The legal and regulatory status of cannabidiol (CBD), a component of the cannabis plant with a huge therapeutic upside, has emerged as a contentious subject in the United States, even though CBD is not intoxicating, has a stellar safety profile, and has no intrinsic abuse liability. When, as expected, CBD becomes an approved pharmaceutical, it will be a matter of enforcement discretion on the FDA’s part as to whether producers of artisanal CBD-rich formulations will be allowed to operate. Accordingly, Project CBD makes the following recommendations to the FDA:
- Do not make CBD a prescription-only drug. This would only serve the interests of a few pharmaceutical companies while hurting patients who have benefited from CBD-rich food supplements, topicals and other artisanal preparations.
- Fast track clinical studies designed to compare the efficacy of CBD isolates and whole plant CBD rich extracts. Let’s learn more about the pros and cons of both in order to maximize their benefits and minimize harm.
- Require safety warnings for CBD isolates regarding drug interactions.
- While facilitating access to pharmaceutical CBD, don’t impede safe access to artisanal CBD-rich products. We recognize that the FDA is generally not in the business of approving plants as medicine. Nor should the FDA be in the business of undermining plant medicine in general and CBD-rich cannabis therapeutics, in particular.
- Prohibit the use of toxic thinning agents and flavoring additives in CBD-rich vape oil products. Several additives (propylene glycol and polyethylene glycol, for example) that are commonly found in CBD vape oil cartridges become toxic when heated and inhaled. Most flavoring additives have not been safety tested for inhalation; some are known to be highly toxic when combusted.
- Publish all FDA test results pertaining to CBD hemp oil products. Artisanal CBD producers have a mixed record thus far with respect to product safety, labeling accuracy, and quality control. The FDA has already documented instances of fraud and product mislabeling when it analyzed the content of several CBD hemp oil items. The bad apples – hemp oil extracts with little or no CBD or excess THC - should not be a pretext for the FDA to prohibit or restrict access to safe, non-pharmaceutical CBD products.
- Don’t privilege pharmaceutical priorities at the expense of the fledgling, domestic CBD-rich agricultural sector and the CBD food supplement and topical industry. In Denver, Colorado, state law permits wholesale manufacturers of CBD extracts and edibles to source hemp biomass from within and outside Colorado provided that it originates from a farmer who cultivates CBD-rich plants under regulations guided by safe consumption criteria.
- Implement procedures to harmonize the patchwork of state regulations regarding CBD. Thus far a coherent regulatory framework is lacking. It’s federally illegal to sell food supplements and other products infused with CBD across state lines, but there’s a gap in federal oversight of CBD manufacturing operations.
Extensive preclinical research has documented the anti-inflammatory properties of single-molecule CBD in animal models of various pathologies, including neuropathic pain, epilepsy, rheumatoid arthritis, irritable bowel syndrome, multiple sclerosis, obesity and diabetes. Scientists are beginning to understand the specific pharmacological mechanisms underlying CBD’s potential as a treatment for cancer, heart disease, addiction, depression and numerous other health disorders. Cannabidiol is a pleiotropic compound that produces many effects through multiple molecular pathways. It taps into how we function biologically on a very deep level: CBD can penetrate the cell membrane and bind to receptors on the nucleus (PPARs), which regulate gene expression and mitochondrial activity.
A 1998 study sponsored by the National Institutes of Health is the basis for a U.S. government patent on the antioxidant and neuroprotective qualities of plant cannabinoids, specifically CBD and psychoactive THC (tetrahydrocannabinol). CBD and THC were found to limit “neurological damage following ischemic insults, such as stroke and trauma.” Both compounds are described as having “particular application … in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.”
But double blind, randomized clinical trials that could “prove” CBD’s efficacy as a medical treatment have gotten short shrift in the United States because of marijuana prohibition. The few clinical studies involving single-molecule CBD that are underway pale in comparison to the enormous amount of anecdotal data already generated by cannabis clinicians and numerous patients in states where the therapeutic use of cannabis is legal.
Since the rediscovery of CBD-rich cannabis in Northern California in 2009, a growing number of physicians have been recommending CBD-infused oil extracts and concentrates for patients – often with good, and sometimes with jaw-dropping, results in difficult-to-treat cases. Until recently, however, single-molecule CBD formulations were not part of the grassroots medical marijuana experience. While scientists focused on the pharmacology of CBD isolates and other single-molecule cannabinoids, medical marijuana product-makers and providers have been dispensing an array of whole plant CBD-rich options – tinctures, sublingual sprays, gel caps, topicals, edibles, and raw herb – to a wide demographic of patients, many of whom turn to cannabis therapy as a last resort.
In addition to whole plant CBD-rich products sold by medical marijuana dispensaries, CBD isolates derived from industrial hemp are currently available via unregulated online storefronts and delivery services. If, as expected, GW Pharmaceuticals wins FDA approval of Epidiolex, an almost-pure CBD anti-seizure medication, in the near future, it will become available on a prescription basis at a hefty price. Millions of uninsured families in the United States won’t be able to afford it.
The pharmaceutical development of cannabinoid compounds is based upon controlled experimentation with molecular isolates in keeping with the assumption that sick people benefit most from predictable, reproducible medicine that never varies. While isolates can facilitate precision dosage and confidence in the chemical make-up of a drug, monomolecular medicine also has serious drawbacks.
Several scientific studies report that pure, single-molecule CBD, while possibly effective at high doses in preclinical tests, has a much tighter therapeutic window and is much less potent compared to a whole plant CBD-rich concentrate. Moreover, whether synthesized in a lab or heavily refined from industrial hemp paste, pure CBD isolates lack the full array of phytocannabinoids and medicinal terpenes found in whole plant CBD-rich cannabis, which includes hundreds of biologically active components. These constituents interact with CBD and THC to create what scientists refer to as an “entourage” or “ensemble” effect, so that the therapeutic impact of the whole plant is greater than the sum of its parts.
It’s not that single-molecule CBD won’t work — pure CBD can be helpful in certain cases, as clinical trials with epidiolex have shown. But whole plant CBD-rich oil has a much wider therapeutic window than a CBD isolate. This was demonstrated in a 2015 preclinical experiment by Israeli scientists who found that single-molecule CBD required a much higher dose to be effective as an anti-inflammatory and an analgesic compared to a whole plant CBD-rich oil extract. Moreover, if one missed the mark slightly, either too low or too high, then the CBD isolate had little impact on pain and inflammation — unlike the full spectrum CBD-rich oil, which was effective at a much lower, and broader, dosage range. “The therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects,” the Israeli researchers concluded.
Other scientists and clinicians have reported similar findings. A 2016 study by Italian researchers found that a whole plant CBD-rich oil extract attenuated inflammation and hypermotility in an animal model of colitis, whereas “pure CBD did not ameliorate colitis” symptoms. “These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD [as a] botanical drug substance for irritable bowel disease treatment.”
Problematic drug interactions are much more likely with high doses of single-molecule CBD, which can inhibit the metabolism of 60 percent of marketed pharmaceuticals. At high doses, CBD will deactivate certain cytochrome P450 enzymes in the liver, thereby altering how we metabolize a wide range of medications, including clobazam, an anti-epileptic drug. This was evident in GW’s epidiolex trials, when children with intractable seizure disorders were given CBD dosages ranging from 5 to 50 mg per kg of body weight. Doctors had to adjust the amount of clobazam the children were taking because of potentially dangerous interactions with epidiolex. Compare the high dose regimen employed by GW Pharmaceuticals to 1 mg per kg of artisanal whole plant CBD-rich oil that cannabis clinicians in California and elsewhere recommend as an initial dosage for treating pediatric epilepsy.
In cancer treatment, the precise dosing of chemotherapy is extremely important; it can be a challenge for doctors to find the maximum effective dose that will not be catastrophically toxic. Many chemotherapy drugs are oxidized by cytochrome P450 enzymes before their inactivation or excretion. This means that for patients also using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the metabolism of chemotherapy drugs and dosage adjustments aren’t made, the chemotherapy agent could accumulate within the body to highly toxic levels.
There is no clearly established cut-off dose below which CBD does not interact with other drugs. Any pharmaceutical or nutraceutical scheme to exploit the health benefits of cannabidiol must reckon with the fact that therapeutically relevant doses of CBD isolates can potentially impact a wide range of medications. Drug interactions are especially important to consider when using life-saving or sense-saving drugs, drugs with narrow therapeutic windows, or medications with major adverse side effects. By and large, however, there have been few problems reported by cancer patients and others who medicate with artisanal CBD-rich cannabis products. The same can’t be said for CBD isolates.
We recognize there is therapeutic value in CBD isolates as well as in whole plant CBD-rich remedies. The FDA should not ordain pharmaceutical CBD as the only legitimate medical option. Single-molecule medicine is the predominant corporate way, the Big Pharma way, but there’s ample evidence that it’s not always the best way to benefit from cannabis therapeutics. Pure CBD is a molecule, not a miracle, and it doesn’t work for everyone. No-THC and low-THC cannabis oil products represent a small slice of the cannabis therapy spectrum. Patients of all ages and economic means should have access to a range of cannabis-based therapeutic options with different concentrations and ratios of CBD and THC, along with other whole plant components.
This report represents a comprehensive response to the FDA’s inquiry and includes a regulatory framework for cannabis and other traditional herbal medicinal products.
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