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A new study on vitamin D and opioid addiction offers a window of hope for the millions of people worldwide suffering from opioid addiction. Published June 11 in Science Advances, the study aligns with earlier evidence of a link between vitamin D deficiency and opioid addiction, suggesting that deficiency may strongly amplify the craving for and effects of opioids. The paper points to the possibility that vitamin D supplementation might help treat the disorder, and it makes a strong case for using vitamin D in a clinical setting.¹ “We may have an opportunity in the public health arena to influence the opioid epidemic,” says lead author David Fisher, MD, PhD.²

Over 16 million people worldwide are opioid-dependent and would meet the criteria for opioid use disorder, with three million in the United States.³ Put to scale: in America, as many patients use opioids regularly as are diagnosed with obsessive-compulsive disorder, psoriatic arthritis, and epilepsy.³ Coordination of care often initially falls to the primary care physician for screening, diagnosis, education, treatment, and referral, and it requires much more than a singular focus on reducing opioid prescriptions.^1,3 Fisher et al advocate that abatement of the opioid crisis must include a rapid expansion of effective treatments, harm reduction interventions, and alleviation of social and economic determinants such as physical and psychological trauma.¹

Promising Parallels: Vitamin D, Pain, & Addiction

Earlier work by Fisher et al laid the foundation for the current study. In 2007, the team found something unexpected: exposure to ultraviolet (UV) rays (specifically the form called UVB) causes the skin to produce the hormone endorphin, which is chemically related to morphine, heroin, and other opioids—all activate the same receptors in the brain.² A subsequent study found that UV exposure raises endorphin levels in mice, which then display behavior consistent with opioid addiction.²

Preclinical data identified an endogenous opioid-mediated addiction-like pathway triggered by UV-induced cutaneous synthesis of ?-endorphin. In this case, maintenance of UV-dependent vitamin D synthesis was suggested as a driver for the evolution of light skin pigmentation.¹ Therefore, the researchers hypothesized that UV-seeking behavior might be driven by vitamin D deficiency to maximize vitamin D synthesis, and that vitamin D deficiency might also sensitize individuals to exogenous (UV-independent) opioids, contributing to opioid addiction. However, unlike UV exposure, exogenous opioid use is not followed by vitamin D synthesis (and its opioid suppressive effects), perhaps contributing to a maladaptive behavior cycle of addiction.¹ Interestingly, studies suggest that the presence of pain itself may be associated with vitamin D deficiency.^1,4-5

To further evaluate whether the link between vitamin D and opioid addiction exists in humans, researchers examined two retrospective data sets of the health records of more than 30,000 patients; they found support for the association in both sets.^1,2 In the first, patients with insufficient vitamin D were 50% more likely to use opioid painkillers compared to patients with normal vitamin D levels; patients who were deficient (severely lacking) in vitamin D were 90% more likely to take opioids. The results were consistent when accounting for factors like age, sex, history of bone fractures, and chronic pain. In the second data group, patients diagnosed with an opioid use disorder—signaling prolonged use—were more likely to be classified as vitamin D deficient or insufficient.^1,2 Other studies support these findings. In a 2009 cross-sectional study examining the prevalence of low vitamin D status among patients in a methadone maintenance treatment program, vitamin D deficiency was prevalent in 36% of patients and vitamin D insufficiency was found in an additional 16%.⁶

To better understand the patterns they saw in the data above, researchers used mouse models, comparing healthy laboratory mice to vitamin D–deficient mice.¹ (These mice either lacked the vitamin D receptor or had vitamin D removed from their diets). They found that modulating vitamin D levels changed multiple addictive behaviors in the mice to both UV and opioids. When the mice were given small doses of morphine, those deficient in vitamin D continued seeking out the drug, whereas this behavior was less common among the mice with normal vitamin D levels. Moreover, when the morphine was withdrawn, the mice with low vitamin D levels were far more likely to develop withdrawal symptoms. “Consider a surgery patient who receives morphine for pain control after an operation. If that patient is deficient in vitamin D, the euphoric effects of morphine could be exaggerated, and that person is more likely to become addicted,” said Dr. Fisher in a press release on the study.² An oral supplementation of vitamin D in the deficient mice restored the morphine preference back to that of the healthy mice who had sufficient levels. These results support the hypothesis that deficiencies in vitamin D receptor signaling are associated with greater physical dependence to opioids, which can be alleviated by correcting vitamin D levels.¹

Which patient subpopulations will benefit most from vitamin D supplementation? Does the critical vitamin D level, above which no additional benefit can be observed, differ between species, and within individuals? These are just some of the follow-up questions researchers have begun exploring. This low-cost intervention could be another tool in the toolbox of primary care functional medicine (FM) clinicians, who are often at the forefront of a patient’s healthcare journey, and who play a critically important role in assessing for opioid use disorder. For further reading on addiction and related topics, please continue to the following IFM-authored articles:

Paul Thomas, MD, on Addiction & Stress in Young Adults 

Chronic Pain & the Brain With Dr. Dave Hagedorn 

Large Meta-Analysis Highlights Effectiveness of Mind-Body Therapies for Opioid-Treated Pain 

References

1. Kemény LV, Robinson KC, Hermann AL, et al. Vitamin D deficiency exacerbates UV/endorphin and opioid addiction. Sci Adv. 2021;7(24):eabe4577. doi:1126/sciadv.abe4577
2. Cunningham J. Vitamin D deficiency may increase risk for addiction to opioids and ultraviolet rays. Massachusetts General Hospital. Published June 11, 2021. Accessed July 6, 2021. https://www.massgeneral.org/news/press-release/Vitamin-D-deficiency-may-increase-risk-for-addiction-to-opioids-and-ultraviolet-rays
3. Dydyk AM, Jain NK, Gupta M. Opioid use disorder. StatPearls Publishing. Updated November 20, 2020. Accessed July 6, 2021. https://www.ncbi.nlm.nih.gov/books/NBK553166/
4. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc. 2003;78(12):1463-1470. doi:4065/78.12.1463
5. Habib AM, Nagi K, Thillaiappan NB, Sukumaran VK, Akhtar S. Vitamin D and its potential interplay with pain signaling pathways. Front Immunol. 2020;11:820. doi:3389/fimmu.2020.00820
6. Kim TW, Alford DP, Holick MF, Malabanan AO, Samet JH. Low vitamin D status of patients in methadone maintenance treatment. J Addict Med. 2009;3(3):134-138. doi:1097/adm.0b013e31819b736d