Sex Differences In Pain Relief with Cannabis

Photos by Larry Utley of a bipolar woman experiencing pain relief with cannabis.
Her face is shown pre-treatment (left) and at 30 and 60 seconds after smoking.

Less than 10% of neurological and pharmacological research is conducted on females in the US, says Dr. Rebecca Craft of Washington State University. Her lab is working to help correct that imbalance, by studying the effects of THC on male and female rats.

Craft's lab took healthy rats, 10 males and 10 females, and dosed them every 15 minutes with THC. At each dosage level, researchers did two tests for acute pain: putting the rats’ tails in 122-degree water and measuring how quickly they pulled their tails out; and applying pressure to their paws and measuring at what level of pressure they retracted their paws. As expected, the analgesic effect of THC increased at higher levels in both sexes, but to a greater extent in females.

Researchers then did a nine-day experiment, injecting the rats twice daily with THC in an amount determined to produce 80% of maximal analgesia (a lesser amount for females). The pain experiments were then repeated, in order to study to what extent tolerance to THC’s pain-relieving effects had taken place. It took more THC to show a pain-relieving response in rats that had received chronic doses, and this effect was also more pronounced in females.

Taken together with a recent study showing that women using cannabis daily reported a higher incidence of “abuse related effects” than men,  Dr. Craft’s work has been reported as being cautionary for women using cannabis medicinally. However Dr. Craft says that it’s hard to relate results, or doses, between acute pain studies in rodents and chronic pain in humans. For example, the opposite effect is found for morphine: male rats are more susceptible to its acute effects and develop greater tolerance, but the same sex difference has not been found in humans.

It’s been theorized that the hormone estradiol in menstruating females is responsible for the observed differences in cannabinoid effects, possibly through the mechanism of beta-arrestin2, an intracellular signaling molecule that interacts with the CB1 cannabinoid receptor in the brain. But some studies Craft’s lab has been working on indicate that sex hormones aren’t responsible for sex differences in tolerance to THC’s pain-relieving effects, although they may have a role in its sedative effects. Also, in rats a different enzyme metabolizes THC into its main active metabolite 11-OH-THC in males and females, but in humans, the enzyme is the same for both sexes.

Dr. Rebecca Craft of WSU

Dr. Craft’s next study will be working with a chronic pain model in rats, mimicking the inflammatory pain of rheumatoid arthritis. Chronic pain models in rodents have also been developed for neuropathic pain of the type experienced by chemotherapy patients and diabetes sufferers.

The work is important: women are more likely to present with chronic pain issues, for diseases like fibromyalgia, IBS, MS and migraine as well as the depression that comes with pain. A new study shows women find cannabis more effective than other pain-treatment modalities.

More human research is needed, Dr. Craft stresses, and also more research on females in both human and animal studies. The NIH has recently announced it will require sex-balancing in upcoming studies. Craft is encouraged by NIDA’s recent pronouncement that the agency will be providing more cannabis for research. Her work is funded by a NIDA grant.

Pointing to these developments, and to the legalization of medical and recreational marijuana that is happening across the US, Craft predicts, “We will see an explosion of information in the coming decades.”