Does Vitamin D Deficiency Play a Role in Opioid Addiction?

Vitamin D deficiency amplifies the craving for, and the effects of, opioids, potentially raising the risk for opioid dependence and addiction, new research suggests. However, some experts are urging caution in interpreting the findings.

The study, which also linked vitamin D deficiency to sun-seeking behavior, points to the potential of vitamin D supplementation to help address the opioid epidemic, the investigators note.

“Even modest rescue of vitamin D deficiency could be beneficial in the prevention and treatment of opioid addiction, especially considering that vitamin D is generally inexpensive, accessible, and safe,” they write.

The study was published online June 11 in Science Advances.

Endorphin Rush

In earlier work, researchers led by David Fisher, MD, PhD, with the Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts, found that exposure to ultraviolet (UV) rays causes the skin to produce the hormone endorphin, which is chemically related to morphine, heroin, and other opioids.

They also observed that UV exposure raises endorphin levels in mice, which leads the animals to display behavior consistent with opioid addiction.

In their latest research, they conducted a series of animal and human studies designed to better understand the relationship between vitamin D and UV-seeking and opioid-seeking behavior.

They first compared normal laboratory mice with vitamin D–deficient mice.

“We found that modulating vitamin D levels changes multiple addictive behaviors to both UV and opioids,” lead author Lajos Kemény, MD, PhD, a postdoctoral research fellow in dermatology at MGH, said in a statement.

When the mice were conditioned with modest doses of morphine, those deficient in vitamin D continued seeking out the drug. This behavior was less common in the normal mice. When morphine was withdrawn, the vitamin D–deficient mice were far likely to show withdrawal symptoms.

Morphine also appeared to work more effectively as a pain reliever in the vitamin D–deficient mice, suggesting that response to the opioid was exaggerated in the setting of low vitamin D.

“When we corrected vitamin D levels in the deficient mice, their opioid responses reversed and returned to normal,” Fisher said in the statement.

The animal data that suggest vitamin D deficiency increases addictive behavior was supported by several analyses using National Health and Nutrition Examination Survey data and MGH patient health records.

The results show an increase in the prevalence of vitamin D deficiency among patients diagnosed with opioid use disorder (OUD) and an inverse and dose-dependent association of vitamin D levels with self-reported opioid use.

Patients with modestly low vitamin D levels were 50% more likely than peers with normal vitamin D levels to use opioids, whereas patients who were severely vitamin D deficient were 90% more likely to use opioids, the researchers report.

“Our results imply that vitamin D–deficient individuals may be at risk for developing tolerance and physiologic opioid dependence more rapidly, experiencing more significant withdrawal, and experiencing greater reward from opioid exposure,” they note.

“Vitamin D supplementation might have a preventative benefit by decreasing opioid reward and possibly diminishing the risk of OUD. Vitamin D supplementation may also improve the beneficial effects of medications for OUD,” they add.

Interpret With Caution

Weighing in on this research for Medscape Medical News, Richard Saitz, MD, MPH, professor, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, urged caution in interpreting the results.

“The human studies are cross-sectional and subject to many biases and may show that opioid use and disorder are associated with vitamin D deficiency (which is not news) and does not at all show deficiency causes disorder or use,” said Saitz.

“All in all, the studies are interesting and could generate hypotheses to be tested in well-designed prospective studies of vitamin D deficiency as a risk factor and vitamin D as a treatment,” he added.

However, he cautioned, that it’s “going way beyond the data” to conclude that vitamin D causes or exacerbates opioid addiction in people, “but suggesting clinical studies be done is certainly reasonable.”

Also weighing in on this research, Kenneth Stoller, MD, director of the Johns Hopkins Broadway Center for Addiction and associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, Baltimore, Maryland, noted that “95% of patients with co-occurring disorders coming to the inpatient unit are vitamin D deficient, so it’s very common in the population.

“It’s hard to know, but I really think that it’s unlikely that vitamin D deficiency is a common pathway for development of addiction ― that is, that they developed an addiction specifically because of the vitamin D deficiency,” Stoller said.

“However, it does make me think that for my patients who are experiencing maybe a partial but not a full response to medications for opioid use disorder, maybe I’ll be more likely to check the vitamin D level and if it’s really off, try them on some supplementation,” said Stoller.

He pointed to a recent study that showed some benefit of vitamin D supplementation on cognitive function and some mental health parameters for people on methadone, “but I don’t think this is necessarily a silver bullet.”

The work was supported by a grant from the National Institutes of Health and the Dr Miriam and Sheldon G. Adelson Medical Research Foundation. Fisher, Saitz, and Stoller have disclosed no relevant financial relationships.

Sci Adv. Published online June 11, 2021. Full text

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