Peripheral neuropathy, the most prevalent chronic complication of diabetes, often results in pain, tingling, and numbness in the extremities.1 Traditional treatment medications, in many cases, can yield suboptimal therapeutic results or significant adverse effects. Medical cannabis, through its effect on the endocannabinoid system, may offer additional treatment options in the future.2 The purpose of this article is to discuss an overview of medical cannabis, the categories of current products, overall chronic pain research, and the current research for peripheral neuropathy in patients with diabetes. The benefits and challenges for incorporating medical cannabis into an ongoing treatment regimen for a case study will also be explored.
Current medication options aim to manage pain and improve function.3 Only 3 are approved by the Food and Drug Administration (FDA) for this indication: duloxetine, pregabalin, and tapentadol. Anticonvulsants like gabapentin and pregabalin modulate abnormal electric activity in the nerves but can cause side effects, such as weight gain and dizziness. Antidepressants including serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic amines (TCA) are also prescribed. The norepinephrine components of duloxetine and venlafaxine, both SNRIs, help with pain relief. Of these aforementioned medications, duloxetine, pregabalin, and gabapentin are often considered first line.
Other medications include a TCA, amitriptyline, which is limited by side effects such as dry mouth, constipation, and blurry vision—especially in older patients.3 Although opioids and opioid-like medications, such as tapentadol, could be used, long-term use is associated with dependency, tolerance, and a range of other side effects. Topical treatments, such as 8% capsaicin patches and 5% lidocaine patches, can provide localized relief but may not address pain effectively in all cases. Despite these options, many with neuropathy continue to experience significant pain and discomfort. This has led researchers to explore alternative treatments, including medical cannabis.4
A 62-year-old woman, Mrs F, is a new patient who complains, “My feet feel like a million bees stinging them.” Mrs F has experienced a sharp and shooting pain in both feet, mostly at night, for the past year. She stopped seeing her previous provider due to not being able to resolve the issue. She states, “This is my most critical problem.”
Her past medical history is significant for diabetes, hypertension, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux, and hypothyroidism. Fortunately, all disease states are controlled, with the exception of diabetes. Her current A1C is 10.4%. On neurologic examination, vibratory sensation is absent over most of both feet. She also has significant loss of protective sensation per monofilament exam. Laboratory results rule out other causes of neuropathy.
Current medications for neuropathy include pregabalin 300 mg daily and duloxetine 60 mg daily, both titrated from starting doses. She tried gabapentin, but dizziness caused her to stop taking it. She tried capsaicin patches and valproic acid with no relief. She states that a friend smokes cannabis for her diabetes pain and that it helps her friend. Mrs F is not open to smoking cannabis but would be for an oral product.
“Cannabis” refers to all products from the Cannabis sativa plant, whereas the term “marijuana” refers to only products that contain high concentrations of Delta-9-tetrahydrocannabinol (THC).5 Over 107 different cannabinoids have been identified from this plant. The main cannabinoids are THC and cannabidiol (CBD). By acting as an agonist on cannabinoid (CB) 1 and 2 receptors, THC is thought to have beneficial effects on pain but also cause euphoria at higher concentrations. The CB1 receptors are mainly in the brain and central nervous system, and CB2 receptors are expressed in peripheral tissues and immune cells.2 By modulating receptors in the immune system, THC may help with neuropathic pain by reducing nerve inflammation and altering pain perception. The cannabinoid CBD when given in combination with THC may enhance a possible therapeutic effect and attenuate the euphoric effects of THC.2
Synthetic THC pharmaceuticals approved by the FDA in 1985 include dronabinol (Marinol) and nabilone (although only available in the United States by its brand name, Cesamet).6,7 These medications are available in capsule form and are considered Schedule III and II, respectively. Syndros is a liquid formulation of dronabinol approved in 2016.8 All 3 synthetic THC medications are approved for the treatment of nausea and vomiting associated with cancer chemotherapy. Both forms of dronabinol are approved, additionally, to treat anorexia associated with weight loss in patients with acquired immunodeficiency syndrome or positive for the human immunodeficiency virus.
Phytocannabinoid-dense botanicals, from which medical cannabis is derived, include the Cannabis sativa, indica, and ruderalis plants.9 Cannabis sativa has a high concentration of THC and low concentration of CBD, and the indica plant has a higher concentration of CBD to THC. The ruderalis plant contains very little THC. Although THC products are considered Schedule I, production of and use of CBD products is legal federally as long as such products contain less than 0.3% THC. Of note, the Drug Enforcement Agency proposed a rule recently to reschedule cannabis from Schedule I to Schedule III, but as of this writing, a final rule has not been issued.10
Cannabidiol oil (Epidiolex) was FDA approved in 2018 for treatment of rare seizure disorders in children, Lennox-Gastaut syndrome and Dravet syndrome.11
Almost half of the states in the United States now allow the use of medical cannabis. Chronic pain in all its forms, including neuropathy, is one of the most consistent qualifying conditions. Thus, it is prudent to be aware of research evidence in this area. A systematic review published by the National Academies of Sciences, Engineering, and Medicine in 2017 stated that cannabis or cannabinoids are effective for treating chronic pain in adults.12 After reviewing 35 randomized controlled trials (RCTs), the authors stated that the evidence is conclusive or substantial.
Other reviews by Whiting et al13 in 2015 and Nugent et al14 in 2017 each stated that the RCTs they reviewed included ≥30% pain reduction for the cannabinoid group than with placebo. Whiting et al13 recommended that those studies give moderate quality evidence of support, and Nugent et al14 recommended that their evidence is limited to alleviation of neuropathic pain with insufficient evidence for other types of pain.
A Cochrane Review published in 2018 stated that cannabis-based medications were better than placebo for substantial and moderate pain relief.15 However, this review of 16 RCTs suggested that a variability in individual responses and side effects limits the benefits, which may be outweighed by the harms. The American Society of Pain and Neuroscience in 2023 gave medical cannabis use for the treatment of neuropathic pain evidence a level 1 with a grade of C, suggesting that additional large-scale RCTs are needed.16 Of note, the neuropathic pain in all of the aforementioned reviews was not associated with just diabetes but with several conditions from which neuropathy can arise.
At the time of this writing, 4 studies have been conducted regarding the use of medical cannabis for the treatment of peripheral neuropathy solely in participants with diabetes.17-20 None have recently been published, however, with a publication date ranging from 2010 to 2015. The journals publishing these studies have impact factors ranging from 4.6 to 16.2. Three of the studies are designed as placebo-controlled, randomized, double-blinded trials, and 2 of those are crossover studies. Although one has an open-label design, it is a follow-up study for an unpublished RCT that can be found on the ClinicalTrials.gov website.21 Pertinent information for these 4 studies can be found in Table 1.
Regarding methodology, the average age of participants ranged from 56.9 to 62.2 years, and all used pain scores as the primary outcome. The interventions used include: three arms of low, medium, and high dose of vaporized THC (one study),17 a one-to-one combination product containing THC and CBD in a sublingual spray (two studies),18,20 and nabilone (one study).19 The lengths of these studies ranged from eight weeks to forty weeks.
Overall, 275 participants total were included in the final analyses of the studies, shown in Table 2. Three of the studies showed a statistical significance, and 118 did not. The Selvarajah et al18 study researchers performed a post hoc analysis and discovered that participants with depression were more likely to have higher (ie, worse) baseline pain scores regardless of being in the control or treatment group. Also, participants with depression were more likely to show greater improvement by the study’s end regardless of group. The authors also noted that a large placebo effect could have also confounded the results.
Of the studies showing statistical significance, the study using vaporized THC displayed pain reduction with the 4% arm (approximately 16 mg) versus placebo, the 1% arm had no effect, and the 7% arm resulted in an increase of pain scores.17 In contrast, the study using nabilone found that all participants using 4 mg, the highest dose, had a reduction in pain intensity of at least 30%.19 Clinically meaningful pain reduction is considered to be either at least a 30% reduction in pain, or a reduction of 2 points on a 0 to 10 numerical visual analog scale, which was achieved by participants taking nabilone versus placebo.
The Hoggart et al20 study by far had the largest number of participants and study duration. In this study, the THC/CBD combination resulted in improved pain scores within the first 4 weeks versus placebo. These pain score differences were maintained over the rest of the 10-month study. Of note, the authors stated that participants achieving pain relief were taking an average of 6.6 sprays sublingually daily, which was approximately 17 mg of THC. Also, participant use of adjunctive analgesics for neuropathy was tracked in this study, and the authors noted no significant increase over the course of the study. The authors suggested that this finding corroborates that addition of medical cannabis yielded the positive results. However, this study had several limitations. No placebo group was compared in this study with the treatment. Also, a 23% dropout rate occurred, but not due to efficacy. Adverse effects of dry mouth, blurry vision, and dizziness accounted for most of the dropouts. Future studies should involve only participants with peripheral neuropathy due to diabetes. Also, they should be large RCTs of significant duration with a comparator group of traditional medications for neuropathy and should account for other analgesic medications being used.
Common adverse effects include dizziness, confusion, changes in mood, disorientation, euphoria, hallucinations, somnolence, and asthenia.2 Cannabis is also associated with impaired short-term memory, motor coordination, and judgment. Due to slowing reaction time, many states do not allow operation of a motor vehicle when taking medical cannabis. Although not as much is known regarding use of vaporized cannabis, smoking cannabis cigarettes can increase symptoms of chronic bronchitis and increase the risk of respiratory tract infections. Long-term use of high doses can be especially harmful for teenagers because it is associated with problems with brain development and reduced intelligence quotient scores. Furthermore, THC is metabolized by the cytochrome P450 enzyme systems CYP3A4 and CYP2C9.22 Concentrations of THC have been shown to double when used with ketoconazole, a common antifungal medication that inhibits CYP3A4 enzymes. Other inhibitors of this enzyme system include erythromycin (and other macrolide antibiotics) and verapamil (antihypertensive medication), which could potentially increase THC concentrations as well. Fluoxetine (antidepressant) and amiodarone can inhibit CYP2C9 enzymes and also potentially increase THC concentrations. Additive effects can occur with THC, such as increasing risk for tachycardia when given with anticholinergic medications and causing depression of the central nervous system when used in conjunction with alcohol and opioids. If using medical cannabis, patients should be followed for possible cannabis use disorder, which is a pattern of cannabis use leading to clinically significant impairment or distress.23 If use has been heavy and prolonged, those patients should be followed for cannabis withdrawal syndrome if use is abruptly stopped. For criteria for these conditions, see Table 3.
Mrs F’s neuropathy continues to significantly affect her quality of life, and traditional therapies have not provided enough relief. An open shared conversation between provider and patient could result in the patient wanting an add-on trial of medical cannabis. We describe the pros and cons of such a decision in the following.
Chronic pain is one of the most common qualifying conditions among states that allow medical cannabis, and significant research has been conducted in this area. Three of 4 studies involving only participants with peripheral neuropathy resulting from diabetes have yielded positive results.
Three other traditional medications have been tried with either no effect or stopped due to adverse effects. Pregabalin and duloxetine have been titrated up to relatively high doses but still have not resulted in maximum pain relief. If doubling the dose of each does not provide further relief or adverse effects occur, medical cannabis could be used as an adjunct third-line choice.
If medical cannabis were selected, it may be prudent not to select an inhaled form because Mrs F has COPD. Although less is known about the vaporized form, other inhaled formulations may worsen symptoms of COPD. Nabilone may be a possible choice, used off-label, and titrated up to the 4 mg dose per day. It is interesting that 2 studies found efficacy with approximately 16 to 17 mg THC on average, 1 with the vaporized form of THC only and 1 with the THC and CBD 1:1 combination in a sublingual form. It would be prudent to start low and titrate slowly, such as 1 to 2 mg daily and doubling the dose regimen every 1 to 3 weeks until the patient found significant pain relief. The target dose regimen would ideally be consistent with the studies, and the provider should provide very close follow-up with the patient.
Medical cannabis, at the time of this writing, is still schedule I.
More quality RCTs are needed, including a large number of participants, a significant length of time to show longitudinal pain relief, and a comparator group using traditional medications for neuropathic pain. Also, studies ideally would be designed to show functional improvement and pain relief.
Mrs F is an older patient with significant comorbidities.
Adverse effects of medical cannabis and drug interactions would need to be closely monitored, and a slow titration would be recommended. Development of cannabis use disorder would need to be monitored while using for therapy, and cannabis withdrawal syndrome would need to be monitored if therapy was stopped abruptly.
Federal regulatory oversight for medical cannabis is lacking.
Medical cannabis is relatively expensive, and many insurance companies do not cover the costs.
Treating peripheral neuropathy in patients with diabetes can be difficult even with multiple traditional medications at higher dose regimens. Medical cannabis presents a promising yet evolving therapeutic option. Although some early studies present encouraging results, wellconducted, large-scale RCTs are needed to fully understand the parameters of such use, including which cannabinoids/combinations would be most effective, dosing, long-term efficacy, and potential adverse effects to avoid. Health care providers are always considering a tailored approach that satisfies individualized needs for pain management. Medical cannabis may, with further research, prove to be a valuable tool in this area.
Justin J. Sherman, PharmD, MCS is an Associate Professor of Pharmacy Practice at the University of Mississippi School of Pharmacy in Jackson, MS.
The author declares no financial association in any product related to the content or development of this article.
The author has not received any funding related to the content or development of this article.
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