Ketogenic diet's surprising impact on opioid sensitivity and withdrawal

By Neha MathurMay 10 2023

In a recent study published in the journal Scientific Reports, researchers at Yale University School of Medicine evaluated the potential effects of a ketogenic diet (KD) on oxycodone responses in a mouse model.

Study: Ketogenic diet enhances the effects of oxycodone in mice. Image Credit: nadianb / Shutterstock

Background

Oxycodone is a prescription opioid that caused an opioid epidemic in the United States (US) involving more than two million individuals with substance use disorder. Of all patients prescribed opioids, 25% misused them, and five to 10 percent subsequently developed opioid use disorder (OUD). Opioid overuse increased by 519% between 1999 and 2019, and oxycodone overdose contributed to 32% of overdose deaths.

The challenge is to maximize the therapeutic potential of prescription opioids, including oxycodone, while minimizing their adverse effects. While KD is recognized to reduce the pain and severity of OUDs, its effect(s) on oxycodone responses remains unknown.

Nutritional deficiencies due to poor diet in the OUD population hinder patient recovery; thus, nutritional interventions or dietary manipulation could improve patient outcomes and dramatically reduce healthcare costs.

About the study

In the present study, researchers used male and female C57BL/6 J mice aged between eight and 15 weeks to examine the sex-based effects of KD on responses to opioids, specifically oxycodone. They created separate mice cohorts for self-administration and osmotic minipump experiments. For self-administration experiments, the team used only one concentration of oxycodone in progressive ratio paradigms but used it in sterile saline for osmotic minipump loading.

The team maintained all mice on either KD AIN-76A Modified diet or Standard chow, which helped them accomplish matching body weight changes for pair-fed mice and 85 to 90% of the initial body weight for self-administration studies. In other words, they generated a Pair-fed Chow group matching the KD group’s bodyweight loss in male mice. Furthermore, they maintained this matching through all three phases of this study, dietary intervention, locomotor activity, and hot plate testing.

The team used locomotor chambers with infrared beams to assess locomotor activity where they habituated separate cohorts of male and female mice for 90 minutes before and after an acute oxycodone challenge. They intraperitoneally (ip) administered two mg/kg oxycodone injection and measured locomotor activity for an additional 90 minutes in 5 minutes bins. Two sequential beam breaks registered as locomotor activity.

In the hot plate assay, the team first tested baseline nociception. Next, they tested 10, 20, 30, and 45 minutes post ip administration of oxycodone at two mg/kg dosage. It helped them evaluate the effects of the KD on modifying sensitivity to the antinociceptive effects of oxycodone.

The researchers measured ketone levels in male and female mice maintained under ad libitum conditions on KD or Chow before diet initiation and on days 4 and 7 post-diet induction. Finally, the team evaluated the effects of KD on physical withdrawal symptoms after chronic oxycodone delivery using a minipump and self-administration of oral oxycodone.

Results

Strikingly, KD enhanced oxycodone-induced antinociceptive and locomotor effects in both sexes of mice. However, despite inducing effective ketosis in both sexes, KD induced bodyweight loss only in male mice. This persisted throughout locomotor and hot plate testing. Overall, KD modulated opioid responses in mice in a sex-specific manner.

So, while in male mice, KD exacerbated oxycodone withdrawal, such an effect was absent in female mice. Likewise, the reduction of oxycodone self-administration by KD, especially in early sessions, was more pronounced in male than female mice.

From a broad perspective, the study data illustrated the significance of metabolic and nutritional state for the therapeutic use of opiates as painkillers and OUD therapy. Both male and KD-fed female mice displayed significantly enhanced latency after oxycodone compared to Chow, suggesting that the ketogenic diet may enhance the antinociceptive effects of oxycodone.

Indeed, the KD enhanced the effects of the opioid. Accordingly, male and female KD mice exhibited robust surges in activity after oxycodone treatment but not Chow-fed mice. The KD-fed female mice displayed markedly lesser activity during baseline and other phases than Chow-fed mice, strengthening the notion that dietary manipulation enhances opioid sensitivity. The KD diet caused β-hydroxybutyrate levels to rise more in the Pair-fed Chow that also did not show enhanced antinociceptive and locomotor responses to oxycodone, indicating that KD, not bodyweight loss, drove these effects.

Interestingly, male KD mice showed augmented jumping behavior after naloxone therapy for OUD, suggesting an improved sensitivity to withdrawal symptoms. On the other hand, KD-fed female mice did not show these effects at all. This finding and the sex-based variations in bodyweight loss suggested KD-triggered sexual dimorphism, which should be explored in future studies among patients with OUD.

After the dietary intervention, KD-fed male mice displayed a marked reduction in oral self-administration. Female KD mice also exhibited a trend reduction compared to Chow-fed control animals. Future studies should evaluate different concentrations of oxycodone to confirm translational relevancy. Furthermore, male and female KD mice exhibited a marked change in motivation on the progressive ratio schedule, indicating limited effects of the KD on motivation.

Conclusions

The study data favor a potential role for a KD as an adjunct to the therapeutic use of opiates for pain management in a clinical setting. Notably, KD more effectively reduced oxycodone consumption in male mice and also selectively enhanced withdrawal in male mice only. However, the accumulation of more scientific evidence and clinical validation is warranted.

Sex-based differences influence treatment outcomes among OUD patients, a complex disorder with multiple variables. Some studies have shown that women develop more severe OUD and have higher withdrawal scores than men, whereas others have shown the opposite. So, more importantly, the study findings highlight the need for clinical evaluation of the dietary and metabolic states, as modulated by sex, during the treatment of OUD and the therapeutic use of opiates (like oxycodone) for pain management.