Vitamin D (VitD) deficiency strongly amplifies the craving for and effects of opioids, potentially increasing the risk for dependence and addiction, according to the findings of a new study led by researchers at Massachusetts General Hospital (MGH). The research results—which also linked vitamin D deficiency to sun-seeking behavior—suggest that taking vitamin D supplements to address the common problem of vitamin D deficiency could help to combat what the scientists describe as “the current opioid epidemic.”
The team, headed by David E. Fisher, MD, PhD, director of the Mass General Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center (CBRC), reported on their findings in a paper in Science Advances, which is titled, “Vitamin D deficiency exacerbates UV/endorphin and opioid addiction.” In their paper, they concluded, “These data suggest an inverse, dose-dependent relationship between VitD signaling and opioid use, independent of known opioid use triggers.”
Opioid use disorder (OUD) is a major medical challenge that is on the increase in the United States, the authors wrote. Survey results in 2018 indicated that some 10.3 million people aged 12 years or older had abused opioids in the past year, and 2 million individuals had OUD. Tackling this issue will require more effective treatments, including drug therapies for OUD and harm reduction interventions, but also measures to address social and economic factors, they pointed out. In addition, “… causative but preventable environmental factors that contribute to opioid addiction are of great interest.”
Human studies have also suggested that ultraviolet (UV) tanning may be addictive, the investigators continued. Research indicates that some people develop urges to sunbathe and visit tanning salons that mirror the behaviors of opioid addicts. Back in 2007, Fisher and his team found something unexpected, that exposure to UV rays, and specifically UVB, causes the skin to produce the hormone endorphin, which is chemically related to morphine, heroin, and other opioids that all activate the same receptors in the brain. Endorphin is sometimes called a “feel good” hormone because it induces a sense of mild euphoria. A subsequent study by Fisher found that UV exposure raises endorphin levels in mice, which then display behavior consistent with opioid addiction. “Recent preclinical data have identified an endogenous opioid-mediated addiction-like pathway triggered by UV-induced cutaneous synthesis of ß-endorphin,” the team wrote.
Fisher and his colleagues speculated that people may seek out UVB because they unknowingly crave the endorphin rush. But that suggests a major contradiction. “Why would we evolve to be behaviorally drawn towards the most common carcinogen that exists?” asked Fisher. Sun exposure is the primary cause of skin cancer, as well as increasing wrinkles and the risk of other skin damage.
Fisher believes that the only explanation for why humans and other animals seek out the sun is that exposure to UV radiation is necessary for production of vitamin D, which our bodies can’t formulate on their own. Vitamin D promotes uptake of calcium, which is essential for building bone. As tribes of humans migrated north during prehistoric times, an evolutionary alteration might have been needed to compel them to step out of caves and into the sunshine on bitterly cold days. Otherwise, small children would have died of prolonged vitamin D deficiency (the cause of rickets) and weak bones might have shattered when people ran from predators, leaving them vulnerable.
This theory led Fisher and colleagues to hypothesize that sun seeking is driven by vitamin D deficiency, with the goal of increasing synthesis of the hormone for survival, and that vitamin D deficiency might also make the body more sensitive to the effects of opioids, potentially contributing to addiction. “… we hypothesized that UV-seeking behavior might be driven by VitD deficiency to maximize VitD synthesis and that VitD deficiency might also sensitize individuals to exogenous (UV-independent) opioids, contributing to opioid addiction,” they continued. “Moreover, a negative feedback loop might exist whereby UV/opioid-seeking behaviors are repressed when VitD levels are restored. This feedback might carry the evolutionary advantage of maximizing VitD synthesis.”
“Our goal in this study was to understand the relationship between vitamin D signaling in the body and UV-seeking and opioid-seeking behaviors,” commented first author Lajos V. Kemény, MD, PhD, a postdoctoral research fellow in dermatology at MGH.
For their newly reported research, Fisher, Kemény, and a multidisciplinary team from several institutions addressed the question from dual perspectives. In one arm of the study, they compared normal laboratory mice with vitamin D-deficient mice that either lacked the vitamin D receptor, or that had removal of vitamin D from their diets. “We found that modulating vitamin D levels changes multiple addictive behaviors to both UV and opioids,” said Kemény. “Importantly, when the mice were conditioned with modest doses of morphine, those deficient in vitamin D continued seeking out the drug, whereas this behavior was less common among the normal mice. When morphine was then withdrawn, the mice with low vitamin D levels were far more likely to develop withdrawal symptoms. “Oral supplementation to rescue VitD deficiency restored the morphine preference pattern back to that of VitD-replete mice, demonstrating that the VitD-dependent effect is reversible.” The results, they said, “collectively support the hypothesis that deficiencies in VitD receptor signaling sensitize animals to opioid-seeking behavior that is reversible upon VitD supplementation.”
The studies also found that morphine worked more effectively as a pain reliever in mice with vitamin D deficiency—that is, the opioid had an exaggerated response in these mice. The results of tests in the mice “… corroborate observations made more than 30 years ago of increased basal pain thresholds, analgesic effects, and faster tolerance to morphine in VitD-deficient rats,” they reported. This might be a concern if the same is found to be true in humans, Fisher pointed out. Consider, for example, a surgery patient who receives morphine for pain control after the operation. If that patient is deficient in vitamin D, the euphoric effects of morphine could be exaggerated, Fisher said, “and that person is more likely to become addicted.”
In another set of experiments in mice lacking vitamin D receptors, the team found that lack of VitD signaling effectively sensitized the animals to rewarding effects of UV, whereas correcting VitD signaling restored normal sensitivity to UV. The results suggested that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. “This feedback may carry the evolutionary advantage of maximizing VitD synthesis,” the authors noted. However, they added, “unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.”
The lab data suggesting that vitamin D deficiency increases addictive behavior was supported by the team’s analyses of human health records. One showed that patients with modestly low vitamin D levels were 50% more likely than those with normal levels to use opioids, while patients who had severe vitamin D deficiency were 90% more likely. Another analysis found that patients diagnosed with OUD were more likely than others to be deficient in vitamin D. The data, they noted, “… suggest an inverse, dose-dependent relationship between VitD signaling and opioid use, independent of known opioid use triggers.”
One of the critical findings of the team’s lab studies could have significant implications, Fisher noted. “When we corrected vitamin D levels in the deficient mice, their opioid responses reversed and returned to normal.” In humans, vitamin D deficiency is widespread, but is safely and easily treated with low-cost dietary supplements, noted Fisher. While more research is needed, he believes that treating vitamin D deficiency may offer a new way to help reduce the risk for OUD and bolster existing treatments for the disorder. “Our results suggests that we may have an opportunity in the public health arena to influence the opioid epidemic,” Fisher concluded.