Poor absorption is a challenge in cannabinoid-based therapy with oral formulations having as low as 4% bioavailability. [1] Increased absorption formulations increase the efficiency and effectiveness of the treatment while also bringing consumer costs down. Theralogix has just launched a broad-spectrum cannabidiol (CBD) product that uses patented technology called VESIsorb® to enhance the absorption of cannabinoids and terpenes. T&T interviewed Mark H. Ratner, M.D., the chief science officer at Theralogix, who shared his insights on the journey and science that led to the creation of TheraHemp®.
Meet Mark.
Can you briefly narrate how you found yourself in the legal cannabis industry?
It’s been a slightly circuitous journey! Our company, Theralogix, has had a strong and growing presence in the reproductive health world for nearly 10 years. Our fertility supplement/prenatal vitamin products are used by more than half the in vitro fertilization (IVF) practices in the U.S. Roughly four years ago, we were researching ‘natural’ approaches to the treatment of endometriosis, a common and debilitating condition because of female infertility, when we came across European studies using PEA – palmitoylethanolamide – an endocannabinoid compound that is also found in certain foods. PEA is produced in human tissues and serves, in some respects, as our ‘body own’ version of CBD. It has anti-inflammatory and analgesic benefits that have been proven in multiple clinical trials. [2] Ultimately, in 2019, we launched a product – Canabrex® – which provides enhanced-absorption PEA.
Our research and development with PEA led us to a strong interest in the human endocannabinoid system and the way in which phytocannabinoids and terpenes affect it. We have several rheumatologists on our Medical Advisory Board, and they quickly became interested in the potential immunomodulatory, anti-inflammatory, and analgesic benefits of hemp/CBD. We spent over a year researching optimal raw materials. Finally, when NSF® International launched the first non-profit, industry-independent hemp/CBD certification program, we chose to produce the first enhanced-absorption, independently-certified broad-spectrum CBD product – TheraHemp®.
What does it mean to receive NSF International content certification?
NSF International is a non-profit standards and testing organization based in Ann Arbor, Michigan. Twenty years ago, they launched the first independent, third-party certification program for dietary supplements. NSF product certification requires the manufacturer to follow a comprehensive program which includes manufacturing facility inspections and good manufacturing practices (GMP) certification, NSF lab testing that validates the content and purity of all label claims, and a complete review of all product labels and marketing materials to assure FDA and Federal Trade Commission regulatory compliance. Every eligible Theralogix product is NSF certified.
In 2020, NSF launched the first independent (i.e. not industry-controlled) certification program for hemp/CBD products. Our product, TheraHemp®, is an enhanced-absorption, broad-spectrum hemp oil softgel, and was the first to achieve certification through NSF’s program. Each softgel provides 20 mg of CBD and 8 mg of beta-caryophyllene. TheraHemp is certified to have ‘non-detectable’ THC, meaning a level below 100 parts per million.
The NSF ‘seal of approval’ provides assurance of content accuracy and purity that consumers must have. The ‘non-detectable’ level of THC provides important assurance for individuals that are subject to work-based drug testing, including commercial drivers, first responders, active members of the military, and others.
Can you briefly describe the VESIsorb delivery system?
VESIsorb® is a patented excipient system that was developed by a Swiss pharmaceutical company – VESIfact AG®. VESIsorb is considered a SEDDS – a ‘self-emulsifying drug delivery system’ designed to enhance the absorption and bioavailability of fat-soluble active pharmaceutical ingredients or APIs. The precise composition of VESIsorb can vary depending on the API and application, however, it is a lipid-based formulation that self-assembles in an aqueous environment into a colloidal delivery system. This colloidal solubilization improves the transport of fat-soluble APIs such as coenzyme Q-10, vitamin D, or cannabinoids, through the aqueous phase of the gastrointestinal lumen to the absorptive epithelium, significantly improving bioavailability.
How was the bioavailability of VESIsorb evaluated?
A 2019 German study published by Knaub et al in the journal Molecules examined the absorption and pharmacokinetics of CBD-VESIsorb vs. CBD in medium-chain triglycerides (MCT). [3] They studied 24-hour blood levels in 16 fasting individuals who were given oral doses of each preparation.
Compared to CBD-MCT, CBD-VESIsorb produced a 440% increase in the maximum blood level of CBD and a 285% increase in the total absorption of CBD over 24 hours. In addition, the ‘peak level’ (TMax) for blood CBD occurred after one hour in the VESIsorb group, compared to three hours in the MCT group.
Regarding your product that combines the effects of CBD with beta-caryophyllene, how did you settle on effective doses of each molecule?
The 20 mg CBD dose was chosen primarily to comply with the requirements for finished product approval by the NSF International Hemp/CBD Certification Program. However, that program has recently raised its ‘dose limit’ and we will most likely produce higher CBD, NSF-certified products in the future.
The beta-caryophyllene (BCP) content was primarily chosen for safety considerations. BCP is found in many foods and spices, and was approved as generally recognized as safe (GRAS) by the FDA in 1997. The average dietary intake in the U.S. has been estimated at 10 mg daily. However, BCP has been clearly shown to be a direct agonist for the CB2 receptor. As such, it has significant immunomodulatory and anti-inflammatory effects. The safety of long-term higher doses, however, has never been studied.
Most hemp/CBD products contain very small amounts of BCP – typical daily doses are well below one mg. One TheraHemp softgel provides eight mg of BCP. This is a dose designed for safety since it is comparable to the amount found in daily dietary intake in the U.S.
Any particular reasons why you chose caryophyllene?
Many terpenes have shown bioactivity, however, only one has shown clear evidence of binding to human cannabinoid receptors. Nearly 15 years ago, BCP was found to be a direct agonist for the CB2 receptor. [4] CB2 receptors are found throughout the immune system, particularly on various types of white blood cells. When activated, the CB2 receptor downregulates the immune response, moderating the release of pro-inflammatory cytokines and chemokines, and reducing the activity of neutrophils, macrophages, and monocytes.
While human clinical research is still underway, many pre-clinical and animal studies have documented the ability of BCP to provide relief for chronic neuropathic or inflammatory pain.
Will you be creating other products that maximize other terpenes?
Randomized clinical trials are underway to examine the effect of various other terpenes, including myrcene, linalool, pinene, and limonene on several endpoints, including sleep, analgesia, and anxiety. As results become available, we fully intend to apply new findings to our product development.
References
[1] McGilveray I. J. Pharmacokinetics of cannabinoids. Pain Research & Management. 2005;10 Suppl A:15A–22A. [journal impact factor = 3.037; times cited = 151][2] Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932-942. [journal impact factor = 4.335; times cited = 75]
[3] Knaub K, Sartorius T, Dharsono T, Wacker R, Wilhelm M, Schön C. A novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology improving the oral bioavailability of cannabidiol in healthy subjects. Molecules. 2019;24(16):2967. [journal impact factor = 4.411; times cited = 26]
[4] Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-9104. [journal impact factor = 11.2; times cited = 613]
