Managing Chronic Pain with CBD

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

by Chris D. Meletis, ND, and Kimberly Wilkes 

Chronic pain is one of the most common complaints affecting modern society with an estimated 25.3 million US adults (11.2%) suffering from this health concern.1 Furthermore, almost 40 million adults (17.6%) have severe levels of chronic pain.1 One of the most severe forms of chronic pain is neuropathic pain, which results from damage to the central or peripheral nervous systems.2 This damage can result from physical trauma such as accidents, surgery, and stroke, diseases such as diabetes, cancer, and immune disorders, and medications such as cancer chemotherapy drugs.2 Neuropathic pain is also often associated with accompanying mental health disorders such as depression, anxiety, sleep problems, and reduced social interactions.3 

Standard first-line treatments for neuropathic pain (such as tricyclic antidepressants and selective serotonin norepinephrine reuptake inhibitors) are often not completely effective on all types of neuropathy.4 In fact, at least 50% of people with neuropathic pain do not notice any clinically meaningful pain relief from their medications.2 Some medications used for neuropathic pain are accompanied by side effects including dizziness, sedation, depression, and sleep disorders,2 making them a bad choice for many people. 

Another widespread source of chronic pain is osteoarthritis of the knee or hip. Osteoarthritis is the most frequent cause of joint problems in the United States.5 An estimated 10% of men and 13% of women aged 60 years or older have knee osteoarthritis.5 In a society where people spend excessive amounts of time staring down at their cell phones or looking at their computer, it’s not surprising that neck pain is another common disorder that annually affects 30% to 50% of the general population.6 Furthermore, at any given time, 31 million people in the US experience low back pain.7 

Opioids are commonly prescribed to treat chronic pain, either as a first or second line of treatment. Sales of opioid drugs nearly quadrupled from 1999 to 2014.8 However, opioid drugs are addictive, and overdose of this medication is common. According to Centers for Disease Control and Prevention statistics, drug overdoses killed 63,632 Americans in 2016 and almost two-thirds (66%) of those deaths were the result of a prescription or illicit opioid.9 

An abundance of research indicates that phytocannabinoids— substances such as cannabidiol (CBD) derived from cannabis and hemp plants – may be effective alternatives. Phytocannabinoids exert much of their actions through the endocannabinoid system, which is involved in pain control. This article will discuss in detail the role of the endocannabinoid system in pain management, how two common phytocannabinoids (THC, the psychoactive component of cannabis and CBD, the non-psychoactive component) differ in their effects on pain, and how a relative newcomer in the realm of natural pain management supplements known as palmitoylethanolamide (PEA) works with the endocannabinoid system to control pain. 

The Endocannabinoid System and Pain 

Endocannabinoids produced within the body, including anandamide (arachi-donylethanolamide) and 2-arachidonylglycerol (2-AG), are able to activate receptors in the endocannabinoid system. Two important receptors in this system that are involved in pain management are CB1 and CB2.10 In the central nervous system, CB2 receptor mRNA is not present in the neuronal tissue of human or rat brains.11 However, it is found in brain cells known as microglia when they are activated.11 Microglia can become activated in states of inflammation and activated microglia themselves can produce pro- inflammatory molecules. The presence of CB2 in activated microglia indicates it may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.11 Activation of CB2 receptors blocks the pain response to thermal and mechanical stimuli,12,13 thermal and tactile hypersensitivity produced by peripheral inflammation,13-15 and neuropathic pain.16 The effects of CB2 receptors on neuropathic pain and inflammation are particularly noteworthy as those conditions are often resistant to treatment, as noted earlier. 

This difference in pathways may explain why in animal models of neuropathic pain cannabinoid receptor agonists last longer compared with morphine.23 

A number of animal studies indicate CBD alone can reduce neuropathic pain. A mouse model of neuropathic pain caused by injury found that CBD alone had beneficial effects on pain reduction.30 Although CBD’s effects were less powerful than THC, CBD administration was not associated with the psychoactive side effects that accompanied THC.30 In a rat model of sciatic nerve pain and inflammatory pain, oral treatment with CBD (2.5-20 mg/kg for neuropathic sciatic pain and 20 mg/ kg for inflammatory pain) or intraplantar injection from a week to 14 days post- injury reduced the sensitization to painful stimuli.31 Cannabidiol administration also correlated with a lower level of several inflammatory mediators, such as prostaglandin E(2) (PGE(2)), lipid peroxide, and nitric oxide (NO).31 In this study, CBD’s beneficial effects on pain appeared to be due to its actions on the vanilloid receptors rather than CB1 or CB2. The authors concluded, “The results indicate a potential for therapeutic use of cannabidiol in chronic painful states.” 

CBD has also been shown to be effective in a mouse model of diabetic neuropathy. In diabetic mice, moderate or high doses of cannabidiol administered intranasally, beginning at onset of diabetes, or high doses of CBD given through an intraperitoneal route were associated with a reduction in the development of two measures of diabetic neuropathy: sensitivity to heat and increased pain after being touched (tactile allodynia).27 This effect lasted during cannabidiol treatment and for the additional four assessments over two months after CBD was discontinued. CBD had no effect on neuropathic pain that was present prior to CBD treatment. One other benefit of CBD was that mice given either medium or high doses of intranasal/intraperitoneal CBD at diabetes onset had lower densities 


Although CBD’s ability to inhibit neuropathic pain is only half that of THC, CBD can be given in higher doses without the psychoactive effects that occur with THC. 


An extensive amount of evidence points to the endocannabinoid system’s role in pain control. According to preclinical studies in animal models, activation of CB1 or CB2 receptors leads to a reduction in chemotherapy-induced allodynia (a pain response from stimuli that don’t normally cause pain.)17 Further evidence that the endocannabinoid system is involved in pain regulation is the similarity between endocannabinoids and the pain reliever acetaminophen. The acetaminophen metabolite and endocannabinoid reuptake inhibitor AM 404 indirectly activates CB1 receptors, which may be responsible for analgesia induced by acetaminophen.18 Likewise, some non-steroidal anti- inflammatory drugs (NSAIDs) are able to influence the cannabinoid system. The inflammatory enzyme COX-2 breaks down anandamide, an endocannabinoid involved in the regulation of pain perception.11,19 NSAIDs inhibit the action of the enzyme COX-2, which in turn prevents anandamide destruction.11,19 Furthermore, clinical studies revealed altered endocannabinoid signaling in patients with chronic pain.20 

Endocannabinoids control pain in a way that is much safer compared with opioids, although they can indirectly work through the same receptors. CB2 receptors indirectly stimulate opioid receptors found in primary afferent pathways.21 Furthermore, CB1 expression 

Researchers are beginning to look beyond the classical CB1 and CB2 receptors as potential mediators of some of the beneficial effects of endocannabinoids and phytocannabinoids. For example, type 1 vanilloid receptors (TRPV1) may regulate some cannabinoid effects. The TRPV1 receptor has been identified in neurons that play a role in pain signaling.17 Other undiscovered cannabinoid receptors may exist, and these receptors may partly mediate some of the analgesic effects associated with cannabinoids.24,25 

THC vs. CBD in Neuropathic Pain 

CB1 receptors inhibit pain signaling pathways.10 CB2 receptors, on the other hand, reduce pain via anti- inflammatory effects.10 THC directly acts on CB1 receptors of the endocannabinoid system,26 which are primarily expressed in the brain, and it can also act on CB2 receptors.27 

CBD, although it has a low affinity for CB1 and CB2 receptors, indirectly acts on the CB1 receptors by suppressing the enzymatic breakdown of the endogenous cannabinoid anandamide, increasing the duration of time anandamide stays in the system.28 As noted earlier, anandamide is involved in the regulation of pain perception. 

CBD’s effects on the CB1 receptor counteract the psychoactive effects of THC.29 In most studies, CBD has thus of microglia in the dorsal spinal cord, an indication of reduced microglia activation.27 

Rodent models of neuropathy caused by chemotherapy drugs indicate CBD is useful in this instance as well. In a mouse model of neuropathy caused by the chemotherapy drug cisplatin, CBD or THC reduced but did not prevent neuropathy symptoms.32 In another mouse study, both CBD and THC alone reduced mechanical allodynia caused by the chemotherapy medication paclitaxel.33 CBD also reduced pain associated with the chemotherapy drug oxaliplatin but not vincristine, while THC significantly reduced vincristine-associated pain but not pain associated with oxaliplatin.33 Doses of CBD or THC that were too low to be effective when given separately, when given together were effective against pain caused by oxaliplatin but not vincristine.33 

Although CBD’s ability to inhibit neuropathic pain is only half that of THC, CBD can be given in higher doses without the psychoactive effects that occur with THC.2 Furthermore, long- term use of CBD has been associated with improved efficacy in regards to pain control compared with short-term administration.2 

With the promising results achieved in animal studies, it is surprising that clinical trials investigating the use of CBD alone on neuropathic pain are lacking. All of the clinical studies have evaluated the use of CBD combined with THC. Many of these studies have found the combination of the two phytocannabinoids to be effective in neuropathic pain.34-36 

Joint Pain and Phytocannabinoids 

Endocannabinoids and phyto- cannabinoids are able to affect pain pathways in the joints. Cannabinoid receptors, including CB1, CB2, GPR55, PPARα, and PPARγ, have been found on human articular cartilage from patients with symptomatic osteoarthritis (OA).37 According to one group of researchers, “Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids.”37 OA leads to a combination of inflammatory, nociceptive, and neuropathic pain. The endocannabinoid system has been shown to reduce all of these types of pain.38 

CBD was studied for its effects on experimental osteoarthritis in rats. After administration of peripheral CBD (100-300 μg) to rats with end-stage OA, there was a dose dependent decline in joint afferent firing rate.39 Furthermore, although 100 or 200 μg of CBD did not produce any benefits, 300 μg CBD was associated with increased withdrawal threshold and weight bearing. Local CBD administration also alleviated acute, transient joint inflammation. Prophylactic administration of CBD blocked the development of subsequent joint pain and nerve damage. The researchers concluded, “These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.” 

In collagen-induced arthritis (CIA), a model for rheumatoid arthritis, CBD at 5 mg/kg per day i.p. or 25 mg/kg per day orally resulted in clinical improvement associated with protection against severe joint damage.40 CBD led to a reduction in IFN-gamma production and decreased synthesis of tumor necrosis factor by knee synovial cells. In vitro, CBD induced a dose-dependent inhibition of lymphocyte proliferation, both mitogen- stimulated and antigen-specific, and suppression of Zymosan-triggered reactive oxygen burst by peritoneal granulocytes.40 In mice, CBD blocked the rise in serum tumor necrosis factor caused by lipopolysaccharides.40 According to the authors, “Taken together, these data show that CBD, through its combined immunosuppressive and anti- inflammatory actions, has a potent anti- arthritic effect in CIA.” 

Despite promising preclinical studies and reports from clinical practice as well as a great deal of in vitro justification as to why cannabinoids likely support joint health,41 there is a paucity of human studies investigating the effects of cannabinoids on joint pain.41 

Phytocannabinoid Use in Other Forms of Pain 

Phytocannabinoids have been studied for their effects on other forms of pain. In a randomized, double-blind, placebo-controlled trial, the semisynthetic THC analog nabilone was shown to reduce pain and improve quality of life and sleep in people with fibromyalgia.42 In another study, kidney transplant patients experiencing pain were given CBD.43 The study included seven patients who were given an initial dose of up to 100 mg/day of CBD. Two participants experienced complete improvement of pain, four had a partial response in the first 15 days, and one subject experienced no change. 

Furthermore, cannabinoid-rich hemp oil reduced body pain and improved other symptoms in girls who had an adverse reaction to the human papillomavirus (HPV) vaccine.44 Other evidence indicates the oil of cannabis seeds reduces pain in patients with chronic musculoskeletal inflammation, an effect attributed to the ideal omega-3/omega-6 ratio content.45 

Treating pain properly involves addressing more than just physical discomfort. Pain is a multidimensional problem that also encompasses impairments in mood, cognition, and function. Cannabidiol has been shown to improve mental health in a number of studies. We addressed the evidence supporting CBD’s role in mental health in greater detail in an article in the Townsend Letter earlier this year. 

The Role of Palmitoylethanolamide (PEA) in Pain Management 

A promising new strategy for resolving pain is to use palmitoylethanolamide (PEA) in combination with CBD. When in pain, the body produces PEA, which acts as a natural painkiller.46 PEA is also found in foods such as egg yolks, peanuts, and soybeans. It is not found in cannabis and is not classified as an endocannabinoid. However, it acts on the endocannabinoid system by helping the body use anandamide more effectively.46 

Accumulating evidence points to the role of neuroinflammation, characterized by infiltration of immune cells, activation of mast cells and glial cells, and synthesis of inflammatory mediators in the peripheral and central nervous systems, in chronic pain.46 PEA is an anti-inflammatory and pro-resolving lipid mediator that reduces mast cell activation and regulates glial cell behaviors.46-48 

A meta-analysis of 12 double-blind, controlled, and open-label clinical trials found that PEA supplementation leads to a progressive decrease in pain intensity that is substantially greater compared to the controls.46 The pain reduction in PEA-treated patients was 1.04 points every two weeks with a 35% response variance explained by the linear model. Conversely, in the control groups, pain reduction intensity was 0.20 points every two weeks with only 1% of the total variance explained by the regression. Pain scores on the Kaplan-Meier estimator was ≤ 3 in 81% of patients given PEA whereas only 40% of control subjects had a score ≤ 3, 60 days after the beginning of the trial. The researchers concluded, “These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.” 


Chronic pain is a debilitating condition that is widespread among the population. Regulating the endocannabinoid system through the use of phytocannabinoids and PEA is an alternative to other pain control approaches associated with potentially dangerous side effects. The 

use of these agents is associated with improvements in pain caused by various forms of neuropathy, joint problems, and other pain disorders. The benefits are achieved through modulation of not only the endocannabinoid system but also indirect influence on opioid receptors. 


1. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015 Aug;16(8):769-80. 

2. Casey SL, Vaughan CW. Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain. Medicines (Basel). 2018 Jul 1;5(3).pii: E67. 

3. Turk DC, et al. Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain. Mayo Clin Proc. 2010 Mar;85(3 Suppl):S42-50. 

4. Dworkin RH, et al. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Mayo Clin Proc. 2010 Mar;85(3 Suppl):S3-S14. 

5. Zhang Y, Jordan JM. Epidemiology of Osteoarthritis. Clin Geriatr Med. 2010 Aug; 26(3):355-69. 

6. Hogg-Johnson S, et al. The burden and determinants of neck pain in the general population: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. J Manipulative Physiol Ther. 2009 Feb;32(2 Suppl):S46-60. 

7. American Chiropractic Association. Patients/Health-Wellness-Information/Back-Pain-Facts-and- Statistics Accessed August 1, 2018. 

8. Centers for Disease Control and Prevention. drugoverdose/data/prescribing.html Accessed August 1, 2018. 

9. U.S. drug overdose deaths continue to rise; increase fueled by synthetic opioids. Press Release. Centers for Disease Control and Prevention. March 29, 2018. releases/2018/p0329-drug-overdose-deaths.html Accessed August 2, 2018. 

10. Miller RJ, Miller RE. Is cannabis an effective treatment for joint pain? Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):59-67. 

11. J Manzanares, Julian MD, Carrascosa A. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. Curr Neuropharmacol. 2006 Jul;4(3):239-57. 

12. Malan TP, et al. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. 2001 Sep;93(3):239-45. 

13. Clayton N, et al. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002 Apr;96(3):253-60. 

14. Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003;119(3):747-57. 

15. Quartilho A, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003 Oct;99(4):955-60. 

16. Ibrahim MM, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10529-33. 

17. O’Hearn S, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Dec;6(Suppl 2):S209-14. 

18. Klinger-Gratz PP, et al. Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla. J Neurosci. 2018 Jan 10;38(2):322-34. 

19. Păunescu H, et al. Cannabinoid system and cyclooxygenases inhibitors. J Med Life. 2011 Jan-Mar;4(1):11-20. 

20. Huang WJ, Chen WW, Zhang X. Endocannabinoid system: Role in depression, reward and pain control (Review). Mol Med Rep. 2016 Oct;14(4):2899-903. 

21. Ibrahim MM, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8. 

22. Jennings EA, Vaughan CW, Christie MJ. Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J Physiol. 2001 Aug 1;534(Pt 3):805-12. 

23. Mao J, et al. Two distinctive antinociceptive systems in rats with pathological pain. Neurosci Lett. 2000 Feb 11;280(1):13-6. 

24. Breivogel CS, et al. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol. 2001 Jul;60(1):155-63. 

25. Hájos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106(1):1-4. 

26. Bhattacharyya S, Egerton A, Kim E, et al. Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors. Sci Rep. 2017 Nov 3;7(1):15025. 

27. Toth CC, Jedrzejewski NM, Ellis CL, et al. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain. 2010 Mar 17;6:16. 

28. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2:e94. 

29. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234-46. 

30. Casey SL, Atwal N, Vaughan CW. Cannabis constituent synergy in a mouse neuropathic pain model. Pain. 2017 Dec;158(12):2452-60. 

31. Costa B, Trovato AE, Comelli F, et al. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007 Feb 5;556(1-3):75-83.

32. Harris HM, Sufka KJ, Gul W, et al. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice. Planta Med. 2016 Aug;82(13):1169-72.

33. King KM, Myers AM, Soroka-Monzo AJ, et al. Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain. Br J Pharmacol. 2017 Sep;174(17):2832-41.

34. Russo M, Naro A, Leo A, et al. Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis. Pain Med. 2016 Jun;17(6):1145-54.

35. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007 Dec 15;133(1-3):210-20.

36. Hoggart B, Ratcliffe S, Ehler E, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. J Neurol. 2015 Jan;262(1):27- 16. Ibrahim MM, et al. Activation of CB2 cannabinoid receptors by 40. 

37. Dunn SL, Wilkinson JM, Crawford A, et al. Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies. Cannabis Cannabinoid Res. 2016 Jan 1;1(1):3-15. 

38. O’Brien M, McDougall JJ. Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids. Curr Opin Pharmacol. 2018 Apr 7;40:104-9. 

39. Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017 Dec;158(12):2442-51. 

40. Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9561-6. 

41. La Porta C, Bura SA, Negrete R, et al. Involvement of the endocannabinoid system in osteoarthritis pain. Eur J Neurosci. 2014 Feb;39(3):485-500. 

42. Skrabek RQ , Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008 Feb;9(2):164-73. 

43. Cuñetti L, Manzo L, Peyraube R, et al. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. 2018 Mar;50(2):461-4. 

44. Palmieri B, Laurino C, Vadalà M. Short-Term Efficacy of CBD- Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. Isr Med Assoc J. 2017 Feb;19(2):79-84. 

45. Shaladi AM, Crestani F, Tartari S, et al. [Cannabinoids in the control of pain]. [Article in Italian, Abstract in English]. Recenti Prog Med. 2008 Dec;99(12):616-24. 

46. Paladini A, Fusco M, Cenacchi T, et al. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016;19:11-24. 

47. Facci L, Dal Toso R, Romanello S, et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80. 

48. Franklin A, Parmentier-Batteur S, Walter L, et al. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci. 2003 Aug 27;23(21):7767-75.