Improving the Safety of Cannabis Products in the United States

Regulate raw cannabis and cannabis isolates and extracts as a separate category of products

Although this may require Congressional authorization, FDA should regulate cannabis and cannabis products apart from foods, dietary supplements, cosmetics, drugs, medical devices, and tobacco products. The agency’s responsibility for regulating tobacco products as a separate category is itself a precedent for cannabis being regulated separately.

Classify cannabinoids as either psychoactive or non-psychoactive

As over one hundred cannabinoids have been detected in cannabis, developing separate regulations for every individual cannabinoid would add unnecessary complication to the regulatory process; until more concrete research into the pharmacological and toxicological specifics of each cannabinoid has been conducted, for now, FDA should classify cannabinoids by their psychoactivity and apply stricter regulations to psychoactive cannabinoids.

Psychoactive cannabinoids should not be sold in foods or dietary supplements, and their sale should be age-restricted. Products containing psychoactive cannabinoids should be sold in child-resistant packaging. Comparatively, age restrictions should not be placed on the sale to and/or consumption of non-psychoactive cannabinoids by minors.

To enhance the agency’s credibility among consumers, concede that there are limited benefits to cannabinoid consumption

In the absence of legitimate safe intake recommendations from public health authorities, consumers risk being misled by manufacturers and retailers acting in bad faith. If the agency concedes that there are at least some limited and specific therapeutic benefits associated with the consumption of cannabidiol and/or other cannabinoids, this will help to dispel the misinformation that cannabinoids can outright ‘cure’ certain diseases and that cannabis is a panacea. Such a concession could demonstrate to consumers that the agency takes an evidence-based approach to the benefits of cannabis and cannabinoids. By taking a balanced view, consumers may be more likely to heed the agency’s warnings about potential adverse health outcomes associated with cannabis and cannabinoid use, such as the risk of liver damage associated with cannabidiol use and the increased risk of testicular cancer associated with cannabis use ^[1].

Prohibit the addition of caffeine and other methylxanthines to foods and beverages containing cannabis-derived cannabinoids, and vice-versa

The addition of caffeine to foods increases their dependence-forming potential, and increases the risk of consumers developing the variety of adverse health outcomes associated with caffeine consumption. FDA should not permit cannabis-derived cannabinoids, either as isolated cannabinoids or as hemp products and/or extracts, to be added to foods containing caffeine, theobromine, and other methylxanthines, nor should cannabis-derived cannabinoids be added to any product containing coffee (Coffea arabica, robusta), tea (Camellia sinensis), cacao (Theobroma cacao), yerba mate (Ilex paraguariensis), guarana (Paullinia cupana), or kola nut (Cola nitida, acuminata).

Until more research is conducted into the risks associated with the consumption of caffeine and cannabinoids together, and a safe intake level is established, keeping the two substances separate would be the safest approach. Furthermore, consumers of cannabinoid-added caffeinated foods risk incorrectly attributing both the positive and negative effects of caffeine to the presence of cannabinoids. The addition of cannabinoids to caffeinated foods could complicate adverse event reporting for both substances.

In practice, this would mean that if caffeinated beverage manufacturers such as Coca-Cola add cannabidiol to their products (which they have expressed interest in doing so in the past ^[2]), such products may only contain cannabidiol; cannabidiol-added versions of caffeinated beverages such as Coke, Pepsi, and Red Bull would not be permitted.

The addition of cannabinoids to foods containing cacao should be prohibited, not only because cacao contains caffeine and theobromine, but because cacao also contains cannabinoids, including anandamide (which is also produced endogenously), as well as N-oleoylethanolamine and N-linoleoylethanolamine, which have been found to inhibit anandamide hydrolysis ^[3]. It is unclear how cannabis-derived cannabinoids interact with anandamide in vivo, thus these compounds should not be permitted to be combined in food products unless and until conclusive evidence can demonstrate that such a combination is safe.

Prohibit the addition of alcohol to beverages containing cannabis-derived cannabinoids, and vice-versa

More research needs to be conducted into the risks associated with the consumption of alcohol and cannabinoids together. As with caffeine, permitting the sale of cannabinoid-added alcoholic beverages could create complications for adverse-event reporting for both substances. The addition of cannabinoids to alcoholic beverages may cause consumers to incorrectly view such beverages as ‘healthy’ or believe that the cannabinoids present might ‘negate’ the harms associated with alcohol consumption. An exemption should be provided for alcohol-based cannabis tinctures and for alcohol used as an excipient in cannabis extracts used as a flavoring.

Classify hemp flowers containing trace levels of cannabinoids as a culinary herb

Given their fragrant properties, hemp flowers with trace levels of cannabinoids should be classified as a culinary herb in the same way that basil, rosemary, thyme, and other herbs are classified. This would create a source of revenue for hemp farmers in the United States. This approach is similar to the way in which poppy seeds, washed of opioid residue, are sold as a spice and decorative food.

Permit the use of hemp extracts as a preservative and a flavoring in food

Rosemary extract is increasingly used as a preservative in foods due to its antioxidant properties. Given that cannabidiol and other substances in hemp have also been found to have antioxidant properties ^[4], FDA should permit the addition of hemp extract to foods as a preservative. When hemp extract is used for this purpose, the terms “preservative” or “antioxidant” should accompany hemp extract in the ingredients list. For example:

Ingredients: extra-virgin olive oil, less than 1% of: hemp extract (preservative).

Products containing hemp extract as a preservative should not be permitted to bear health claims approved for cannabinoids or hemp, however, the overall quantity of cannabinoids present in the product should be disclosed on the label. Recognizing hemp extract as a preservative and/or flavoring would increase the number of foods to which hemp could be added, thus potentially increasing the revenues of hemp farmers in the United States.

Establish health claims for hemp seeds, seed oil, fiber, and/or protein

Establishing health claims, such as ‘heart healthy’-type claims, for hemp foods such as hemp seeds and hemp protein would potentially divert consumers’ focus away from cannabidiol and draw attention to the healthful properties of hemp as a whole, such as it being a source of protein, fiber, and essential fatty acids. The increased consumer interest in hemp foods which may result from approval of health claims would lead to increased revenues for hemp farmers in the United States.

Establish health claims for non-psychoactive cannabinoids and permit the addition of small quantities of non-psychoactive cannabinoids to foods and beverages

The addition of non-psychoactive cannabinoids to foods should be permitted under a two-tier framework.

1. Cannabinoids added to any foods of non-animal origin with “disqualifying nutrient levels” specified in 21 CFR 101.14.

   In the same way that caffeine and quinine (indicated for the treatment of migraines and malaria respectively) can be added to foods regardless of the food’s nutritional composition, small quantities of cannabidiol or other cannabinoids could be added to any food, provided that the foods are not of animal origin, due to the lack of evidence surrounding the interaction between cannabinoids and foods of animal origin.

2. Cannabinoids added to certain foods which meet the requirements for bearing a qualified health claim.

   Non-psychoactive cannabinoids could be added to certain foods which meet the definition of ‘low in fat’, ‘low in saturated fat’, ‘low in cholesterol’, and ‘low in sodium’, and provide a significant quantity of one vitamin and one element per RACC, at concentrations greater than those specified in the tier above, provided that these concentrations are lower than those specified in OTC drug monographs and prescription-only preparations of cannabinoids, specified in detail below.

   The optimal regulatory approach for adding non-psychoactive cannabinoids to foods would be an approach similar to 21 CFR 101.83, “plant sterol/stanol esters and risk of coronary heart disease”, which enables plant sterols and stanols to be added to foods for the purposes of reducing the risk of heart disease. Plant sterols and stanols are not presented as substances which are required by the body, the health claim is limited in scope, and clearly indicates that the beneficial effect of sterol and stanol consumption is intended to reduce the risk of developing a disease, rather than treating or curing an existing disease. Cannabidiol and other cannabinoids could occupy a similar role in foods.

Require a ‘reversal agent’ to be sold with every dosage unit of psychoactive cannabinoids

There is precedence for adding a reversal agent to a drug; in the United Kingdom, Paradote and Pameton were over-the-counter preparations of paracetamol (acetaminophen) and methionine ^[5]. Methionine was included in the preparation in order to reduce damage to the liver caused by paracetamol overdose. Although questions remain surrounding the efficacy of those specific preparations, the notion of adding a reversal agent to a drug product is not novel. An ‘antidote’ could be added to psychoactive cannabinoids. Some evidence suggests that this reversal agent could itself be cannabis-derived, with cannabidiol being the main candidate, however further research needs to be conducted into the efficacy of cannabidiol (and other components of cannabis) as reversal agents for tetrahydrocannabinol. When sufficient research demonstrates that a particular substance can effectively act as a tetrahydrocannabinol reversal agent, FDA should create a new category of OTC drug products for tetrahydrocannabinol reversal agents, which could perhaps be marketed with the ‘drug purpose’ of ‘THC antidote’.

FDA should permit the sale of tetrahydrocannabinol reversal agents as separate products, however, the agency should also require that every dosage unit of tetrahydrocannabinol be sold with a reversal agent, as a separate item within the same product, for example, as a tablet alongside a cannabis cigarette. The increased cost to the manufacturer of having to include this reversal agent would effectively act as a tax on psychoactive cannabinoid products, which would likely be passed on to consumers. These regulations should apply to all psychoactive cannabinoid products, including State-legal products.

If cannabidiol or other cannabis-derived substances, specifically, are found to reverse the effects of psychoactive cannabinoids, FDA should require that these substances should be sourced from hemp grown in the United States, as this would increase the revenues of domestic hemp farmers.

Require substances which reduce the negative side effects of psychoactive cannabinoids to be added to cannabis products containing significant concentrations of such cannabinoids

A study ^[6] by Sharma et al. indicates that the coadministration of tetrahydrocannabinol and the benzoflavone moiety in Passiflora incarnata extract in mice resulted in “a marked attenuation of withdrawal effects” and “prevented the development of tolerance and dependence”. Further human studies on the specific effects of tetrahydrocannabinol and benzoflavone coadministration are required, however, the principle remains valid: the addition of one or more substances to tetrahydrocannabinol to reduce its negative effects, such as the development of dependence, has the potential to significantly improve the health of tetrahydrocannabinol consumers.

Prohibit the sale of cannabinoids in dietary supplements and cosmetics

The optimal regulatory environment for psychoactive and non-psychoactive cannabinoids would be over-the-counter drugs. The worst regulatory environments for cannabinoids would be dietary supplements and cosmetics. Regulating cannabinoids as OTC drugs ensures that FDA, rather than FTC, oversees the advertising of such drugs, and ensures that manufacturers abide by pharmaceutical GMPs, rather than food GMPs. As many products sold as hemp-derived ‘cannabidiol’ dietary supplements have been found to contain no cannabidiol whatsoever, levels of tetrahydrocannabinol exceeding 0.3%, and even synthetic cannabinoids, it is abundantly clear that dietary supplement regulations are not stringent enough to withstand the number of bad actors in the marketplace. These existing regulations have led to a ‘wild west’ marketplace which presents a major risk to public health. Until manufacturer registration, product pre-approval, and adverse event reporting is mandatory for all dietary supplements and cosmetics, FDA must not permit the sale of any cannabinoids in these categories of products until the regulations which apply to such categories can be strengthened. The author respectfully urges the agency to take immediate enforcement action to halt the sale of dietary supplements and cosmetics containing cannabidiol and other cannabinoids.

Alternatively, the agency could apply special regulations to non-psychoactive cannabinoids in dietary supplements and cosmetics, to ensure that product pre-approval and adverse event reporting would be mandatory. However, applying these requirements to a select group of manufacturers would appear arbitrary and somewhat unfair.

Develop monographs for over-the-counter formulations of specific cannabinoids

The 2017 National Academy of Sciences report ^[1] into the health effects of cannabis and cannabinoids could serve as a starting point for OTC monographs; the report argues that although many of the purported health effects of cannabis are unproven, there is “conclusive or substantial evidence that cannabis or cannabinoids are effective … for the treatment of chronic pain in adults … antiemetics in the treatment of chemotherapy-induced nausea and vomiting … for improving patient-reported multiple sclerosis spasticity symptoms”, and “moderate evidence that cannabis or cannabinoids are effective for … improving short-term sleep outcomes in individuals with sleep disturbance”. Therefore, indicated ‘drug purposes’ for OTC preparations of cannabidiol and other cannabinoids could include:

1. ‘Pain reliever’ (internal and external)
2. ‘Anti-nausea’
3. ‘Muscle relaxant’
4. ‘Nighttime sleep aid’

Preserve the prescription-only pathway for minor cannabinoids, cannabinoid derivatives, non-harmful synthetic cannabinoids, and high doses of cannabinoids

As over one hundred cannabinoids have been identified in cannabis alone, FDA should maintain an open pathway for pharmaceutical firms to develop prescription-only formulations of minor cannabinoids.

Prescription-only pharmaceutical preparations of cannabinoids should be limited to isolated and/or synthesized cannabinoids, or dosages/concentrations of cannabinoids greater than those permitted in foods and OTC drugs. In the same way that Epidiolex® contains only isolated cannabidiol and no other trace cannabinoids or cannabis constituents, despite being derived from cannabis, new prescription-only cannabinoid medications should only contain isolated cannabinoids. Equally, in the same way that Marinol® contains synthetically-derived tetrahydrocannabinol which is identical to naturally-derived tetrahydrocannabinol, new synthetically-derived cannabinoid medications (which are identical to those naturally-occurring in cannabis) should only be available with a prescription.

FDA can help to preserve the incentives for pharmaceutical firms to develop prescription-only cannabinoid medications by ensuring that the concentration and/or dosage of cannabinoids in prescription-only medications is higher than those permitted for cannabinoids added to foods, beverages, over-the-counter drugs, and tobacco substitutes. This is already demonstrated through the recommended dosage for Epidiolex® ^[7]; a patient with Lennox-Gastaut syndrome or Dravet’s syndrome weighing fifty kilograms may need to consume as much as 1,000 mg of cannabidiol per day – 1,000 mg of cannabidiol is significantly greater than the total quantity of cannabidiol in many cannabidiol supplements and cosmetics currently sold for general use and intended to last the consumer for several weeks or months.

Additionally, an immediate action that FDA could take would be to expand the indications for Epidiolex® to enable it to be prescribed for all types of epilepsy. Going further, specific rulemaking permitting the off-label prescribing of Epidiolex® would expand access to patients with conditions beyond epilepsy. FDA should also fast-track the approval of Sativex® and other cannabinoid medications.

Permit the sale of hemp-based tobacco substitutes

Tobacco regulations in Switzerland ^[8] permit the sale of hemp as a tobacco substitute, with a limit of 1% tetrahydrocannabinol, which is higher than the 0.2%/0.3% permitted in other jurisdictions. There is no limit on the cannabidiol content of these products. Such tobacco substitutes are sold in Swiss convenience stores and other retailers. FDA should look to Swiss policies as a sensible middle-ground between strict prohibition and unregulated free-for-all, both of which coexist in various aspects of the marketplace in the United States.

FDA should use its powers as the agency responsible for the regulation of tobacco products to create a new regulatory category for hemp (specifically hemp flowers) as a tobacco substitute. By permitting hemp to be sold as a tobacco substitute, such products could provide tobacco consumers with another safer, but not safe, alternative to tobacco products. Although the smoking of hemp carries the risk of lung cancer and other adverse health outcomes, cannabidiol and other non-psychoactive cannabinoids have not been found to be habit-forming. Unlike nicotine replacement therapy and ENDS, hemp-based tobacco substitutes are nicotine-free, providing consumers with a way to smoke without consuming nicotine.

In hemp-based tobacco substitutes specifically, permitting up to 1% tetrahydrocannabinol by weight, rather than the 0.3% currently permitted, could have a beneficial effect – as consumers currently have no Federally-legal means of accessing tetrahydrocannabinol, the slightly higher concentration of tetrahydrocannabinol could help to divert consumers from State-legal products containing much higher concentrations of tetrahydrocannabinol.

Unlike the Swiss model, which permits the combination of tobacco and hemp in cigarettes, FDA should ensure that hemp (and cannabinoids generally) cannot be added to tobacco products, and vice-versa, ensuring that hemp-based tobacco substitutes remain separate from tobacco products. Such a policy ensures that adverse event reporting for hemp-based tobacco substitutes is not confounded by the presence of nicotine and other tobacco-derived substances. Unlike tobacco products such as cigarettes, FDA should not permit manufacturers of hemp-based tobacco substitutes to add any excipients to their products. The agency should ensure that hemp-based tobacco substitutes are manufactured from hemp flowers alone, in order to prevent hemp extracts and isolates from being added to hemp flowers to artificially increase cannabinoid content.

Additionally, the agency should require that the rolling paper used to contain the hemp in hemp-based cigarettes be manufactured from hemp itself, specifically hemp grown in the United States, as such a requirement would provide an additional source of revenue for domestic hemp farmers. This rule should apply to State-legal psychoactive cannabis cigarettes, in addition to Federally-legal products.

Require all cannabis-based cigarettes to be fitted with a filter and fire-safe bands

Filters on cigarettes reduce the quantity of tar, pesticides, and other harmful substances consumed by the user during smoking; fire-safe bands on cigarettes reduce the risk of such products starting a fire. An analysis by Yau and Marshall states that the implementation of fire-safe cigarette legislation results in a “19% decrease in the rate of fire-related deaths in the home” ^[9]. FDA should require all cannabis cigarettes to be manufactured with fire-safe bands and a filter made from cotton, activated carbon, and/or other materials, even if such products are not entered into interstate commerce. This would mean that both Federally-legal non-psychoactive hemp-based tobacco substitutes, as well as State-legal psychoactive cannabis products, would be required to include built-in measures to protect the end-user.

FDA should also require that cannabis cigarettes be easily deconstructible – to be manufactured with perforated paper, for example – to enable the contents of the cigarette to be removed and subsequently vaporized by the consumer, if desired. Such a requirement would make the choice to vaporize the product, rather than smoke it, easier. FDA should permit the sale of ‘heat-not-burn’ hemp products, similar to recently-approved IQOS ‘heat-not-burn’ tobacco devices ^[10] manufactured by Philip Morris International.

FDA should require all non-finished cannabis products, namely cannabis flowers, to include a statement on the product label which advises consumers to use a filter if combusting the product and that vaporizing the product results in a reduced risk of adverse health outcomes such as lung cancer. Manufacturers should also be required to include the same Surgeon General’s warning which is required on tobacco products, regardless of whether the products are Federally-legal or State-legal only.

Prohibit reference to cannabinoids without disclosure of cannabinoid content

Many products on the market feature the term ‘CBD’ in the product name or elsewhere on the product, yet the quantity of cannabidiol in the product is not disclosed – terms such as ‘hemp extract’ or ‘hemp isolate’ are used instead. FDA should ensure that no product may bear the term ‘CBD’ or make reference to any cannabinoid, whether in the product name or elsewhere on the packaging, without disclosing the quantity of cannabidiol or other cannabinoids present in the product. Furthermore, hemp-derived products which do not contain any cannabinoids should be required to bear a statement to this effect; such statements could include: ‘cannabinoid-free’, ‘cannabidiol-free’, or ‘contains no cannabidiol (CBD)’.

Require cannabinoid and terpenoid labelling on all products

All detectable cannabinoids should be listed on the product label, not only cannabidiol and tetrahydrocannabinol. The disclosure of all cannabinoids and terpenoids present in cannabis products will make redundant the use of terms such as ‘broad spectrum’ and ‘full spectrum’. FDA should require that cannabinoids be listed as their full names, followed by an optional abbreviation in parentheses. For example:

Prohibit the use of ‘indica/sativa/hybrid’, ‘strain’, and ‘spectrum’ terminology

FDA should prohibit the use of terms such as ‘indica’, ‘sativa’, and ‘hybrid’ on cannabis products. These terms have become associated with certain types of psychoactive effects – despite evidence indicating that such distinctions in fact have no consistent bearing on psychoactive effects – and as such, the use of these terms effectively constitutes a tacit drug claim. Similarly, FDA should not permit cannabis products to be labelled with strain names such as ‘Blue Dream’ or to be labelled as ‘full spectrum’ or ‘broad spectrum’; consumers’ understanding of what therapeutic effects to expect from cannabis products should be based solely on the active ingredients and chemical composition of the product in question – the concentration and ratio of cannabinoids and terpenoids – as is the case with conventional drugs and dietary supplements.

Prohibit manufacturers from making health claims for cannabis and cannabinoids

Except for health claims approved for cannabinoids added to foods and drug claims for OTC cannabinoid preparations, even if manufacturers’ ability to make health claims for cannabis products is significantly curtailed, manufacturers of cannabis products will still be able to make claims regarding the geographic origin of the cannabis used, the extent to which the cannabis is free from contaminants, the composition of the product (concentration of cannabinoids, terpenoids), and the ecological footprint of the product. Limiting manufacturers’ ability to make health claims places a responsibility on the consumer to conduct their own research. However, to ensure that consumers researching the efficacy and appropriate dosage of cannabinoids do not fall victim to misinformation, particularly on the internet, FDA should prioritize the development of its own guidelines for safe cannabinoid use and risk reduction practices.