Study Finds Data Scarce Where US FDA Wants To Gauge Hemp Safety – Reproductive Toxicity
Executive Summary
First systematic mapping study of safety concerns for consumer use of cannabidiol identifies knowledge gaps for reproductive and developmental toxicity. No traditional, guideline-compliant developmental and reproductive toxicity study was available in the public domain through December 2020.
Male reproductive toxicity data US regulators emphasize are needed to determine the safety of using cannabidiol and other hemp ingredients in dietary supplements weren’t available two years after hemp was de-scheduled as a controlled substance and its use in supplements had become widespread.
That is among the findings of a literature search of published studies, in response to the Food and Drug Administration’s standing request for data to determine safe levels for hemp ingredients in food and supplements, assessing potential health outcomes after exposure to CBD and other hemp ingredients.
Reproductive and neurological/developmental toxicity were flagged as data gaps by researchers at scientific consulting firm ToxStrategies Inc. led by Rayetta Henderson. Hence, a well-designed, guideline-compliant CBD reproductive toxicity study is justified.
The review, published online on 14 October in the journal Cannabis and Cannabinoid, found that the three most frequently studied outcomes were neurological, carcinogenic and pharmacokinetics.
Conversely, developmental, reproductive,hepatic and gastrointestinal outcomes were among the less frequently examined categories.
The review also found the two primary outcomes linked to the most adverse events were reproductive and neurological/developmental.
Evidence Mapping For Neurological, Reproductive Outcomes
Male reproductive toxicity from exposure to CBD and other hemp ingredients has been one of the red flags the FDA has referenced since hemp was de-scheduled as a controlled substance in the 2018 farm bill, a five-year reauthorization of spending for US Department of Agriculture programs. (Also see "Funding For US FDA Work On Cannabinoids Regulatory Pathway Drives Progress Only So Far" - HBW Insight, 7 Apr, 2021.)
Because of those concerns, Henderson and her colleagues performed evidence mapping for neurological/developmental and reproductive outcomes to identify areas for potential additional research.
From available information on the effects of CBD on the male reproductive system, “data are insufficient for deriving a point of departure for human health risk assessment for reproductive and/or developmental toxicity,” wrote the authors.
From a review of selected full-length articles, the authors verified that no traditional, guideline-compliant developmental and reproductive toxicity study was available in the public domain as of December 2020.
“This systematic map provides an important baseline from which to identify topics that may be suitable for further research related to the safe use of CBD,” wrote the authors.
Of the 403 studies with neurological primary outcomes, 3.2% showed adverse outcomes associated with CBD exposure; six of those studies comprised healthy human populations.
However, drug interactions and general toxicity outcomes often were secondary outcomes within studies; for example, when the primary outcome of a study was neurological, the investigators may have also reported on general toxicity. Likewise, drug interactions might have been reported as part of a clinical trial.
Although Congress de-scheduled hemp in 2018, the legislation maintained the FDA’s authority over the botanical’s use in products subject to its regulatory oversight. The agency is allowing sales of hemp-containing supplements under enforcement discretion; its official position is that hemp is precluded from being used in food and supplements because hemp ingredients are approved for use a drug available in the US. (Also see "Safety Concerns Are US FDA's Answer To Question On Regulatory Pathway For Hemp’s Lawful Use" - HBW Insight, 14 Jun, 2022.)
1,001 Studies Administered CBD Alone
The review used 2,834 studies found from searching PubMed and Embase from 1972 through 2020; 1,001 administered CBD in isolation.
For CBD-only studies, study populations or study models were mostly experimental animals, followed by in vitro models and human trials.
The review includes 393 studies evaluating the safety of CBD administered alone in the three years since hemp was de-scheduled compared to 607 publishedin prior years.
The number of studies published on all cannabis-derived substances is significantly higher and continues to grow; for instance, a keyword search for “cannabis” in PubMed in December 2021 resulted in more than 27,000 hits.
“For this reason, it is critical that data on CBD continue to be collected systematically and reviewed as they become available,” the authors wrote.
Mapped studies were restricted to those with evaluation limited to either CBD or Epidiolex, a synthetic CBD Rx drug approved in the US. Studies that assessed other hemp-derived materials like hemp extract or other cannabinoid oils, or administered CBD in combination with other substances, such as tetrahydrocannabinol, were excluded.
The number of CBD studies reported on neurological outcomes was 532, on carcinogenic outcomes 129 and on pharmacokinetics 188.
The primary outcome of 43 studies was an adverse event or a potential toxic effect. But associated dose levels were not evaluated as part of the mapping exercise.
Adverse events were most often reported in studies measuring neurological/developmental outcomes, 13, and reproductive, 12.
Overall, 12 of the 19 CBC studies which mainly assessed developmental and reproductive effects found adverse events. The remaining studies mostly concentrated on general toxicity, drug interactions and hepatic outcomes.
Database A Starting Point For Additional Analysis
In addition to the systematic mapping exercise underscoring the need for a quality and guideline-compliant reproductive toxicity study of CBD, the mapping database can serve as a starting point to conduct additional analysis, including systematic reviews on key subtopics of interest, like the potential toxicity of CBD exposure to the male reproductive system.
The authors pointed out that studies using an oral route exposure are most valuable when evaluating human hazard and/or risk after ingestion of CBD in foods or dietary supplements. However, accurate categorization of exposure routes was challenging to ascertain without reviewing the full-length articles. The review was limited to screening titles and abstracts (TIAB).
Based on the interim mapping exercise, immune outcomes represent a promising emerging research area in CBD. The review found a range of immunomodulatory effects from CBD, from immunosuppressive observations to benefiting the immune system.
With screening for the systematic mapping study based solely on TIAB, limitations are obvious that would’ve been alleviated by assessing full-length studies for data extraction and more accurate characterization. In fact, some studies had no abstracts.
Another impediment to mapping CBD only were cases of complex exposures, such as co-exposures, CBD in mixtures and/or drug interactions. These cases often required further review and notation
“These limitations and their potential for increasing the uncertainty of the systematic mapping results should be taken into consideration,” wrote the authors.
Nonetheless, the subset of data presented provides a comprehensive overview of safety-related studies on CBD which can be updated to support more research about the safe use of CBD.
The authors plan to release updates to their mapping, which in turn can help develop health benchmarks for exposure to CBD.