While cannabidiol (CBD) is fast becoming a common compound for pain and anxiety relief, the exact pathways and dosage have remained elusive. A recent study, published in the journal PAIN, identified new pathways, beyond the endocannabinoid system, which explain its analgesic and anti-anxiety benefits. They are surprisingly different than what was once believed. This research from the Research Institute of the McGill University Health Centre (MUHC) and McGill University offers encouraging news for chronic pain and anxiety sufferers.
Cannabis indica and sativa are the two main cannabis strains that produce the pharmacological principles 
known as tetrahydrocannabinol (THC) and cannabidiol (CBD). Dr. Gabriella Gobbi’s team demonstrated that CBD does not act on the CB1 cannabinoid receptors like THC, but through the mechanism that binds specific receptors involved in anxiety (serotonin 5-HT1A) and pain (vanilloid TRPV1). Researchers were able to extrapolate the exact dosage of CBD displaying analgesic and anti-anxiety properties without the risk of addiction and euphoria classically produced by the THC.
In animal models of neuropathic or chronic pain, we found that low doses of CBD administered for seven days alleviate both pain and anxiety, two symptoms often associated,” says first author of the study Danilo De Gregorio, a post-doctoral fellow at McGill University in Dr. Gobbi’s laboratory.
Methods / Using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.).
- Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT1A receptors.
- Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test.
- Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
- Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY.
Our findings elucidate the mechanism of action of CBD and show that it can be used as medicine without the dangerous side effects of the THC,” says Dr. Gobbi, who is also Professor of Psychiatry at the Faculty of Medicine at McGill University and staff psychiatrist at the MUHC. “This research is a new advancement for an evidence-based application of cannabis in medicine.”
Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions. Lead author Dr. Gobbi sees this as advancement for the evidence-based application of cannabis in medicine with CBD likely offering a safe alternative to THC and opioids for chronic pain, such as back pain, sciatica, diabetic, cancer or post-trauma pain.
