Repeated administration of cannabidiol (CBD) is needed to reduce neuropathic pain and related anxiety, new research suggests.

In a study designed to evaluate the dose, treatment duration, and mechanism of action of CBD, the drug modulated nociception, decreased anxiety-like behavior, and increased serotonin activity in a rodent model of neuropathic pain.

CBD also acted on some specific receptors but not others, a finding that paves the way for future therapeutics based on this active component of cannabis.

"These results are clinically relevant, as CBD is known to exhibit few side effects and supports the initiation of clinical trials testing the efficacy of CBD-based compounds for treating neuropathic pain and comorbid mood disorders," the investigators write.

One-time acute treatment is likely insufficient.

"The most effective neuropathic pain relief occurs after 1 week of daily CBD treatment," senior author Gabriella Gobbi, MD, PhD, professor of psychiatry, Neurobiological Psychiatry Unit, McGill University, Montreal, Canada, told Medscape Medical News.

Using in vivo electrophysiology, these experiments demonstrated that CBD decreases serotonin firing after an acute injection. However, after 1 week of treatment, the firing of serotonin increased through the desensitization of the 5-HT1A receptor.

This is the same mechanism observed for selective serotonin reuptake inhibitors, which "also require a few days or weeks before having a therapeutic effect — likely because some neuroplastic event occurs at the level of the receptors," Gobbi said.

"Translating this to a clinical setting, these results suggest that the best treatment with cannabidiol will be a chronic treatment, but further clinical studies have to confirm this," she added.

The findings were published online in Pain.

Growing Research Interest

Research interest in CBD, a noneuphoric and nonaddictive cannabis component, is growing. Investigators are assessing a wide range of potential indications, including treatment of chronic pain, nausea, psychosis, and anxiety, as well as epilepsy.

In addition, in June, the US Food and Drug Administration (FDA) approved a purified formulation of CBD (Epidiolex oral solution, GW Pharmaceuticals) to treat two rare forms of epilepsy.

The current study is not the only one to evaluate CBD for the treatment of neuropathic pain. Previous researchers assessed CBD alone or in combination with tetrahydrocannabinol for this indication.

However, few studies have explored the effect of CBD on 5-HT neurotransmission in the dorsal raphe nucleus (DRN), Gobbi and colleagues write. This region of the brain is important because it is involved in both mood disorders and pain, they note.

The investigators studied 229 adult male Wistar rats. They assessed the effects of both acute CBD therapy and repeated low-dose CBD on neuropathic pain modulation and responses.

Through a series of tests, they studied the firing activity of neurons, nerve desensitization, and reactions to mechanical allodynia. They also evaluated behavior using an open field test, a forced swim test, an elevated plus maze test, and a novelty-suppressed feeding test.

Electrophysiologic recordings demonstrated that neuropathic pain provoked a maladaptation of 5-HT neurotransmission. This action in turn caused a decrease in the firing activity of spontaneously active DRN 5-HT neurons.

Effective Doses

The investigators also sought clarity on an effective dose of CBD. CBD has been used therapeutically in doses ranging from 2.85 to 50 mg/kg/day, "meaning that its therapeutic dose is still unclear," the researchers note.

For acute treatment, they administered cumulative injections of 0.05 to 0.25 mg/kg of CBD and 10 to 50 mg/kg of D-lysergic diethylamide acid (LSD). They also administered a single injection of the 5-HT1A antagonist WAY 100635, the AM 251, and/or the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine.

By pretreating with these antagonists and then administering CBD, the investigators demonstrated that the 5-HT1A and TRPV1 receptors are involved in the agent's mechanism of action and ruled out involvement of the CB1 receptor.

Repeated treatment showed that the lowest IV CBD dose needed to cause a significant decrease in 5-HT neuronal activity was 0.10 mg/kg. The difference was significant compared with vehicle preinjection in Bonferroni post hoc analyses (n = 9; P < .05).

In addition, a 0.25-mg/kg dose of CBD "completely shut down neuronal activity" (n = 9 ; P < .001), the researchers report.

Using the spared nerve injury model of neuropathic pain, "we found that repeated CBD treatment was able to prevent mechanical allodynia and anxiety-like behavior in rats experiencing neuropathic pain, but through different mechanisms," they write.

The investigators note that TRPV1 channels were required for the antiallodynic but not the anxiolytic effects of CBD. In contrast, 5-HT1A receptors were required for the anxiolytic and, to a lesser extent, the antiallodynic effects of CBD.

These receptors are essential because multiple studies have demonstrated "that the 5-HT1A receptor is crucial for the mechanism of anxiety and depression relief," Gobbi said.

"Very Surprising" Results

Gobbi noted that in the past 15 years, investigators have conducted many preclinical studies with THC, CB1 agonists, and fatty acid amide hydrolase inhibitors or endocannabinoid enhancers. However, "it was very surprising to see that CBD has a mechanism of action that is different from its 'cousin' drugs."

The preclinical findings of this research support future clinical trials, Gobbi added.

"These animal studies suggest the indication for CBD use in humans' neuropathic pain and comorbid anxiety," Gobbi said. "We have a better idea about the doses in humans, [because] the FDA has conversion tables to translate doses from animals to humans, and...we know more about the length of treatment."

Could the findings have new implications, given recent government approvals for use of cannabis? "I hope so," she answered.

"Canada has legalized recreational cannabis and made medicinal cannabis more accessible, but little is yet known about medical cannabis. A lot of patients are using mixtures of THC [and] CBD without knowing the appropriate indications, doses, side effects, and interactions with other drugs," Gobbi noted.

"This research — I hope — will encourage more systematic medical cannabis research to help patients and doctors to make more evidence-based choices," she said.

Caution Urged

Commenting on the findings for Medscape Medical News, Yasmin Hurd, PhD, professor of neuroscience, psychiatry, and pharmacologic sciences, Icahn School of Medicine at Mount Sinai, New York City, said this is an interesting study "that provides strong preclinical findings in support of the antinociception and antianxiety effects of CBD relevant to the condition of neuropathic pain."

Hurd added that she applauds the investigators' use of multiple approaches — behavioral, pharmacologic, and electrophysical measurement of cell firing — because this strengthened the overall findings. She also said the research strategy provided insights about the different biological mechanisms associated with CBD's analgesic and anxiolytic properties.

"Clinical trials are of course still necessary, but the findings suggest that CBD may be potentially beneficial as a future treatment in reducing chronic pain and anxiety, which are often comorbid in neuropathic pain and related conditions," she said.

Hurd, who was not affiliated with this study, has authored a review article on the potential role of marijuana as an alternative to opioids for the treatment of addiction.

When also asked by Medscape Medical News to comment on the study, Joshua Aviram, PhC, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel, was less enthusiastic.

"Although mechanistic observations on animal models are critical to the understanding of phytocannabinoids activity, human chronic pain is much more complicated than the mere nociception process," Aviram said.

"Until these findings can be substantiated in high-quality controlled trials or even cohort studies on chronic pain patients, no responsible clinical implications can be drawn from these findings on CBD activity," he added.

Aviram, principal investigator of a systematic review and meta-analysis on the efficacy of cannabis-based medicines for pain management, was not affiliated with the current study.

The study was supported by a matching grant from the Ministere de l'Economie Science et Innovation du Quebec and Aurora Cannabis Inc. Dr Gobbi, Dr Hurd, and Mr Aviram have disclosed no relevant financial relationships.

Pain. Published online August 27, 2018. Abstract

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