FDA, Researchers Still in the Weeds on Cannabis, CBD, and Gender

Liz Scherer

December 02, 2020

The acceptance of medical marijuana and cannabidiol (CBD) products is picking up momentum across the United States. Case in point, last month an additional five states voted to legalize medicinal or recreational cannabis, putting more pressure on the medical, research, and regulatory communities to provide some guidance.

The US Food and Drug Administration (FDA) took a step in that direction recently with a day-long virtual symposium held by its Office of Women's Health. The session focused on gender differences in the use of CBD and cannabis-based products, potential sex and gender interactions with regard to anxiety, pain, and pregnancy, and other outcomes.

In a keynote delivered to more than 600 healthcare practitioners, policymakers, patients, and other stakeholders, Douglas Throckmorton, MD, deputy director for regulatory programs at the FDA's Center for Drug Evaluation and Research, underscored the complexities of cannabinoid therapeutics and the logistical and regulatory challenges the agency faces.

"Not only does the category involve a broad spectrum of cannabinoid compounds well beyond CBD and [tetrahydrocannabinol (THC)], but FDA is charged to regulate all of the products potentially containing these compounds in a setting where federal and state legislation might be at odds," said Amy Abernethy, MD, PhD, Principal Deputy Commissioner of Food and Drugs at the FDA.

CBD Research Lacking

A number of panelists at the symposium highlighted that while women comprise the majority of patients using CBD or THC to treat conditions such as anxiety, pain, and sleep, they've been historically underrepresented in research. "Women are not sharing the risks, nor are they sharing the benefits of research equally," said Betty Jo Salmeron, MD, staff clinician in the Neuroimaging Research Branch at the National Institute on Drug Abuse.

Not only are these differences exemplified in sex-specific differential rates of/therapeutic response to these conditions, but also in the dearth of data available to guide clinical practice. Researchers know that women are driving use of CBD across the nation, but regulatory obstruction means that available data mostly derive from animal or observational studies.

Take anxiety, for example. Cinnamon Bidwell, PhD, assistant professor and director of the Center for Research and Education Addressing Cannabis and Health at the University of Colorado at Boulder, has been evaluating the effect of THC and CBD use on anxiety in an ongoing cohort study.

"Preliminary data show that relative to THC, CBD users had a significantly greater trend toward reductions in self-reported anxiety," Bidwell said, noting that the differences were even greater in women. "Women who started at higher levels of anxiety had larger declines after 4 weeks of self-directed use."

"These sex differences are also observed [with] cannabinoid analgesic effects, but so far, the data (mostly from meta-analyses) are quite a mess," said Daniel Clauw, MD, professor of anesthesiology, medicine, and psychiatry at the University of Michigan in Ann Arbor.

"When we look at THC and CBD in animal models of pain, it seems that CBD might be more effective for pain states that are nociceptive, whereas THC might be more effective [for] neuropathic pain," he explained. Combined, they might activate cannabinoid receptors in both the brain and the periphery to address a third category: central sensitization.

This is where their utility — or lack thereof — comes into play: "We know that women are more pain- and sensory-sensitive in the central nervous system, and that this pain responds to an entirely different set of treatments," Clauw said.

Increasing Use, Sex-based Tolerance

"Cannabis use is increasing in women (especially in ages 26 and older), but there are also profound differences in male and female responses," said Ziva Cooper, PhD, associate professor and director of the UCLA Cannabis Research Initiative.

Animal studies have correlated circulating sex hormones to THC pharmacokinetics and the need for acute vs chronic dosing. This is borne out in human data that demonstrate increased tolerance and greater abuse liability in women using THC to treat pain. Conversely, while THC use appears to increase pain threshold levels in men, the same is not true for women.

In part, the differential effects of THC and CBD on reward and intoxication might explain the tolerance. "Cannabis use disorder (CUD) rates are around 30%, which is similar to rates seen in heroin and cocaine addiction," said Yasmin Hurd, PhD, Ward-Coleman Chair of Translational Neuroscience and director of the Addiction Institute at Mount Sinai Behavioral Health System. "But CUD escalates faster and more severely in women."

Still, data have shown that CBD might have a role for treatment of addiction disorders. For example, both animal and human data have shown that oral CBD reduced cue-induced heroin-seeking behavior, including anxiety. Data have likewise demonstrated a reduction in binge drinking in men. Dosing also matters, but "we still don't have those specific data," Hurd said.

A Pregnant Pause

Like other conditions, there are limited data on the effects of CBD use in pregnancy, in part because pregnant women have by and large been excluded from clinical studies.

Researchers have older data that demonstrate that "the endocannabinoid system (ECS) is present in the placenta. Because CBD is lipophilic, it can cross the placenta, and inhibit fetal liver enzymes, disrupt synaptogenesis, and the developing neurotransmitters system" (all of which are regulated by the ECS and CB1, CB2 receptors), explained Mark Zakowski, MD, professor of anesthesiology at Cedars-Sinai Medical Center in Los Angeles, California.

The dearth of clinical data means that practitioners often have to rely on pregnant women to report usage or use prenatal appointments for those dialogues. But it is not happening. Zakowski said that one reason is that "health practitioners have to contend with the fact that pregnant women report using cannabis and CBD for pain, nausea, and anxiety, but 20% won't tell their physicians."

The National Survey on Drug Use and Health shows that the percentage of pregnant women reporting cannabis use has more than doubled over the past 15 years but that the majority cut back after the first trimester, said Katrina Mark, MD, associate professor of obstetrics, gynecology and reproductive sciences at the University of Maryland School Medicine in Baltimore. "Women who continue to use cannabis do so because they have tried to quit and can't, or more likely, because they qualify use as medicinal."

Anecdotally, women say that they often seek concrete information from practitioners, but in half of these encounters they are either met with silence or are informed about cannabis/CBD legal issues.

The irony could not be greater. "We find ourselves today with a situation where there's two substances that we have the best data for being harmful to the user and to the fetus, i.e. legal alcohol and cigarettes," Salmeron said. "And then we've got research on potentially valuable therapeutics that's been totally thwarted."

Several of the panelists agreed that what is needed is a shift in practitioner attitudes.

"When it comes to clinical interaction, explanation and counseling really can get to more accurate answers," said Nathaniel DeNicola, MD, environmental health expert at the American College of Obstetricians and Gynecologists. It's akin to asking about tobacco use during pregnancy; if you explain the link between smoking and fetal development outcomes, you get a different answer. 

The Path Forward

Throughout the seminar, agency participants emphasized that they're "all in" and working across various institutes at the National Institutes of Health to coordinate research and data dissemination.

"The science of CBD and other cannabinoids has become an FDA priority," Abernethy said.

The FDA's Office of Women's Health Cannabis Working Group Docket will remain open indefinitely for scientific and public comment.

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