A New Regulatory Pathway is Ahead

Since the 2018 Farm Bill, the FDA has been looking at the food ingredients and dietary supplement pathways, within the Federal Food, Drug, & Cosmetic Act (FDCA), to regulate CBD products. Over four years later, an important update from the FDA finally came on January 26th, 2023 stating “…the FDA has concluded that a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks”. They noted that the food and supplement pathways have limited resources, and are not regulated or enforced enough to manage all the potential risks with CBD products. They also expressed that they “…have not found adequate evidence to determine how much CBD can be consumed, and for how long, before causing harm”.

Safety is the overarching concern that the FDA has when it comes to CBD. Safety studies are necessary now more than ever in the CBD industry and demonstrate integrity as an ingredient manufacturer. When discussing the safety of dietary ingredients, supplements, and CBD products, there are many acronyms that can be a cause for confusion. Below we dive into the acronyms within these studies, what they really mean when it comes to ingredient safety, and what’s next for the CBD industry.

NOAEL

The acronym NOAEL stands for No Observed Adverse Effect Level. The NOAEL is defined as, “the highest dose where the effects observed in the treated group do not imply an adverse effect to the subject”. The NOAEL has been used to develop “safe” doses, or margins of safety for food ingredients and contaminants. In order to determine the NOAEL for a given ingredient, it must go through clinical toxicity studies.

Toxicity studies are “experiments in which different ways and durations of exposure to experimental animals are used to detect various toxicity endpoints. The purpose is to determine the level of harmlessness, type of toxicity, target organ, and dose-response relationship, and provide important data for safety evaluation or risk evaluation”. Essentially, toxicity studies determine the level that a particular ingredient becomes toxic to the body and establishes an amount that a certain substance will produce adverse effects.

Mars Petcare has recently carried out a toxicity study, using Kazmira’s CBD ingredient input, that demonstrates safety of long-term daily cannabidiol use in healthy dogs. The study provides evidence that a once-daily oral dose of 4 mg CBD/kg body weight is well tolerated in clinically healthy dogs over a 6-month period. This toxicity study contributes data that should be considered in future establishment of a NOAEL by regulatory bodies such as EFSA, FSA, and FDA. 

Toxicology reports can inform you of potential problems with your products ahead of time, ensure they’re safe to use, and demonstrate that you’re a responsible manufacturer by investing in these types of studies. Performing toxicity studies on your dietary ingredient before it’s brought to market, ensures you’re aware of any unwanted outcomes, and allows you to address these unwanted effects before they can impact your customers. Knowledge of NOAEL, as determined in your animal toxicology reports, can then be used to arrive at a safe starting daily dose in human subjects, also referred to as an ADI.

ADI

The acronym ADI stands for Acceptable Daily Intake. ADI is “an estimate of the amount of a substance (such as a food additive) that can be safely consumed on a daily basis over a person’s lifetime without posing a health risk”. ADI’s lay the groundwork for legislation around consumable ingredients. Growing public health concerns regarding safety of dietary and food ingredients demand greater transparency around these products. Understanding ADI will increase the consumers knowledge, and thus their confidence, regarding food safety assessments on these products.

Once you’ve performed the necessary Phase 1 toxicity studies and arrived at a NOAEL, you can then find your ADI for human consumption. ADI’s for CBD products are displayed in CBD milligrams per day. To find the CBD Acceptable Daily Intake we first begin with our NOAEL. Multiply the NOAEL by a factor of .7 (average human weight in the US (70 kg) / acceptable safety factor in the US and abroad (100)). Finally, multiply this number by the purity of the CBD extract, resulting in the CBD ADI (mg/day). 

NOAEL x .7 x CBD purity = CBD ADI (mg/day)

GRAS

The acronym GRAS stands for Generally Recognized As Safe. When discussing GRAS, the FDA states, “any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excepted from the definition of a food additive”. The only ways to prove your ingredient safety, via GRAS, is either through scientific studies or if an ingredient was used in food pre-1958, you can use experience based on that common use in food. Once you’ve done the necessary Phase 1 toxicity studies and arrive at your ADI, you can apply for the GRAS notification program.

According to the FDA, the GRAS notification program “…provides a voluntary mechanism whereby a person may inform FDA of a determination that the use of a substance is GRAS, rather than petition FDA to affirm that the use of a substance is GRAS”. So there are two types of GRAS statuses you can obtain for your ingredient, FDA-Notified GRAS and Self-Affirmed GRAS. You can self-affirm that your product is GRAS status based on the conclusion of a scientific expert panel who reviews your ADI established through toxicology studies. Most GRAS determinations use this process. On the other hand, you can petition the FDA to review your ingredient and provide you with a GRAS status by way of a letter, responding with no questions (approved) or objecting, stating there’s not a sufficient basis for a GRAS conclusion.

NDIN

The acronym NDIN stands for New Dietary Ingredient Notification. The FDA’s NDIN process states, “the Federal Food, Drug, and Cosmetic Act (the FD&C Act) requires that manufacturers and distributors who wish to market dietary supplements that contain “new dietary ingredients” notify the Food and Drug Administration about these ingredients. Generally, the notification must include information that is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing a new dietary ingredient will reasonably be expected to be safe under the conditions of use recommended or suggested in the labeling”. While similar to GRAS, NDIN applications generally have a higher safety threshold to obtain (Phase 1 & Phase 2 toxicity studies) and unlike GRAS, the only way to apply is to send your NDIN application to the FDA for review and approval.

It’s important to note that NDI approved ingredients are only approved for use within dietary supplements, not all food ingredients. Generally, NDIN approval only comes after conducting both Phase 1 and Phase 2 toxicity studies, rather than just the Phase 1 toxicity studies that you need for GRAS. One potential advantage to NDIN is that within the process, they will mostly keep your submitted documentation between you and the FDA, making it a good option for proprietary research and documentation. Due to the need for FDA review of NDIN’s, there’s a higher rate of objections in the NDIN process compared to the GRAS notification program. That being said, NDIN approval can be seen as more credible than obtaining a GRAS status.

Why are These Acronyms Important?

NOAEL, ADI, GRAS, and NDIN are four tools used by companies to ensure the safety of dietary ingredients, and could be especially important when it comes to showing the safety of CBD products. Although the FDA believes there should be a new pathway forward for CBD, they’ve not given any insight into what that pathway might be or when they’ll know the regulatory logistics for it.

The FDA may utilize some parts of the food ingredients and dietary regulatory pathways, but we expect the new framework to look quite different. This is why, at the very least, it’s important for CBD manufacturers to carry out these safety studies regardless, and at least arrive at an NOAEL and ADI for their hemp extract. That way manufacturers are ready to apply their ADI to any of the new notification programs that are built into this new regulatory CBD framework. 

Where is CBD Heading?

Looking towards the future, the FDA concluded that, “Some risk management tools could include clear labels, prevention of contaminants, CBD content limits, and measures, such as minimum purchase age, to mitigate the risk of ingestion by children”. These new tools could provide insight to customers, and are valuable disclosures that help to assist consumers when purchasing CBD products. Among the new risk management tools mentioned by the FDA, anticipate even more stringent rules to be in place for the industry.

When speaking to Marijuana Moment, Shawn Hauser, a partner at Vicente Sederberg LLP, said “It’s likely we will see FDA continue to maintain its non-enforcement approach and deference to the states, except where products have material public safety concerns… I expect we will continue to see more robust state regulatory programs governing finished hemp products, including limitations on THC content and synthetics”. This is already being addressed in states such as Colorado and Washington, where THC content and use of synthetic compounds are recommended label requirements by both the SB 22-205 Colorado Task Force, regarding intoxicating hemp products, and the new Washington bill SB 5367.

Stephen Oliver with Canna Consultants recently posted a few of his thoughts about where the CBD industry is headed. He states, “CBD Products: Medicinal and Prescription only above 15-20mg per day by Q1 2024. Restrictions on supplements such as single dose products (gummies): limits at 10mg and a maximum ADI/RDI of 15-20mg. Nothing other than GMP produced CBD Isolate or Synthetic CBD. Zero tolerance on THC in consumer products”. He goes on to say, “In the face of virtually zero enforcement, it is left to those of us who invest in compliance and customer satisfaction to set the standards”. The primary theme behind all these future industry assessments boils down to the root of it all, safety.

Concluding Thoughts

The FDA inaction around CBD, makes it that much more crucial for customers to demand transparency from manufacturers about the safety of their products. In a highly saturated and unregulated industry, it’s important to know that the ingredients in the CBD products you’re buying are indeed safe to consume. If the FDA isn’t going to provide a pathway soon to regulate these types of products, manufacturers should be continually proving the safety of their ingredients regardless. Customers are already ingesting these products on a daily basis, making it that much more important for them to know how much a “safe” daily dose truly is.