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Hemp Oil Extract and Palmitoylethanolamide (PEA) Synergize to Enhance Pain Relief

Most patients seeking pain relief rely on the following three families of drugs: opioids, gabapentinoids, and nonsteroidal anti-inflammatory agents (NSAIDs). These widely used drugs are associated with serious side effects.1 During the past decade there has been an increasing interest in cannabis-derived natural products for pain management with a better safety profile and adequate pain relief. However, we still know surprisingly little about the effectiveness on pain of nonintoxicating cannabis-based products—conventionally referred to as “industrial hemp.”

To fill this knowledge gap, researchers at the University of California, Irvine evaluated the analgesic effects of two natural ingredients—both individually and in combination—in in vivo experiments. The first ingredient was a proprietary, organic, full-spectrum hemp oil extract. The second ingredient was PEA. PEA is a bioactive compound found in lipid extracts of foods, as well as our body.2,3 A large number of animal and human studies indicate that PEA produces safe and effective pain relief in chronic and acute pain conditions, for example, neuropathic, arthritic, headache, and low back pain.2,4,5

The first experiment, known as the formalin test, involved moderate pain caused by chemically induced injury in the animal paw. It was a model that mimicked acute tissue injury pain in humans. The second experiment, known as the chronic constriction nerve injury test, was a model that mimicked peripheral neuropathic pain in humans.

The study showed that hemp oil extract alone was modestly effective in treating acute and chronic pain. PEA alone showed a dose-dependent effect in reducing acute and chronic pain. Surprisingly, the hemp oil extract strongly enhanced the analgesic effects of PEA such that the combination of the two compounds exerted greater-than-additive alleviation of pain-related behaviors in both models of pain. Further investigations showed that this synergism was partially supported by hemp oil extract’s extending the life of PEA in the blood circulation, and therefore prolonging its actions.

The study findings have been published in the journal Pharmacological Research.6


Hemp, CBD, and PEA

Why is this clinically relevant?

  • This study demonstrated that a combination of a proprietary, organic, full-spectrum hemp oil extract and PEA is associated with greater-than-sum effect in alleviating acute and chronic pain behaviors.
  • Given the rising concern of opioid use disorders and their associated side effects, identifying promising alternative therapies without causing apparent undesirable effects is crucial.

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  1.  Varrassi G et al. Towards an effective and safe treatment of inflammatory pain: a delphi-guided expert consensus. Adv Ther. 2019;36(10):2618-2637.
  2. Petrosino S et al. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 2017;174(11):1349-1365.
  3. Schuel H et al. N-Acylethanolamines in human reproductive fluids. Chem Phys Lipids. 2002;121(1-2):211-227.
  4. Gabrielsson L et al. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932-942.
  5. Lo Verme J et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol. 2005;67(1):15-19.
  6. Tagne AM et al. Palmitoylethanolamide and hemp oil extract exert synergistic anti-nociceptive effects in mouse models of acute and chronic pain. Pharmacol Res. 2021:105545.


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