Vitamin D Deficiency Drives Opioid Addiction in Mice

David Fisher, a dermatologist at Massachusetts General Hospital (MGH) and a coauthor of the study, previously studied the molecular pathways behind tanning. When exposed to UV radiation, keratinocyte and melanocyte cells in the outermost layer of skin upregulate a gene called POMC that produces a protein that is then further cleaved into a number of peptides, including hormones involved in producing melanin pigment. Fisher and his colleagues then found that POMC also promotes the production of endorphins, feel-good hormones that are chemically related to opioids such as morphine and heroin, activating the same receptors in the brain. Follow-up work by researchers at MGH, including Fisher, and Harvard Medical School found that chronic UV exposure caused mice to display behavior consistent with opioid addiction. 

It’s so darn clear that this provides the critical preliminary, preclinical work that should be used to drive prospective trials of vitamin D repletion in individuals with opioid use disorders.

—W. Michael Hooten, Mayo Clinic

UV radiation triggers the synthesis of vitamin D. Fisher and his colleagues, including MGH physician-scientist Lajos Kemény, hypothesized that UV radiation, vitamin D, and opioids might actually be linked through a shared reward pathway in the brain. It would explain, Kemény says, why studies have shown that humans can develop addictive-like behaviors towards tanning.

To see whether the link between vitamin D and opioid addiction holds true in humans, the researchers first scoured two retrospective data sets—the first included roughly 20,000 participants in the National Health and Nutrition Examination Survey, while the second included almost 3,000 patients admitted to MGH between 2014 and 2016 with an opioid use disorder and more than 8,000 matched controls. 

In the first data set, patients with insufficient vitamin D, meaning they would be recommended to take a supplement, were 50 percent more likely to use opioid painkillers compared with patients with normal vitamin D levels, and those who were deficient, or severely lacking in vitamin D, were 90 percent more likely to take opioids. These results held true even when the researchers accounted for factors such as age, sex, history of bone fractures, and chronic pain. Similarly, in the data from MGH, patients diagnosed with an opioid use disorder—signaling prolonged use—were more likely to be classified as vitamin D deficient or insufficient. Finding support for the association between low vitamin D and opioid use in two independent data sets “speaks for itself that this could be something that warrants further investigation,” Kemény tells The Scientist.

The addiction–vitamin D link in mice

The researchers next turned to mouse models to better understand the patterns they had seen in the clinical data. They prompted vitamin D deficiency either by feeding mice a vitamin-deficient diet for eight weeks or by creating transgenic mice that lacked the vitamin D receptor. Half of the diet-deficient mice resumed a normal diet for a further eight weeks before examining how they responded to morphine. 

All were run through a classic assay called the conditioned place preference (CPP) test, in which mice are placed in a chamber with multiple compartments and trained to anticipate morphine in one. During a test session, researchers measure how long they spend inside the morphine chamber.

Only the highest dose of morphine prompted control mice with normal vitamin D levels to prefer that compartment, but deficient mice were fourfold more sensitive to the drug when averaged across all doses the team tested, regardless of how vitamin D deficiency was induced. When the team restored vitamin D using supplements, they found that the effect was reversible: mice that had their vitamin D replenished behaved more like the control mice. And when the researchers made the test easier—by adding more sensory cues to signal in which location they’d receive morphine—and ran it again with new mice, the findings held. “The really strong result here is that when we utilize two quite different protocols with quite different models—with tactile cues, without tactile cues, with different numbers of conditioning sessions—we see the same effect,” Kemény says. 

Next, the researchers wanted to know whether vitamin D deficiency influenced how mice respond to opioids. For this test, they first placed control and deficient mice on a hot plate and measured their response to physical pain, called nociception. Then, they gave the mice morphine and ran the test again. Vitamin D–deficient mice were able to stay on the plate longer, meaning that morphine worked more effectively as a pain reliever, and again, the effect was reversed when vitamin D was restored. In mice that lacked opioid receptors, the heightened pain threshold from a lack of vitamin D disappeared, demonstrating that this effect is opioid-mediated. 

Mice spent more time in compartments they associated with UV exposure, suggesting a lack of vitamin D sensitized the mice to the rewarding effects of UV.

Taken together, the team’s work “is a fantastic achievement since it highlights the role of vitamin D and untangles some of the molecular mechanisms and environmental factors involved in regulating [nociception] using mice and humans,” Abdella Mohammed Habib, a clinical biochemist at Qatar University who was not involved in the work, tells The Scientist in an email. “It nicely builds on previous solid experimental data and gives impetus for identifying the role of vitamin D in the pain signaling pathway.” 

A link to sunlight, and patient care

To link their work to UV radiation, the team exposed transgenic mice lacking vitamin D receptors to UV. Similar to the team’s opioid findings, daily exposure to low-dose UV increased analgesia in the vitamin D–deficient mice compared with control mice. UV exposure also produced similar findings during a CPP test—mice spent more time in compartments they associated with UV exposure, suggesting a lack of vitamin D sensitized the mice to the rewarding effects of UV.

Kemény speculates that this behavior may have an evolutionary basis. To strike the right balance between the benefit of UV—namely, vitamin D production for bone strength—and its drawback—specifically, cancer risk—mice and humans may have evolved molecular pathways that induce the same feelings one might get when taking opioids, but then tamp down on the craving once vitamin D levels are at a sufficient level. Put more simply: people who are vitamin D deficient would feel compelled to seek out the sun, receiving that endorphin rush when they do. But once their bodies generate enough vitamin D, the feedback should stop. In the case of opioids, which don’t synthesize vitamin D, there is no molecular switch to turn off the craving. “When we do opioids, we get the reward without the benefit of vitamin D supplementation,” Kemény says.

The association between vitamin D and opioid response has “direct clinical relevance, now, to patient care,” Hooten tells The Scientist, even without “hardcore, randomized, controlled trial data” in humans. Vitamin D is easily measured using blood draws, and the risks of administering it are low. Checking vitamin D levels prior to a patient’s surgery, for example, could determine whether they are likely to have a heightened tolerance to morphine or whether they are more likely to develop an addiction. 

“It’s so darn clear that this provides the critical preliminary, preclinical work that should be used to drive prospective trials of vitamin D repletion in individuals with opioid use disorders,” Hooten says. “And the beauty of it, in my mind, is that it’s not as if this is a high-end, multi-thousand-dollar intervention. It’s vitamin D.”