We are in dire circumstances. Given the staggering scope of the opioid epidemic, the unmet needs of many struggling with pain and mental health issues, and popular pressure from the massive CBD economy, business-as-usual with respect to regulating CBD is not a viable path forward for the FDA. There’s no precedent for regulating a substance that’s at once a pharmaceutical, a wellness nutraceutical, an essential oil extract, and an herbal preparation that can be inhaled, ingested, imbibed, or applied topically.

The FDA, however, only recognizes the medical utility of isolated components of cannabis. Single- molecule CBD and single-molecule THC are both FDA-approved prescription pharmaceuticals. But herbal cannabis, the natural source of CBD and THC, isn’t an FDA-approved therapy, and any cannabis plant (or derivative) with more than 0.3 percent THC remains a federally illegal Schedule I substance, which, by definition, can’t have medical value.

There are occasions when public health priorities and pharmaceutical prerogatives are not equivalent. We believe this is the case with CBD and cannabis. We urge the FDA to prioritize public health over private interests, and to steadfastly maintain this focus at the core of its decision-making process.

Extensive preclinical research has shown that CBD is a safe, non-intoxicating, anti-addictive, neuroprotective antioxidant.⁵⁶⁷ Given CBD’s intrinsic, low-risk profile and many potential benefits, it should be legally available in many forms without a prescription. Sensible regulations can ensure CBD product safety without going through expensive, time-consuming clinical trials. The goal should be easy public access to diverse CBD-rich product options – pharmaceutical, nutraceutical, and artisanal – that are subject to rigorous manufacturing and compliance oversight.

Concerns that non-pharmaceutical cannabis commerce will undermine drug development initiatives are misplaced. Artisanal cannabis won’t disincentivize clinical pharmaceutical development; if anything, the opposite has proven to be the case. It has inspired pharmaceutical innovation. Charlotte’s Web, an artisanal, whole plant, CBD-rich hemp oil, was featured as a miraculous anti-seizure remedy on CNN in 2013. Five years later, the FDA approved Epidiolex, a pharmaceutical CBD isolate, for refractory pediatric epilepsy.

Pharmaceutical researchers are already developing synthetic compounds that target the endocannabinoid system for therapeutic benefit.⁸ Some of these compounds activate or block or otherwise modulate the same cannabinoid receptors in the brain and body that respond to THC and other cannabis components. Medical scientists are also experimenting with endocannabinoid reuptake inhibitors and other compounds that are designed to improve “endocannabinoid tone” without binding directly to cannabinoid receptors. The slow pace of drug development in these areas since the discovery of the cannabinoid receptor type 1 (CB1) thirty years ago cannot be attributed to public (albeit illegal) availability of CBD and cannabis.

Whole Plant and Isolated CBD

While favoring single-molecule therapies and the pharmaceuticalization of individual cannabis components, federal policy has stymied clinical research that could validate the therapeutic use of herbal cannabis and its full-spectrum derivatives. Prohibitionists rely on this artificial gap in clinically relevant research to argue that there’s insufficient proof that cannabis is truly a disease modifier. Cannabis flower, with few exceptions, is still forbidden territory for medical scientists. Because of cannabis prohibition and consequent research restrictions, few rigorous probes have analyzed the therapeutic impact of whole plant cannabis extract, and fewer still have compared the results with single-molecule outcomes.

A noteworthy exception is a groundbreaking 2015 Israeli study, which documented the superior therapeutic properties of whole plant CBD-rich cannabis extract as compared to single-molecule CBD in an animal model of pain and inflammation.⁹ Both CBD alone and the full spectrum CBD-rich oil had measurable anti-inflammatory and analgesic effects. CBD isolate, however, required a very high and precise dose to be effective, whereas the whole plant extract had a broader therapeutic window and worked well at much lower doses.

“A lot of research has been made to isolate and characterize isolated single constituents of traditional herbal medicine to find their rationale for therapeutic uses,” the Israeli report concluded. “However, our data together with those of others provide legitimation to introduce a new generation of phytopharmaceuticals to treat diseases that have hitherto been treated using synthetic drugs alone. The therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects.”

Therapeutic Synergy

In June 2018, Spanish researchers documented the greater potency and superior efficacy of a full spectrum THC-rich cannabis oil extract compared to single-molecule THC in a preclinical breast cancer study.¹⁰ Both single-molecule THC and full-spectrum THC-rich cannabis oil were shown to have antitumor properties, but the full-spectrum oil performed better than the THC isolate in vitro and in animal models of three different breast cancer subtypes. The Spanish scientists also found positive synergistic effects between the standard chemotherapy drugs and either formulation of THC.

A small but growing body of clinical data formed the basis of a September 2018 meta-analysis by Brazilian scientists, who determined that whole plant CBD-rich extracts are as effective as CBD isolates, if not more so, in treating refractory seizure disorders.¹¹¹² Perhaps the most striking conclusion of this study was the dramatic difference in doses required for isolates compared to full spectrum CBD-rich oil extracts. The mean dosage for epileptics using pure CBD was 25.3 mg/kg/day, but for CBD-rich extracts it was 6.0 mg/kg/day.

In other words, CBD in a whole plant extract including THC (cannabis), was over four times more potent than pure CBD. Whole plant CBD was also associated with fewer side effects than single-molecule CBD formulations – probably due to the lower dose of CBD required when administered as a whole-plant extract. Regulatory policy that prioritizes public health should not privilege isolates over full-spectrum cannabis remedies. Single-molecule and full-spectrum CBD can both be highly effective therapies for a number of conditions. Citizens are best served by having access to a wide range of well-regulated, cannabinoid- based product options.

Real-World Data

There’s an abundance of anecdotal and survey-based evidence that doctors and dispensaries have accumulated over the years in states where medical cannabis is available through licensed dispensaries or elsewhere via the unregulated black market.^13141516 The significance of this real-world CBD evidence should not be discounted just because it doesn’t meet the gold standard of double-blind, randomized clinical trials, which don’t always reflect real-world outcomes.

The gold standard might be optimal for assessing single-molecule pharmaceutical interventions aimed at single, primary outcomes. But that standard cannot account for the complex interplay between cannabis components and the endocannabinoid system. By acting as receptor agonists and antagonists, reuptake inhibitors, and allosteric modulators, CBD and other plant cannabinoids elicit many effects that combine synergistically.

Double-blind randomized clinical trials, while clearly important, aren’t the only way – and might not be the best way – to assess the therapeutic value of a “crude” plant with numerous constituents and myriad effects.

Cannabis contains several hundred compounds, including various flavonoids and polyphenols, aromatic terpenes, and dozens of minor cannabinoids, in addition to CBD and THC. Many of these compounds have specific healing attributes, but when combined they create what scientists refer to as a holistic “entourage effect” or “ensemble effect,” so that the therapeutic impact of the whole plant exceeds the sum of its single-molecule parts.¹⁶ Scientists may not fully understand the biochemical nuances and intricacies of the entourage effect, but we are well past the point of questioning its existence and significance.

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