Recently ACS was asked to provide a response to the request for information from Congress with regard to regulation of CBD and derivatives. The full response is available below.
Dear Honorable Members of Congress,
I write to you on behalf of the Association of Cannabinoid Specialists. I am a physician, a cannabinoid specialist with over 12 years of practice solely focused on these medications, and an Instructor of Medicine at Harvard Medical School.
The Association of Cannabinoid Specialists is an international non-profit of physicians and other health professionals who specialize in using cannabis or cannabinoids for the treatment of patients. We are the experts on how these substances should be used in both medical and non-medical settings. The proper and safe regulation of cannabinoids is of primary concern to us for our patients’ well-being.
The Farm Bill of 2018 essentially made a mistake by allowing the extraction and sale of cannabinoids to consumers. The intention to provide farmers with a new crop, hemp, is laudable and can be achieved by allowing hemp to be used for a wide array of industrial processes including the production of concrete, paper, and textile (1). However, it should not be used to produce chemicals with biological activity for use by consumers.
Cannabinoids Have Risk, Intoxication Is Not The Only Concern
In the discussion about cannabinoids, often the concept of intoxication is used as the bright-line between permissible and non-permissible. As physician-scientists, we believe this is not a valid line to draw. While intoxication is a potentially dangerous effect of some cannabinoids, other cannabinoids that do not produce intoxication have risks as well (2-4). All of the cannabinoids presently known are biologically active. This means they can interact with the human body to change the normal functioning. This is the definition of a medication. All medications have risks and side effects. In the case of cannabinoids, many of those risks remain to be characterized.
Do we know if CBD or its derivatives like HHC and others might cause cancer or neurodegeneration or liver failure? In fact, we do know that CBD can interact with many common medications and also can cause direct liver toxicity (5-10). We know far less about longer term issues and about the effects of those derivatives.
How Cannabinoids Should Be Regulated
The FDA is correct that CBD and it’s derivatives do not meet the standard for food or supplements on the basis of the known effects and risks, as well as the unknown risks. They are correct that, leaving aside the “exclusionary clause,” the risks known and unknown are too great for the food and supplement pathway.
The alternative pathway, at present, is the drug development pathway. This is expensive and time consuming specifically because it requires significant research in both non-humans and humans to prove safety and efficacy. This is exactly what is required: to prove that CBD and other cannabinoids are safe to use, have proven benefit, and to outline the parameters by which they can be safely and effectively used. Any new, third pathway designed by Congress specific to hemp or cannabis simply circumvents this tried-and-true approach to ascertaining the safety and efficacy of hemp/cannabis.
Reference has been made to the studies that allowed approval of Epidiolex as demonstration of the safety of CBD for general consumption. This is false. In fact, it is from the Epidiolex studies that we know there are risks of drug interactions and direct liver toxicity (5-10). Epidiolex was approvable because those risks were known, and it is only available by prescription under the care of a physician. It is the responsibility of the physician to know how to use the medication, including counseling the patient on risks and symptoms of concern, monitoring for adverse events, and prescribing the dose to be taken. None of these safeguards would be in place for over-the-counter (OTC) CBD products.
Furthermore, the “exclusionary clause” does preclude making OTC or competing products until such time as Jazz Pharmaceutical’s patent runs out. Defying this aspect of the law or overturning it will have dire consequence for drug development worldwide going far beyond the discussion of hemp/cannabis.
The Cannabis Industry Is Not Benign and Must Be Regulated
Since CBD and other cannabinoids (except THC (11-16)) have yet to have any proven value to consumers or patients, access to them is solely to the benefit of industry. Evidence for potential risk to pregnant women and children exists, yet studies have also shown that industry, in the absence of legal restrictions, has been promoting use of cannabinoids to pregnant women (17).
Ultimately, as cannabinoid-medicine physicians, we value rigorous scientific investigation of all cannabinoids and other cannabis derivatives. We need to know that they are safe to use (and under what circumstance) and have demonstrable benefit to disease states. This can only be achieved via the current FDA drug development pathway.
The current state-legal systems demonstrate that we will never get the data that we need if similar systems are emplaced federally. Many cannabis companies talk about the medical value of their products or of cannabis more generally, yet to date none have invested the time and money needed to prove their point. Realistically, no company will invest in this research if they can simply go to market with unproven products. Pharmaceutical companies make the investment and do the research because without it they cannot go to market. We must enforce this process to ensure the research gets done.
The First Step Needed
It is our contention that the FDA new drug pathway is fine as is, and a new pathway will only undermine the safety and efficacy data that is developed. We believe that the Farm Bill should be amended to restrict the sale of “all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers,” to research uses or to companies that manufacture FDA approved medications.
Further we content that the real issue at present is a lack of enforcement against companies that are selling products that are neither proven safe nor legal since they are not FDA approved. We call upon Congress to reinforce the authority of FDA to regulate these chemicals, and other executive agencies like USDA and FTC to assist in enforcing these regulations.
Protecting Patients Using State-Legal Products
However, in doing so, and by re-asserting the primacy of the Federal government over states, we endanger the current state-legal medical programs. This, too, would be unacceptable as it would leave millions of Americans without access to medication that they use presently for very real illness under the care of physicians.
Providing a Clear Path Forward
Therefore, we call for a sunset-provision. We ask Congress to assert a moratorium on new cannabis or cannabinoid products nationally. We ask that the cannabis industry be given 10 years in which to meet the standard set by the FDA new drug pathway or become a recreational product company only. We ask that Congress enact law that sets a national safety testing standard akin to the state of Massachusetts, requires states to provide reciprocity that honors medical prescriptions from other states, and requires of physicians a written (or electronic) prescription for cannabis products.
Further, Congress should reassert the role of FDA in enforcing the ban on medical claims made by cannabis companies, including those operating in the recreational market. No statements should be made by any company as to the utility of their products unless FDA approved. At present, FDA simply does not have the budget to enforce these rules and Congress should allocate funds for this purpose.
State-legal cannabis companies should be limited to selling cannabis and simple extractions thereof, but not be allowed to chemically alter the cannabinoids or terpenes nor their inherent ratios.
Specific Needs and Steps
Cannabinoid products should specify their constituent compounds in milligrams, not percentages nor ratios. THC should be measured as THC + THCA, unless product is intended to be used as THCA (18), then an unit dose should be 20mg but the THC limited to <= 1%. A standard dose of THC (+THCA) should be 5mg in the recreational market. In a medical market useful increments should be 5mg, 10mg, and 20mg. These should be clearly marked on the package to be sure that patients can tell the per piece dose at a glance.
In the medical market at least, smoking should be discouraged (19), despite benign data on long term use (20). Vape pens, on the other hand, have significant associated risks and nowhere near the long-term safety data that we have for smoking cannabis. Vape pens should either be banned or required to meet safety standards that ensure vaporization, not combustion, and no extraneous chemicals are inhaled as a result of chemical reactions or contact with the machinery (21-23). Flower vaporizer machines, on the other hand, are safer devices specifically because they do appropriately control for temperature using direct measurement and a microprocessor controlled negative feedback loop (24). These should be required to meet FDA medical device standards and maintained as the preferred inhalation device.
A Robust Visionary Research Agenda With Funding
We also believe that NIH should be doing more to fund and stimulate a well-planned long-term research agenda. They should map this agenda publicly to address areas not yet well understood and provide definitive answers to current questions. Groups like National Academy of Science, Engineering, and Medicine have provided guidance on research that needs to be done (16). Congress will need to appropriate additional funds to cover this research agenda on an ongoing basis.
Association of Cannabinoid Specialists provide more details via their white-paper here: https://assets.nationbuilder.com/acs/pages/75/attachments/original/1666115916/A-FederalFramework-of-Regulation-for-Medical-Cannabis-Use.pdf?1666115916
By reinforcing the role of the FDA new drug pathway, bolstering FDA’s budget to enforce current regulation, emplacing a moratorium on new hemp/cannabis derivative products, enforcing the ban on medical claims made, and most especially requiring physician prescriptions, Congress can right the wrongs instituted under the 2018 Farm Bill. Providing a clear glide-path for the cannabis industry to meet the bar set by FDA over a known, finite period of time will allow patients to continue to get their state-legal medication until the industry can meet the FDA regulation. In doing so, Congress will protect American’s safety,
allow the cannabis industry to grow into a legitimate pharmaceutical industry, and encourage real medication development that has proven safety and efficacy.
Jordan Tishler, MD
President, Association of Cannabinoid Specialists
Harvard Medical School
Association of Cannabinoid Specialists (ACS) is an international association of healthcare professionals on the forefront of cannabinoid medicine. Because ACS was founded by physicians, we are uniquely positioned to ensure the highest standards in the practice of cannabis medicine, safeguard patient care with clinical best practices, and interface with other stakeholders in the cannabis community. We are an advocacy organization striving to provide guidance to law makers and regulators at every level of cannabis control. For all of ACS’ constituents, we provide evidence and experience-based education to support the premise that cannabis should be treated as a medicine and, therefore, patients and related laws and regulations need to be created, modified, and viewed differently than recreational-use laws and regulations.
1. McPartland, J. M., & O’Sullivan, S. E. (2023). Origins of Cannabis sativa in Ireland and the Concept of Celtic Hemp: An Interdisciplinary Review . Cannabis and Cannabinoid Research, X(X), 1–11. https://doi.org/10.1089/can.2022.0263
2. Brown, J. D., Winterstein, A. G., Brown, J. D., & Winterstein, A. G. (2019). Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use. Journal of Clinical Medicine, 8(7), 989. https://doi.org/10.3390/jcm8070989
3. Stout, S. M., & Cimino, N. M. (2014). Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabolism Reviews, 46(1), 86–95. https://doi.org/10.3109/03602532.2013.849268
4. Yin, H. Y., Hadjokas, N., Mirchia, K., Swan, R., & Alpert, S. (2020). Commercial Cannabinoid Oil-Induced Stevens-Johnson Syndrome. Case Reports in Ophthalmological Medicine, 2020, 1–5. https://doi.org/10.1155/2020/6760272
5. Gingrich, J., Choudhuri, S., Cournoyer, P., Downey, J., & Muldoon Jacobs, K. (2023). Review of the oral toxicity of cannabidiol (CBD). Food and Chemical Toxicology, 176, 113799. https://doi.org/10.1016/J.FCT.2023.113799
6. Kutanzi, K. R., Ewing, L. E., Skinner, C. M., Quick, C. M., Kennon-McGill, S., McGill, M. R., … Koturbash, I. (2020). Safety and molecular-toxicological implications of cannabidiolrich cannabis extract and methylsulfonylmethane co-administration. International Journal of Molecular Sciences, 21(20), 1–14. https://doi.org/10.3390/ijms21207808
7. Turck, D., Bohn, T., Castenmiller, J., De Henauw, S., Hirsch-Ernst, K. I., Maciuk, A., … Knutsen, H. K. (2022). Statement on safety of cannabidiol as a novel food: data gaps and uncertainties. EFSA Journal, 20(6), e07322. https://doi.org/10.2903/j.efsa.2022.7322
8. Yamaori, S., Ebisawa, J., Okushima, Y., Yamamoto, I., & Watanabe, K. (2011). Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences, 88(15–16), 730–736. https://doi.org/10.1016/j.lfs.2011.02.017
9. Ewing, L. E., Skinner, C. M., Quick, C. M., Kennon-McGill, S., McGill, M. R., Walker, L. A., … Koturbash, I. (2019). Hepatotoxicity of a Cannabidiol-rich cannabis extract in the mouse model. Molecules, 24(9). https://doi.org/10.3390/molecules24091694
10. Geci, M., Scialdone, M., & Tishler, J. (2022). The Dark Side of Cannabidiol: The Unanticipated Social and Clinical Implications of Synthetic Δ 8 -THC. Cannabis and Cannabinoid Research, X(X), 1–13. https://doi.org/10.1089/can.2022.0126
11. Casarett, D. J., Beliveau, J. N., & Arbus, M. S. (2019). Benefit of Tetrahydrocannabinol versus Cannabidiol for Common Palliative Care Symptoms. Journal of Palliative Medicine, 22(10), 1180–1184. https://doi.org/10.1089/jpm.2018.0658
12. Li, X., Vigil, J. M., Stith, S. S., Brockelman, F., Keeling, K., & Hall, B. (2019). The Effectiveness of Self-Directed Medical Cannabis Treatment for Pain. Complementary Therapies in Medicine. https://doi.org/10.1016/J.CTIM.2019.07.022
13. Hameed, M., Prasad, S., Jain, E., Dogrul, B. N., Al-Oleimat, A., Pokhrel, B., … Stein, J. (2023). Medical Cannabis for Chronic Nonmalignant Pain Management. Current Pain and Headache Reports, 1–7. https://doi.org/10.1007/s11916-023-01101-w
14. Koppel, B. S., Brust, J. C. M., Fife, T., Bronstein, J., Youssof, S., Gronseth, G., & Gloss, D. (2014). Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 82(17), 1556–1563. https://doi.org/10.1212/WNL.0000000000000363
15. Naftali, T., Bar-Lev Schleider, L., Dotan, I., Lansky, E. P., Sklerovsky Benjaminov, F., & Konikoff, F. M. (2013). Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association, 11(10), 1276-1280.e1. https://doi.org/10.1016/j.cgh.2013.04.034
16. Practice, H., Division, M., & Academies, N. (2017). The Health Effects of Cannabis and Cannabinoids. https://doi.org/10.17226/24625
17. Dickson, B., Mansfield, C., Guiahi, M., Allshouse, A. A., Borgelt, L. M., Sheeder, J., … Metz, T. D. (2018). Recommendations From Cannabis Dispensaries About First-Trimester Cannabis Use. Obstetrics & Gynecology, 131(6), 1031–1038. https://doi.org/10.1097/AOG.0000000000002619
18. Nallathambi, R., Mazuz, M., Ion, A., Selvaraj, G., Weininger, S., Fridlender, M., … Koltai, H. (2017). Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts. Cannabis and Cannabinoid Research, 2(1), 167–182. https://doi.org/10.1089/can.2017.0027
19. Weinberger, A. H., Platt, J., Copeland, J., & Goodwin, R. D. (2018). Is Cannabis Use Associated With Increased Risk of Cigarette Smoking Initiation, Persistence, and Relapse? The Journal of Clinical Psychiatry, 79(2), 0–0. https://doi.org/10.4088/JCP.17m11522
20. Tashkin, D. P. (2013). Effects of marijuana smoking on the lung. Annals of the American Thoracic Society, 10(3), 239–247. https://doi.org/10.1513/AnnalsATS.201212-127FR
21. Lim, C. C. W., Sun, T., Leung, J., Chung, J. Y. C., Gartner, C., Connor, J., … Chan, G. C. K. (2022). Prevalence of Adolescent Cannabis Vaping: A Systematic Review and Metaanalysis of US and Canadian Studies. JAMA Pediatrics, 176(1), 42–51. https://doi.org/10.1001/jamapediatrics.2021.4102
22. Oar, M. A., Savage, C. H., Rufer, E. S., Rucker, R. P., & Guzman, J. A. (2022). Thermography of cannabis extract vaporization cartridge heating coils in temperatureand voltage-controlled systems during a simulated human puff. PloS One, 17(1), e0262265. https://doi.org/10.1371/journal.pone.0262265
23. McDaniel, C., Mallampati, S. R., & Wise, A. (2021). Metals in Cannabis Vaporizer Aerosols: Sources, Possible Mechanisms, and Exposure Profiles. Chemical Research in Toxicology, 34(11), 2331–2342. https://doi.org/10.1021/acs.chemrestox.1c00230
24. Lanz, C., Mattsson, J., Soydaner, U., & Brenneisen, R. (2016). Medicinal Cannabis: In Vitro Validation of Vaporizers for the Smoke-Free Inhalation of Cannabis. PloS One, 11(1), e0147286. https://doi.org/10.1371/journal.pone.0147286