We have been inundated with rhetoric regarding the legal commercialization of Cannabis sativa (marijuana) and its many hybridized variants for both recreational and compassionate medical use in a variety of situations.1 Many western states (Colorado, Washington, and Oregon) have legalized its cultivation and use,2 with at least 25 more states on board after the referendum of the 2016 general election. Dr. Sanjay Gupta presented an informative series on “cannabis capitalism” entitled Weed # 1, 2, and 3 on CNN, wherein he supports its medicinal but not its recreational use for a number of reasons.
Unfortunately, the federal government (DEA) has classified cannabis in Schedule I along with heroin, cocaine, and LSD as “drugs dangerous to public health and of no medical benefit.” Its growth and consumption have been handled within each state, while interstate transport for sale and use is a federal crime. This contradiction can be easily corrected by Congress and the DEA by reassigning cannabis out of Schedule I and into Schedule III with all the other marketed CNS-active drugs.3 Interestingly, cannabis is legal in Canada, the U.K., and the EU nations for both recreational and medicinal use. Many Asian countries have grown and used cannabis for generations as small family-owned crops, without any regulations or problems. There are many U.S. businesses licensed to grow cannabis on an industrial scale either in open fields or in large environmentally controlled greenhouses as the source of the raw material for extracting CBD for “compassionate medicinal use,4 without regard to its potential unlicensed recreational use, with the problem of prosecuting DUI cases left unsolved.5 Hemp, a related species of cannabis, is also cultivated as a source with a high yield of CBD and very low THC content. It has an added advantage in that the biomass left after the extraction process can be used in other industrial applications.
Glands of the flower buds of cannabis produce the euphoric agent delta 9-tetrahydrocannabinol (THC) along with a host of other yet-to-be-characterized cannabinoids, including cannabidiol (CBD)—the medicinally active compound reported anecdotally to control/reduce certain types of seizures in epileptics. CBD has also been reported to benefit people afflicted by PTSD and Parkinson’s and Alzheimer’s diseases, without any quantifiable clinical evaluation using statistically valid control studies in patient populations. However, considerable research was conducted at the NIH in the 1960s by Dr. Julius Axelrod and his team on the medicinal use of CBD in epilepsy and other CNS-related problems. They even took out a patent on its use in these situations, but it did not proceed any further.1
There is much real research that universities are ready to pursue once cannabis is decriminalized so that funds may be obtained through NIH grants. The chemical characterization and pharmacological evaluation of THC, CBD, and the many potentially active cannabinoids present in the relatively crude cannabis oil extracts/mixtures now being used to treat patients in the many legalized clinics open for business, where the patient will pay all expenses for treatment received, leaves room for much-needed regulation and oversight. The question of quality control of the extraction methods for guarantee of dosage integrity (mg amount of the active medicinal compound[s]) has to be resolved using state-of-the-art analytical methods available for the purpose.
The euphoric agent THC has mind-altering euphoric properties, as do a variety of other drugs.6 Since these compounds are phenolic in nature, they possess UV-absorption (220–235 nm). HPLC analysis using UV detection has been applied for the QA of hemp oil extracts.7 HPLC analysis can also be used to determine not only the potency (mg per g) of THC/CBD in cannabis oil preparations used as the administered product, but also to test for terpenes, pesticides, and mycotoxins in the product, where extensive field cultivation is being used to grow the crop. To this end, a turnkey HPLC analyzer for the quantitative determination of these compounds is marketed by Shimadzu Scientific Instruments (Columbia, MD) as the Cannabis Analyzer for Potency. The method could also be used in forensic toxicology and law enforcement in prosecuting DUI cases using noninvasive sampling such as saliva or alcohol swabs from fingers or skin.5,7
Pharmacokinetic evaluation of CBD and THC and the many potentially active cannabinoids present in the approved medicinal product (oil) when administered either orally or transdermally will require very sensitive and selective HPLC/MS/MS methods for quantitation of the above analytes.9 Since all of these compounds are phenolic in nature, they can be chemically derivatized to yield electron-capturing molecular entities that will enable very sensitive and selective quantitation with either positive or negative ion detection using GC/ECD or LC/MS/MS systems.9
The cannabis industry is growing rapidly and is estimated to become a billion-dollar industry within a few years. The DEA, FDA, and NIH must join together to sort out the legal, commercial, and medicinal ramifications of this very complex enterprise. I believe that the generic drug industry and the FDA could team up to monitor the pharmaceutical formulation of cannabis extracts collected from legally licensed growers of the raw material, separate the THC and CBD pharmacologically active compounds, and formulate them separately into either a quality-assured oral dosage form, a transdermal delivery system (TDDS), and/or a pressurized metered dose inhaler (pMDI). The 3M Company (Maplewood, MN) has extensive manufacturing expertise in these dosage forms. The FDA approved the first commercial CBD product called Epidiolex (GW Pharmaceuticals, Cambridge, U.K.), a strawberry-flavored syrup for the treatment of certain forms of epilepsy in children.10
The pharmacokinetics/bioavailability evaluation of these CBD formulations in patient populations will require the validation the above-mentioned methods in biological fluids (blood, plasma, saliva).7 The NIH can evaluate the clinical safety and efficacy of these formulations in small, controlled patient studies to validate their approval by the FDA. All of this will take several years and many Ph.D. degrees to materialize, but it is high time to start acting scientifically after we rushed headlong politically into voting to approve the Cannabis Referendum in the presidential election of November 2016.
- Barcot, B. Weed the People: The Future of Legal Marijuana in America. Time Books: New York, NY, 2015.
- Barcot, B. and Scherer, M. The great pot experiment. Time May 25, 2015, 39–44.
- Erickson, B.E. Legal marijuana: is it time to relax marijuana’s legal status? Chem. Eng. News June 20, 2016, 28–32.
- Bomgardner, M. Nurturing cannabis: growers are handicapped by shifting rules and major research gaps. Chem. Eng. News May 21, 2018, 28–34.
- Armaud, C.H. Working to help police detect drugged driving. Chem. Eng. News Mar 28, 2016, 20–21.
- Kemsley, J. Psychedelic medicines: new approaches to intractable mental health conditions. Chem. Eng. News Mar 28, 2016, 28–32.
- Young, C. and Clifford, R. The quantitative determination of phytocannabinoids in hemp oils using HPLC with UV detection. Cannabis Sci. Technol. 2018, 1(2), 38–43.
- Halford, B. Cannabis analysis takes off. Chem. Eng. News Dec 9, 2013, 32–33.
- Lebel, P. Walton, K.C. et al. Rapid determination of 24 synthetic and natural cannabinoids for LC-MS-MS screening in natural products. Current Trends Mass Spec. Mar 2015, 8–14.
- Halford, B. Medicine from marijuana (cannabidiol). Chem. Eng. News July 23, 2018, 28–33.
J. Arthur F. de Silva, Ph.D., is a pharmaceutical R&D executive (consultant) based in North Port, FL; e-mail: [email protected]