The kratom alkaloid mitragynine required cannabinoid CB1, CB2, and TRPV1 receptors to relieve neuropathic pain in mice, and it restored disrupted endocannabinoid levels in the spinal cord.
Read this if you use kratom for pain management and want to understand how it interacts with the endocannabinoid system.
Complete blockadeCB1+CB2+TRPV1 antagonists completely blocked mitragynine's neuropathic pain relief
What the researchers found
Mitragynine's effectiveness against chemotherapy-induced neuropathic pain was partially reduced in cannabinoid receptor knockout mice and completely blocked by pharmacological CB1, CB2, and TRPV1 antagonists. This cannabinoid involvement was specific to neuropathic pain — it did not significantly affect mitragynine's efficacy in an inflammatory pain model. Chemotherapy (oxaliplatin) disrupted the endocannabinoid lipidome in the spinal cord, and repeated mitragynine exposure prevented this disruption.
Why it matters
Kratom and cannabis are both widely used for self-treating pain, and users commonly combine them. This study provides a biological rationale for why the combination might work — kratom's pain relief partly depends on the same cannabinoid receptors that cannabis activates.
The numbers in context
- Complete blockade of neuropathic pain relief with CB1+CB2+TRPV1 antagonists
- Partial attenuation in cannabinoid receptor knockout mice
- Cannabinoid involvement selective for neuropathic (not inflammatory) pain
- Oxaliplatin disrupted spinal cord endocannabinoid lipidome
- Mitragynine prevented oxaliplatin-induced lipidome disruption
How the study worked
Mouse models of chemotherapy-induced peripheral neuropathy (oxaliplatin) and inflammatory pain (formalin). Tested mitragynine with CB1, CB2, and TRPV1 antagonists and in cannabinoid receptor knockout mice. Measured spinal cord endocannabinoid lipidome by HPLC-MS/MS.
Who was studied
Wildtype and cannabinoid receptor knockout mice with chemotherapy-induced and inflammatory pain
What this study cannot tell us
Mouse models may not translate to human neuropathic pain. Mitragynine was given intraperitoneally, not orally as in human kratom use. The specific signaling mechanisms connecting opioid and cannabinoid pathways were not fully elucidated.
How to read the evidence
Preclinical animal study with genetic and pharmacological controls. Strong mechanistic evidence but requires human validation.
When this study was published
Published in 2023. Represents growing scientific interest in kratom's mechanisms of action.
The bigger picture
The overlap between opioid and cannabinoid pain pathways has been recognized for years. This study extends that understanding to kratom alkaloids, suggesting that the common practice of combining kratom and cannabis for pain may have a pharmacological basis.
Questions still open
- Would combining mitragynine with cannabinoids produce synergistic pain relief?
- Does chronic kratom use alter endocannabinoid tone in humans?
- Could this cannabinoid mechanism explain some of kratom's abuse potential?
Read the original research
Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.
Life sciences, 328, 121878
Citation
Farkas, Daniel J; Inan, Saadet; Heydari, Laila N; Johnson, Clare T; Zhao, Pingwei; Bradshaw, Heather B; Ward, Sara Jane; Rawls, Scott M. (2023). Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.. Life sciences, 328, 121878. https://doi.org/10.1016/j.lfs.2023.121878