Cannabidiol (CBD) is a bioactive cannabinoid of the plant Cannabis sativa L. Unlike tetrahydrocannabinol (THC; D9-tetrahidrocannabinol), CBD has non-psychotropic effects and is consumed as a food supplement by millions of people today1,2. There are almost 1200 studies, reported on ClinicalTrials.gov, exploring the potential indications of CBD on Parkinson’s disease, stroke, inflammations, epilepsy, chronic pain and many psychiatric conditions3-6. Previous studies have demonstrated that the oral bioavailability of CBD is very low7,8. Methods for accelerating the transport of ingested CBD to the bloodstream and preventing first-pass (hepatic) metabolism have been created through the use of inventive dietary supplements with various lipid formulations9-11. As interest in cannabidiol (CBD) as an important ingredient for health and wellbeing grows, innovative pharmaceutical companies are focused on creating more individualized and bioavailable delivery systems.
In Croatia, the Agency for Medicines and Medical Products (HALMED) approved the cannabidiol-based drug Epidyolex, which was also approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), with the availability of all relevant data on the drug, including interactions with other drugs12-14. CBD is registered in the European Union under the name Epidyolex, but in the USA it is officially known as Epidiolex. Marinol® and Syndros® (both contain dronabinol), and Cesamet® (nabilone) are synthetic cannabinoids approved by the FDA. Dronabinol and nabilone are indicated for nausea and vomiting, mainly in malignant diseases. The EMA has also approved Sativex® (oral spray, solution) containing nabiximol (THC:CBD=1:1), indicated for spasticity in multiple sclerosis. This paper reports on two randomized, placebo-controlled, crossover studies that assessed the effects of a new lipophilic oral CBD formulation (DehydraTECHTM2.0 CBD) on hypertensive participants. Important results include CYP450-genotype-dependent metabolism, sex-based pharmacokinetic variations, and improved early cardiovascular effects. These findings are extremely important for nutraceutical makers exploring efficacy and safety.
The patented process that dehydrates long-chain fatty acids high in oleic acid with CBD, reduces the metabolism of the first pass through the liver. Therefore, the DehydraTECH™2.0 CBD formulation has increased and accelerated bioabsorption of the active content. The effects of the unique DehydraTECH™2.0 CBD formulation were evaluated and compared with the effects of generic CBD in our initial study (HYPER-H21-1)15.
The primary indication of increased CBD concentration was found to be a decrease in heart rate, with the bioavailability-enhanced formulation demonstrating a greater impact than generic CBD. Additionally, the DehydraTECH™2.0 CBD formulation demonstrated a superior impact on the initial lowering of MAP (mean arterial pressure) and diastolic blood pressure. Due to CBD’s improved absorption, nearly every participant ingesting DehydraTECH™2.0 CBD displayed higher concentrations of CBD in their plasma and urine samples.
Based on gender, our study’s findings revealed variations in CBD metabolism. In urine samples taken 180 minutes after ingesting DehydraTECH™2.0 CBD, men’s CBD concentrations were significantly greater than women’s.
Six of the 24 participants in the initial study were receiving medication therapy (levothyroxine, lorazepam, diazepam, celecoxib, and acetylsalicylic acid).
Their samples’ CBD concentration values significantly differ from the mean values. We conclude that the metabolism of CBD can be affected by the consumption of these prescription drugs (as well as all other drugs metabolized by the same CYP P450 enzymes), and that this should be considered when calculating the optimal dosage of CBD.
During or following the research, no significant adverse effects have been noticed or reported. The only minor adverse effects were noted: relaxation with drowsiness and diarrhea after taking generic CBD, and relaxation without drowsiness after taking DehydraTECH™2.0 CBD.
To observe the relationship between the achieved concentration of CBD in the samples and the metabolism with the genetic variability of cytochrome P450, the study included the analysis of polymorphisms of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*17 and CYP3A4 genes. After ingesting the DehydraTECH™2.0 CBD formulation, participants with a slow/weak metabolizer (engl. poor metabolizer-PM) at CYP2C9*2*3 enzyme showed increased CBD concentration in the plasma in 180 minutes.
For the first time, during a 12-week period, the concentrations of CBD and metabolites were analyzed in our second study (HYPER-H21-4)16.
Men had higher concentrations of CBD than women did, according to an analysis of the CBD concentrations in plasma at the first time point of testing, which was measured 2.5 weeks following CBD ingestion. At the next time point (after 5 weeks), the concentration of CBD was higher in women than in men. Even when they stopped taking their CBD medication and entered a two-week washout period, the study revealed noticeably greater CBD concentrations in women than men.
CBD accumulates more easily in a lipophilic environment because of its high lipophilicity. This slows down the elimination process and affects the cumulative concentration.
Women had much larger percentages of body fat than men did, but their percentages of muscle tissue and water were significantly lower. The increased levels of CBD in women’s plasma at later test periods are presumably explained by this.
Unlike men, who did not have a single sample that was positive for CBD or its metabolites, the woman’s plasma revealed that it contained CBD even 50 days after the last consumption of the CBD preparation. Men had a lower percentage of fat tissue than women, and since there was less CBD accumulation in fat tissue, there was more CBD in the bloodstream. In addition, CBD is eliminated in the urine, excreting from the body faster in men than in women. Compared to men, women had significantly higher levels of 7-COOH-CBD metabolites at all time points.
The concentrations of CBD and its metabolites in the samples did not differ significantly from the results for subjects who were not receiving therapy for hypertension, including angiotensin-converting enzyme-ACE inhibitors, calcium channel blockers, and thiazide diuretics.
Our clinical studies were complemented by a survey assessing the understanding and attitudes of Croatian physicians, pharmacists, and students in Split, Zagreb, and Osijek toward the therapeutic use of cannabidiol (CBD)17. The pharmacological understanding of pharmacists, physicians, students, patients, and recreational users about cannabis and medications derived from cannabinoids is inadequate, according to earlier research done in various nations18-22.
The majority of participants claimed that they needed more information regarding CBD, indicating that both groups lacked knowledge about the substance.
Students were found to consume CBD at a considerably higher rate than physicians and pharmacists. Compared to university students, a much higher proportion of doctors and pharmacists read scientific articles on CBD.
Even though they have considerable knowledge about the benefits, side effects, and interactions of CBD, medical professionals commonly do not prescribe or promote it.
We believe that, apart from a lack of knowledge, the explanation is the high price of the product. This is why medical professionals generally think that health insurance should cover the cost of this prescription drug.
CBD is rapidly establishing itself as a premium functional ingredient in the dietary supplement industry. Despite strong consumer interest, healthcare practitioners in Croatia report insufficient formal education, which limits their readiness to recommend CBD products. Formulations targeting stress management, sleep support, and inflammation remain the most in demand, while differentiation through extraction technology, product stability, and certified purity will be essential for competitive positioning in the nutritional supplement market.
Contact: ana.batinic05@gmail.com
References:
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