The present longitudinal observational study demonstrates the potential long-term benefits of inhaled cannabis as an adjunctive therapy for painful diabetic neuropathy (DN) in a cohort of 52 patients refractory to conventional treatments. Over a 5-year follow-up period, patients exhibited significant reductions in pain severity (BPI pain severity decreased from a mean of 9.0 to 2.0), pain interference (from 7.5 to 2.2), and neuropathic symptoms (LANSS score from 19.4 to 10.2), alongside marked improvements in pain relief (from 1.6% to 9.0%). These symptomatic improvements were accompanied by enhanced glycemic control (HbA1c reduced from 9.77% to 7.79%) [17], substantial tapering of concurrent analgesics (e.g., morphine equivalents from 66.8 mg to 4.5 mg, gabapentin from 415.4 mg to 11.5 mg), and no major adverse events attributable to cannabis. The improvement in glycemic control is important, though relatively small, as in most longitudinal observational trials, glycemic control worsens over time, and a sensitivity analysis (Section 3.6) assessed confounders, reinforcing the need for RCTs to establish causality. The single-center design and small sample size (n = 52) may introduce selection bias, with baseline characteristics compared to [3] to contextualize generalizability.

Notably, the protective effects on neuropathy were more pronounced in patients initiating cannabis prior to oxaliplatin exposure in related contexts [18], although our focus was on DN. Positive correlations between cannabis dosage and pain relief (r = 0.74, p < 0.001), alongside negative correlations with narcotic use (r = −0.43, p < 0.001) and pain interference (r = −0.43, p < 0.001) occur. These correlations are associative, not causal, necessitating RCTs to make a definite causality connection.

These findings suggest cannabis may serve as an adjunctive therapy, indicating the need for randomized trials to assess efficacy and determine optimal usage. These findings align with emerging evidence on the endocannabinoid system’s modulation of neuropathic pain and suggest inhaled cannabis as a viable option for managing refractory DN, potentially reducing polypharmacy and improving quality of life [16,19,20]. The quick and enduring pain relief results from our study matched both laboratory research and medical findings about cannabinoids as pain relievers [21]. The endocannabinoid system—which contains CB1 and CB2 receptors, endogenous compounds anandamide (AEA) and 2-archidonoylglycerol (2-AG), along with regulatory enzymes—functions as the primary system for pain modulation, inflammation, and neuroprotection [9,21]. The DN models present with elevated endocannabinoid levels because the system is disrupted by hyperglycemia, which results in compensatory nerve damage protection [21]. Activation of CB1 receptors inhibits neurotransmitter release and central sensitization, while CB2 receptors attenuate peripheral inflammation and oxidative stress [10]. The LANSS questionnaire items showed that patients who inhaled THC-rich cannabis experienced relief from sensory symptoms such as tingling and allodynia [5].

Research on streptozotocin-induced DN rodent models confirms that cannabinoids block nerve damage and modify nociceptive signals [12]. The dual benefits of pain relief together with metabolic improvement from inhaled cannabis therapy remain speculative because our observational design does not establish cause and effect [16]. Excluding prior cannabis users may overlook variability in endocannabinoid receptor density or tolerance, as suggested by Woodhams et al. [11], warranting the inclusion of diverse exposure histories in future studies.

The decrease in conventional analgesic medication use demonstrates that cannabis functions as an opioid-saving drug, which is vital during the current opioid crisis [8].

Patients in our study decreased their morphine-equivalent doses by more than 90%, reduced their gabapentin doses by 97%, duloxetine by 93%, and pregabalin by 79% without developing rebound pain. Research on plant-derived medications for neuropathies shows that THC and CBD cannabinoids produce better pain relief and nerve function improvement compared to placebo while allowing patients to lower their doses of anticonvulsants and antidepressants [22,23]. The combination of opioid receptor interaction and endocannabinoid modulation can enhance endogenous opioid signaling mechanisms [19,20]. The baseline medication regimens included high gabapentin doses because patients were treatment-resistant according to guidelines, which report first-line agent effectiveness in only approximately 50% of cases [23]. The variability in patient-reported dosing (0.5–43 g/month) highlights the need for standardized vaporization protocols to improve accuracy, a limitation acknowledged for future research.

In the current observational study, cannabis therapy caused few clinically important side effects. No serious adverse events occurred, although 15.4% of patients experienced mild side effects, including dry mouth and euphoria, during the titration period [24].

The risks of cognitive problems, psychiatric effects, and cardiovascular complications associated with cannabis use remain a concern for vulnerable patients, such as those with diabetes comorbidities, since 30.8% of our cohort had congestive heart failure. Research indicates that THC use at high levels might cause cognitive impairment; however, strict medical-grade inhalation (20% THC, <1% CBD) produces minimal adverse effects according to prior reviews, which report that chronic pain patients can tolerate these effects [24]. It is highly advisable to assess cardiac function during cannabis therapy due to possible vascular events.

The need for individualized dosing becomes necessary because of pharmacokinetic variability, which results in rapid inhalation effects compared to oral absorption—as shown by our patients’ monthly dose increase to approximately 43 g [24,25]. Studies demonstrate that inhalation methods outperform sublingual delivery methods for acute pain management because they provide better dose control and perform better in low back pain models according to research [16]; however, this creates an inherent inter-patient dosing variability point as the amount of active ingredients absorbed is difficult to ascertain with smoking.

The adoption of cannabis depends on cultural factors and accessibility issues that affect specific population groups like Israel’s Arabic minority, which makes up 20% of the citizenry. Islamic beliefs consider recreational use to be haram (forbidden) yet permit medical cannabis use because it qualifies as zarurat (necessity). Multilingual education is needed for our single-center patient population due to limited Arabic resources, resulting in unequal access to cannabinoid medicine. Government initiatives to provide educational programs in Hebrew and Arabic would help to achieve better equity as shown by recent studies [19].

Observational studies do not include randomization or a placebo control, therefore, the results may be influenced by placebo effects or the natural progression of the disease. The research results are likely to be overstated because this study was conducted at a single center with only fifty-two participants, with two deaths recorded, while missing data were handled using an intent-to-treat approach. The analysis of this study was complicated by the fact that all patients had end-organ damage and took multiple medications at the beginning of the study, and the self-reported results might be biased. This study’s strengths include its prolonged five-year follow-up, which is uncommon in diabetes nephropathy research, as well as its detailed assessment tools (BPI, LANSS, and HbA1c) which deliver real-world data about long-term effectiveness, although these do not offset methodological flaws.

The lack of biomarker data limits the mechanistic understanding; future studies should measure endocannabinoid levels (e.g., anandamide). Devices like PainSense, which measure salivary biomarkers (e.g., IL-6 and cortisol), or the AlgometRx Nociometer, which uses pupillometry, could complement subjective scales in future RCTs, providing mechanistic insights and personalized dosing. Such emerging devices like the PainSense salivary diagnostic tool or AlgometRx Nociometer (NCT06507748) could address the biomarker gap, enabling objective validation of cannabis therapy outcomes in DN.

Inhaled cannabis is both safe and effective for treating refractory painful DN because it provides pain relief as well as metabolic advantages and allows for reduced medication use. The evidence supports incorporating inhaled cannabis into multimodal DN treatment plans because ADA guidelines promote individualized patient care approaches [2]. Future studies should be randomized controlled trials that compare inhalation methods to other administration techniques, while evaluating biomarkers including endocannabinoid levels, to establish causality and find the best dosing approaches and reduce disparities [21,26,27].

The worldwide increase in diabetes cases and neuropathic complications may pave the way for cannabinoid therapies to revolutionize diabetic neuropathy care by striking a balance between safety and effectiveness [5,25]. Global disparities in cannabis access, particularly in culturally sensitive regions, underscore the need for objective diagnostics like salivary biomarker devices to standardize therapy and improve equity across diverse populations.