A Deeper Understanding: Interview with Dr. Weerts

Do Women Have a Higher Risk of Cannabis Withdrawal Symptoms?

Elise M. Weerts, Ph.D., a behavioral pharmacologist, neuroscientist, and professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, is undertaking a clinical study focused on withdrawal symptoms in women who are regular cannabis users. Talking with CBMD, she discussed her research, why she’s interested in studying the effects of cannabis, and especially, why she’s exploring how cannabis affects women.

CBMD: How did your academic and professional background lead to your current research interests?

Dr. Weerts (EW): I became interested in studying cannabis primarily because of its widespread use. My background includes studies examining the rewarding effects of drugs and determining whether or not various drugs produce physical dependence. I am particularly interested in how chronic drug use affects the brain and the relationship of these neuroadaptive changes on behavior. The cannabinoid system is really interesting in that it regulates many key behavioral processes such as appetite, food intake, learning and memory, and mood. It also interacts with other key systems in the body involved in stress and reward processing.

In collaboration with my colleague, Dr. Ryan Vandrey, we examined data collected in treatment-seeking cannabis users. We asked men and women about different symptoms they experienced the last time they attempted to quit. This included questions about a range of different behaviors and effects including ones specific to cannabis withdrawal.

Our study revealed that women reported more withdrawal symptoms than men, despite using similar amounts of cannabis. In particular, women had higher scores than men in two specific domains: changes in mood and nausea and stomach pain. They also experienced these symptoms as being more severe.

The primary behavioral effects of cannabis are attributed to its major constituent delta-9-THC, which activates cannabinoid receptors in the brain. There are two major types of these receptors—type 1, which are primarily in the brain, and type 2, which are in organs and tissues throughout the body. We can measure cannabinoid receptors in the human brain using a technique called positron emission tomography (PET) brain imaging. In PET imaging, we inject a radiotracer that binds to the cannabinoid type 1 receptor and allows us to visualize cannabinoid receptors in the brain and the density of receptors in different brain regions.

By comparing images from people who use cannabis with scans of people who do not use cannabis, we can learn more about potential cannabis-induced changes in the brain’s cannabinoid system. This study is an early phase study that focuses specifically on women.

CBMD: What was the impetus for the study?

EW: Prior PET imaging to explore the effects of cannabis use on the cannabinoid system has included almost all men. Those studies found that type 1 cannabinoid receptors were lower in men with cannabis use disorder, when compared to healthy volunteers, and this was correlated with expression of withdrawal during early abstinence. After a month of abstinence, scans were repeated and cannabinoid receptors had increased.

These data suggest that with repeated cannabis use, the brain adapts by downregulating the number of cannabinoid receptors, and such downregulation may be the primary mechanism associated with cannabis withdrawal. But since these studies did not include women, we still don’t know if women show changes similar to those seen in men. PET studies in male and female healthy normal volunteers who do not use cannabis have shown women have more cannabinoid type 1 receptors than men in many key regions. These biological differences in cannabinoid receptor density may be important for observed sex-related differences in the effects of cannabis. Women also show a faster progression from first use of cannabis to first admission for treatment of cannabis use disorder, and experience worse treatment outcomes.

There is good evidence from preclinical studies in animal models, that females are more sensitive to some cannabinoids like delta-9-THC. When compared to males, females show higher cannabinoid-induced motor impairment. Females also developed tolerance to these effects more rapidly when exposed to the same dosing regimen as males and were more sensitive to the dependence-producing effects of cannabinoids.

These data lead me to believe that innate sex differences in cannabinoid receptors and cannabis sensitivity, combined with possible sex-specific neuroadaptive changes associated with chronic cannabis use, may contribute to greater withdrawal severity and relapse in females with cannabis use disorder.

The current study will help us learn more about how cannabis use affects the brains of women and about cannabis withdrawal under supervised abstinence undertaken in inpatient conditions.

CBMD: Why is it important that this study focuses on women?

EW: Women are underrepresented in the majority clinical studies, particularly those with brain imaging. Even when women are included in research, the numbers enrolled are generally lower, and studies often don’t include enough women to demonstrate sex-specific differences in behavioral or physiological outcomes.

Females have been excluded from studies involving neuroimaging and studies examining drug withdraw prospectively, largely due to difficulty in controlling for the estrous cycle (changes caused by reproductive hormones) and its potential impact on withdrawal symptom expression or on changes in the brain. This has slowed our understanding of potentially important sex differences in cannabis withdrawal and effects of cannabis on the brain.

CBMD: How common is the occurrence of withdrawal symptoms in cannabis users?

EW: Physical dependence on any drug and occurrence of withdrawal symptoms are typically related to the duration and amount of use. The more you use and the longer you use the more likely you are to experience symptoms when you stop using it.

CBMD: What is cannabis use disorder?

EW: A substance use disorder has a number of features that differ from medical use and many different drugs, including cannabis, share these features, which include:

  • Using more
  • Difficulty stopping or controlling use of the drug
  • Spending significant amounts of time getting, using, or recovering from use of the drug
  • Using a drug in risky situations, like driving a car or continuing to use despite worsened psychological or physical problems
  • Experiencing psychological and physiological symptoms when abruptly stopping drug use

CBMD: How do cannabis withdrawal symptoms compare in severity to withdrawal symptoms from other substances?

EW: Abrupt discontinuation of cannabis use can lead to discomfort and symptoms that are clinically meaningful. Common symptoms are:

  • Irritability, anger, or aggression
  • Nervousness or anxiety
  • Sleep difficulty (for example, insomnia, disturbing dreams)
  • Decreased appetite or weight loss
  • Restlessness
  • Depressed mood

Common physical symptoms include abdominal pain, shakiness/tremors, sweating, fever, chills, or headache.

Some of these symptoms are comparable to withdrawal from other substances but are most comparable to those in heavy tobacco users who quit smoking, although cannabis withdrawal symptoms but can be more severe.

CBMD: What are the potential applications of the study data beyond an expanded understanding of how cannabis affects cannabinoid receptors and withdrawal symptoms?

EW: This study is the first step towards increasing our understanding of cannabis’ effects on the brain. The study will also examine the subjective drug effects of cannabis, and its effects on cognitive performance. By comparing these data in women with data we already have in men, we can examine differences in cannabis effects in men and women.

CBMD: What do you think are the biggest roadblocks to cannabis-focused research and how can they be overcome?

EW: Cannabis and all drugs derived from the plant are classified by the Drug Enforcement Agency (DEA) as a Schedule 1 compound. Drugs in Schedule 1 are those with no verified medical use and are highly controlled. Researchers who want to study cannabis or any of its components have to first be approved by the DEA for a Schedule 1 drug license, and usually an additional certificate from the state for controlled dangerous substances. Then, once completing this hurdle, researchers have to obtain the drug from government resources that have carefully tested and verified its purity. This is a lengthy process. Not all the compounds scientists are interested in studying are available for human research. Rescheduling cannabidiol or allowing exceptions for research of cannabis and other cannabinoid constituents, would greatly increase the ability to study these drugs. There just aren’t enough studies demonstrating medical potential.

CBMD: How long does it take to become dependent on cannabis and does dependence always develop?

EW: First, I’d like to highlight that the word “dependence” is often misunderstood by the general public. The medical term “dependence” refers to physical dependence. Physical dependence is defined by physiological and behavioral symptoms that emerge when a person stops taking a drug and which can be reversed by administration of the drug. These symptoms are typically referred to as withdrawal. Withdrawal is time-delimited, in that symptoms emerge and then gradually decline over time. The fact that withdrawal is reversed by administration of the original drug provides evidence that the symptoms are related to drug use. Cannabis withdrawal has been empirically demonstrated and is included in the most recent revision to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

CBMD: What percentage of users become dependent on medical cannabis?

EW: Prospective studies evaluating the development of physical dependence in medical cannabis users is lacking.

Analysis of data from medical cannabis dispensaries have shown medical cannabis users also can develop problems and cannabis use disorder with increasing use, particularly in younger users.

With regard to cannabis use in general, the National institute on Drug Abuse recently publish a report suggesting about 30% of cannabis users develop cannabis use disorder. Of these, about 9% can show physical symptoms of dependence.

CBMD: Are there common medical or co-conditions for dependence on medical cannabis and other substances?

EW: Co-use of cannabis with other substances and comorbid substance use disorder is common. In particular, cannabis co-use is often reported by individuals who also use alcohol, tobacco or other nicotine products, opioids, or cocaine. Unfortunately, people who have problems with one drug often misuse other drugs as well.

Substance use disorders are also more common in individuals who have psychological disorders.

CBMD: Do you think cannabis and/or cannabidiol have a role to play in helping people with substance use disorders?

EW: The cannabis plant contains hundreds of constituents, many of which we know very little about. I maintain an open mind about the potential medical utility of cannabis and its constituents. I think it’s critical that medical use of any drug, including cannabis and/or cannabidiol, be based on scientific data. The gold standard is the placebo controlled, double blind, clinical trial. For medical use, we must demonstrate that the effectiveness of a treatment is greater than that of a placebo, determine appropriate dosing information, and also assess potential risks, including adverse effects, misuse liability, and possible drug interactions.

There is promise for the medical use of cannabidiol. It does not appear to produce psychoactive effects like delta-9-THC or synthetic cannabinoids and has no known misuse liability. Recently, the FDA approved an oral formulation of pure cannabidiol for the treatment of seizures associated with severe forms of epilepsy. The DEA has not yet made a scheduling determination for this formulation, although medical use would most likely require reclassification from its current status as Schedule 1 controlled drug.

There is also some exciting work that suggests cannabidiol may have utility for reducing neuroinflammation and may help reduce use of opioids.