly powered from a scientific perspective. Thus, there is a lack of high-quality randomized controlled trials that can clearly assess the effects (Eagleston LRM et al. 2018; Sheriff Tet al. 2020).
• UV protection by CBD: Evidence of cytoprotective compound against UV-induced metabolic changes in fibroblastic skin cells (Gęgotek A et al. 2019).

CBD is not risk-free. Preclinical and clinical studies have reported adverse effects (ADEs) and toxicity following CBD ingestion.

In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injury, reduction in spermatogenesis, organ weight changes, alterations in the male reproductive system, and hypotension (although at higher doses than recommended for human pharmacotherapies).

In humans, systemically applied cannabidiol may cause drowsiness and dizziness (10%). Symptoms are more common at the beginning of treatment and may subside with continued treatment. They are more severe in patients receiving concomitant clobazam. Other CNS depressants, including alcohol, may increase somnolence and sedation effects.

Other adverse effects are known for CBD in humans:

• very common: drowsiness and dizziness (10%).
• frequently: malaise, diarrhoea, loss of appetite, skin rashes
• insomnia, sleep disturbances, inner restlessness
• increased incidence of infections (Huestis MA et al. 2019).

There are marked pharmacokinetic interactions with other antiepileptic drugs, especially clobazam.

Hypersensitivity to the active substance. Patients with elevated transaminase levels exceeding three times the upper limit of normal and bilirubin levels exceeding two times normal.

Caution should be exercised with regard to prescribing in patients with moderate (Child-Pugh B) or severe hepatic impairment (Child-Pugh C). A lower starting dose is recommended in patients with moderate or severe hepatic impairment. Dosage titration should be performed as indicated in the table below.

Food supplements: In Germany, foods containing cannabidiol are offered in the food supplement sector without health claims, but with an explicit reference to the contained CBD. When CBD is administered orally in a corn oil formulation, no bioconversion to THC occurs in humans (Crippa JAS et al. 2020).

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