Cannabidiol and multi-modal exercise for chemotherapy-induced peripheral neuropathy in cancer survivors

Abstract

Purpose

This study explored the effectiveness of cannabidiol (CBD) alone and in combination with multi-modal exercise (MME) to improve signs and symptoms of chemotherapy-induced peripheral neuropathy (CIPN), quality of life (QoL), and functional capacity in cancer survivors.

Methods

Cancer survivors (n = 27) with CIPN were enrolled in a 4-month interventional open-label study. Participants underwent two consecutive 2-month interventions: CBD (up to 300 mg/day) and CBD combined with MME. They were assessed using the painDETECT questionnaire for CIPN-related neuropathic pain and the Functional Assessment of Cancer Treatment/Gynecological Oncology-Neurotoxicity-13 (FACT-GOG-Ntx-13) questionnaire for CIPN neurotoxic symptoms (Ntx), perceived physical function (PPF) and overall QoL. Their functional status was examined through gait speed and timed up and go for mobility, the 9-hole peg test for manual dexterity, a hand-held hydraulic dynamometer for hand grip strength, and five repetitions sit-to-stand for dynamic balance, upper/lower extremity and overall strength.

Results

Positive effect sizes were measured by Cohen’s d or Cohen’s r with 95% confidence intervals (CI) from mean scores, and were d 0.62, CI 0.03–1.20 for Ntx; d 0.62, CI 0.09–1.26 for PPF; and r 0.401, CI 0.13–0.61 for hand grip strength after 2 months of CBD alone. After adding MME to CBD for another 2 months, the effect sizes were d 0.526, CI -0.15–1.19 for painDETECT; d 0.862, CI 0.67–1.55 for CIPN neurotoxic symptoms; d 1.03, CI 0.30–1.74 for perceived physical function; r 0.447, CI 0.15–0.67 for overall QoL; r 0.339, CI 0.03–0.59 for gait speed; and r 0.389, CI 0.08–0.63 for manual dexterity.

Conclusions

The study provides a proof of concept for the therapeutic effect of CBD alone and in combination with MME to improve symptoms’ burden, QoL and functional impairments related to CIPN in patients who are cured from cancer. Future randomized studies are needed to confirm the causal effects of CBD and exercise on CIPN, and to replicate our findings.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00520-025-09553-z.

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a distal and primarily sensory-neurological syndrome experienced by 70–80% of cancer survivors after receiving taxane and/or platinum-based chemotherapies [1, 2]. The pathophysiology of CIPN is multi-factorial and includes increased axonal degeneration and microtubule instability, altered retrograde axonal transport of growth factors, impaired neuronal mitochondrial function, altered peripheral vascularization and inflammation [1, 2]. Typical symptoms include sensory neuropathy (paresthesia, neuropathic pain, allodynia, and hyperalgesia) and a reduction or loss in proprioception, sensation to touch, vibration and joint position [3]. Neuropathic pain may be due to alterations in the brain areas responsible for pain processing [4]. Sensory symptoms combined with impaired or loss of proprioception lead to decreased strength and balance, gait instability, and increased risk of falls [5].

To date, effective pharmacological and non-pharmacological treatment options for CIPN are scarce [6]. The top pharmacological treatment currently recommended by the American Society for Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) for CIPN is duloxetine, a serotonin–norepinephrine reuptake inhibitor. However, duloxetine is often poorly tolerated, and it may be less effective in treating certain CIPN manifestations such as allodynia, hyperalgesia and paresthesia [6]. As nerve damage and inflammation are among the main aetiologies of CIPN, cannabidiol (CBD) and multi-modal exercise (MME) may be safer and more effective in treating this condition due to their anti-inflammatory, analgesic and blood flow promoting effects.

CBD is the main non-psychomimetic chemical of the Cannabis sativa plant. It exerts its effects by binding to several canonical and non-canonical cannabinoid receptors, thereby stimulating the endocannabinoid system (ECS), which is involved in the regulation of many physiological processes such as food intake, immunomodulation, inflammation and analgesia [7]. Cannabis-based therapies targeting the ECS may serve as novel treatment options for conditions like chronic pain and chemotherapy-associated nausea and vomiting [8, 9]. For CIPN, preclinical evidence has demonstrated that cannabinoids can exert anti-nociceptive effects and mitigate cold and mechanical allodynia in rodents [10]. In this regard, CBD was shown to reduce CIPN symptoms in a pre-clinical mouse model [10]. In clinical studies, it also appeared to attenuate early symptoms of CIPN, reduce numbness/tingling, and improve sensory function in patients undergoing chemotherapy [11, 12]. Interestingly, CBD increases endocannabinoid levels by inhibiting their degradation [13].

Exercise is a cost-effective and non-pharmacological option for CIPN patients who do not wish to use the drug approach. It is effective in managing certain negative side effects of chemotherapy, like fatigue, while improving physical function and quality of life (QoL) [14, 15]. In relation to CIPN, recent evidence from clinical trials has shown that MME, comprising aerobic, resistance and sensorimotor training, may positively influence CIPN in patients with different cancer primaries treated with neurotoxic chemotherapies [16]. Two systematic reviews and meta-analyses exploring the available evidence on MME for CIPN revealed that combining different exercises could improve CIPN symptoms and QoL in patients with cancer [16, 17].

Emerging evidence also suggests a synergistic crosstalk between the ECS and physical exercise [18]. Physical exercise can activate the ECS and promote an increase in the endocannabinoids, such as arachidonoylethanolamide (AEA) and 2-aminoacylglycerol (2-AG). The activation of the ECS may also increase the expression of cannabinoid receptor 1 (CB1) which (1) improves mood through reducing anxiety and increasing dopamine and serotonin and (2) increases neurogenesis, neuroplasticity, and brain-derived neurotrophic factors [19]. In a preclinical study, a single session of resistance exercises activated the ECS and promoted anti-nociceptive effects [20].

As a follow-up of our studies on exercise and cannabinoids to relieve cancer pain [21, 22], we wanted to investigate the effectiveness of CBD alone and in combination with MME to improve CIPN symptoms, overall QoL and functional capacity in cancer survivors.

Methods

Study design and participants

In this interventional open-label study, cancer survivors with CIPN were recruited from the Cancer Rehabilitation, Cancer Pain, and Medical Cannabis Programs at the McGill University Health Centre, as well as from the Palliative Care Program at the Jewish General Hospital between October 2022 and October 2023. The participants included adult cancer survivors (of different sexes, genders, and ethnicities), who were in cancer remission, had received taxane and/or platinum-based chemotherapies, and were diagnosed with CIPN by both the treating oncologist and the MD investigator (AV). We excluded participants who had (1) dementia, disabling orthopedic and neuromuscular disease, psychosis, cardiac abnormalities, or severe end-organ disease such as cardiac failure, hepatic failure, sepsis, or anemia (hematocrit < 30%), (2) medical or recreational cannabis use within the past 30 days, or (3) plans for surgery, chemotherpay and/or radiotherapy over the study period (4 months). Study participants were allowed to continue with hormonal therapies. This study received ethical approval from the Research Ethics Board of the McGill University Health Centre (MUHC REB 2022–8570). It was conducted in conformity with the Declaration of Helsinki. All participants provided written informed consent.

Procedures

Detailed information about the study procedures was previously published [23]. In brief, study participants had three visits (baseline-V1, 2-month follow-up-V2, and 4-month follow-up-V3) and underwent two consecutive phases of interventions. The physician-investigator prescribed first a CBD isolate for 2 months (phase I), followed by a combined CBD and MME for another 2 months (phase II).

CBD intervention

The cannabidiol isolate (Clear Oil, Spectrum Therapeutics, Smith Falls, ON, Canada) is THC-free, contained 50 mg/mL CBD, and was made for delivering high doses of CBD. Over 8 weeks (Phase I), the oil was administered orally; the dose was gradually titrated upward, starting from 20 up to 300 mg/day if tolerated. The patients then maintained their highest tolerated doses over the course of the following 8 weeks (Phase II) while completing the MME intervention.

MME intervention

The MME comprised moderate intensity exercise completed at least three times weekly, including one supervised exercise session per week with a kinesiologist. All prescribed exercises followed the American College of Sports Medicine (ACSM) guidelines of exercise prescription and can be seen in the frequency, intensity, time and type (FITT) table (Table 1) [24]. Progressions to maintain moderate intensity in the aerobic exercise program were administered when the participant’s target heart rate (THR) was not being met or when the Borg 6–20 rating of perceived exertion (RPE) was ≤ 12. All participants were educated on how to properly perform each movement safely.

Table 1.

Frequency, intensity, time, and type (FITT) table for exercise prescriptions and progression for cancer survivors with CIPN

	Aerobic	Balance	Resistance
Frequency	At least 5 ×/week	At least 3 ×/week	3 ×/week
Intensity	40–60% HRR/RPE 12–16	-	60–80% 1-RM/RPE 12–16
Time	At least 20 min/day	20 min/day	20–30 min/day
Type	Treadmill, cycle, NuStep, walking outside/mall	Tandem stand, tandem walk, single leg stance, single leg shoulder press	Wall slide, Romanian deadlift, calf raises, push-ups, standing row, abdominal crunch
Progressions	Increase speed or time until THR/RPE 12–16 being met	Static: increase time in balance pose or progress to eyes closed. Dynamic: increase in time, torso rotation	Increase resistance and decrease sets and/or reps, or no change in resistance and an increase in sets and/or reps

HRR heart rate reserve, RM repetition max, RPE rate of perceived exertion

Measurements

Demographic and clinical data were collected at baseline; each participant also completed a series of self-reported questionnaires and performed several functional tests (see below).

CIPN neurotoxic symptomology, perceived physical function and quality of life (QoL)

The Functional Assessment of Cancer Treatment/Gynecological Oncology-Neurotoxicity-13 (FACT-GOG-Ntx-13) version 4 measured changes in (1) CIPN neurotoxic symptoms [25] (FACT-Ntx), (2) perceived physical function (FACT-GOG-Ntx Trial Outcome Index (FACT-TOI)) [24], and (3) overall QoL (FACT-G) [23]. The FACT-GOG-Ntx-13 is established as a valid and reliable tool in assessing neuropathy [26]. It consists of 40 items and 5 subscales: physical well-being (7 items), social well-being (7 items), emotional well-being (6 items), functional well-being (7 items) and CIPN neurotoxic symptomology (13 items). Items are measured on a five-point Likert scale (0 = not at all and 4 = very much). Detailed information about the specific subscales used were previously published [23]. In brief, higher total scores for each of these subscales indicate improvement in the respective outcome [25]. Clinically meaningful improvements (CMIs) were defined as 1.38, 4.00, and 3.00 score changes in FACT-Ntx, FACT-TOI, and FACT-G, respectively [25, 26].

CIPN-related neuropathic pain

The painDETECT questionnaire is a validated self-administered tool that can screen for neuropathic-like symptoms. It consists of nine items which assess the pain course, the presence of radiating pain, and pain severity (seven questions where 0 = never and 5 = very strongly). The combined score of these items ranges from 0 to 38 and classifies the type of pain experienced. Scores 0–12 indicate nociceptive pain where a neuropathic component is unlikely (< 15% probability), scores 13–18 are considered unclear/mixed pain where a neuropathic pain component is ambiguous, and scores 19–38 indicate neuropathic pain (neuropathic component is likely (> 90% probability)) [27]. A shift toward the nociceptive category of pain (i.e., lower score) is considered a clinical improvement.

Functional tests

The gait speed test (GS) has excellent test–retest reliability and is responsive to clinically meaningful change [28]. The GS assessed mobility through the time it took the participant to walk 4 m at their usual pace. Before starting the test, the participant was asked to stand with both feet touching the starting line. Timing stopped once one foot was completely across the end line. The test was performed twice, with a 30-s break between tests, and the better of two tests was used for scoring. A clinically meaningful change in gait speed was set at 0.1 m/s [28].

The timed up and go (TUG) has high test–retest reliability and reproducibility [28]. It assessed agility and balance [29]. Participants began seated, stood up, walked 3 m, turned around a cone, and returned to the seated position [29].

Five repetitions sit-to-stand (5 × STS) is a reliable measure of lower body muscle strength and mobility [30]. It also assesses dynamic balance through the time it took to rise from a chair and to return to a seated position five times [30]. The test was stopped if the participant became tired or short of breath during repeated chair stands, used their arms, or had not completed five stands after 1 min.

Hand grip strength (HGS) assessed muscle strength through the Jamar® hydraulic hand dynamometer (Sammons Preston, Bolingbrook, IL) [31]. The Jamar® has good to excellent test–retest reproducibility and excellent inter-rater reliability in clinic and research [31]. Patients were seated with their arm bent at a 90° angle, and two strength measures were taken per arm and measured in kilograms. The peak measure was retained for analysis.

The 9-hole peg test (9-HPT) is a gold standard tool commonly used in research and clinical practice for assessing neuromuscular disease and dysfunction [32]. It also measures manual dexterity [32]. A pegboard with nine holes was placed with a container with nine pegs on the side of the tested hand. The pegs were picked up and put into the pegboard one at a time and thereafter returned to the container. Two consecutive trials were performed with the dominant hand, followed by two consecutive trials with the non-dominant hand. The time taken to complete the test was recorded to a maximum of 180 s [32].

Measuring adherence and compliance

Adherence and compliance are two complementary measures, which document patient behavior for interventions. We included both measures to better determine the feasibility of our CBD and MME interventions. Adherence was defined by the frequency in which each mode of exercise was done by participants, and compliance as the extent to which the patient’s behavior matches the prescribers’ recommendations for the type of intervention and its timing. CBD intake and exercise adherence and compliance were categorized into three groups: (1) adherent and compliant, (2) adherent but not compliant, and (3) non-adherent and non-compliant as described below for CBD and MME:

CBD

A patient was considered adherent for CBD if he/she took CBD daily. Weekly adherence scores were measured out of 4 points. The scores were averaged, and participants were categorized as non-adherent (0%), mildly (14–43%), moderately (57–71%), mostly (86%), or fully (100%) adherent. Similarly, a group mean was calculated from the total average compliance scores for all participants; they were categorized as non-compliant (0%), mildly (1–33%), moderately (34–66%), mostly (67–99%), or fully (100%) compliant (Appendix I).

MME

Patients were scored 1 point for each mode of exercise completed in full that week (at least 5 days of aerobic, at least 3 days of balance, and 3 days of resistance exercises per week) for a total of 3 adherence points (Appendix I). A patient would be considered compliant if he/she adhered (1–3 points) to their weekly exercise program and followed the exercises as prescribed by the kinesiologist that week. A patient’s compliance was scored out of 4 as follows: 4 = 100% exercises completed, 3 = 75–99%, 2 = 50–74%, 1 = 25–49%, and 0 = 0–24% of exercises completed. Weekly adherence and compliance means were tallied and averaged for an overall score.

Statistical analysis

Baseline characteristics were summarized using means for continuous data and percentages for categorical data. Cohen’s d was calculated along with its 95% confidence interval (CI) from the estimated marginal means of a linear mixed model, with fixed effects of time (as a proxy of intervention), to determine the effect size across visits; differences of 0.2, 0.5, 0.8, and 1.2 indicate a small, medium, large, and very large effect, respectively [33, 34]. For non-parametric data determined by the Shapiro–Wilk test, Cohen’s r with its CI was measured using the repeated Wilcoxon matched-pairs signed-rank test to estimate effect sizes across visits; 0.1, 0.3, and 0.5 indicate a small, medium, and large effect size, respectively [33, 35]. To avoid bias, all data points collected were used in calculating means, and no data points were excluded (such as for dropouts). Analyses were performed using IBM SPSS v.29 software and RStudio for the effect sizes and their confidence intervals.

Results

Participants and flow diagram

A total of 27 participants (female, 21; male, 6) were enrolled in the study. Figure 1 shows a flow diagram indicating their progression through the study. Their demographic and clinical characteristics are reported in Table 2.

Fig. 1.

Flow diagram indicating participants’ progression through the study. ICF, informed consent form

Table 2.

Clinical and demographic characteristics of study participants (N = 27)

Parameter	n (%)
Age (years; mean ± SD, median)	62.9 ± 11.2, 63
	Sex assigned at birth; n (%)
Female	21 (77.8)
Male	6 (22.2)
	Cancer diagnosis; n (%)
Breast cancer	14 (51.9)
Gynecological cancers	3 (11.1)
Colorectal cancer	3 (11.1)
Lymphoma	2 (7.4)
Pancreatic cancer	1 (3.7)
Tonsillar cancer	1 (3.7)
Gastric cancer	1 (3.7)
Tongue cancer	1 (3.7)
Bladder cancer	1 (3.7)
	Months since last chemo regimen; n (%)
> 6 months	15 (55.6)
≤ 6 months	12 (44.4)
	Type of chemotherapy; n (%)
Platinum	9 (33.3)
Taxane	7 (25.9)
Taxane + platinum	7 (25.9)
Vinca-alkaloids	4 (14.8)

Adherence and compliance

Adherence and compliance were calculated according to algorithms reported in Appendix 1.

CBD

At the 2-month follow-up, patients (n = 21) had a mean adherence score of 3.87/4 (SD ± 0.27). The mean compliance score was 3.62/4 (SD ± 0.41). At the 4-month follow-up, patients (n = 13) had a mean adherence score of 3.75/4 (SD ± 0.62), and the mean compliance score was 3.52/4 (SD ± 0.63). At both time points, patients were mostly taking CBD daily where 3 points = mostly adherent or taking CBD every day 86–99% of the time. Compliance at both time points indicated patients were taking 67–99% of the prescribed dose every week. Reasons for non-adherence and compliance: forgetting, logistics (unable to order/receive CBD in time), adverse events and/or cost of CBD.

MME

A group mean was calculated from the total average adherence scores of participants. The average weekly adherence score was 2.09/3 (SD ± 0.55) meaning, on average, participants completed 69.7% of the prescribed number of days of exercise every week. Similarly, a group mean was calculated from the total average compliance scores for all participants. The average weekly compliance score was 2.39/4 (SD ± 0.98) where a score of 2/4 implies people were completing 50–74% of their prescribed exercises every week for 8 weeks. Reasons for not completing exercise included stress, vacation, other physical activity done, injury and/or fatigue.

Patient reported outcomes

After 2 months of CBD treatment, 57% of participants experienced clinically meaningful improvements (CMIs) in their CIPN neurotoxic symptoms (FACT-Ntx) and perceived physical function (FACT-TOI) scores (data not shown). A medium to large effect size was also observed for FACT-Ntx (Cohen’s d 0.62, CI 0.03–1.20) and FACT-TOI (Cohen’s d 0.68, CI 0.09–1.26) in mean scores, however, a small effect size was observed for the FACT-G mean scores (Cohen's r 0.18, CI -0.11–0.45) (Fig. 2, a–c). Comparing 2-month with 4-month follow-ups, medium to large, large to very large, and medium effect sizes were found for FACT-Ntx (Cohen’s d 0.548, CI -0.16–1.25), FACT-TOI (Cohen’s d 0.935, CI 0.18–1.67), and FACT-G (Cohen’s r 0.400, CI 0.05–0.66), respectively (Fig. 2, d–f).

Fig. 2.

Improvements in CIPN neurotoxic symptoms, perceived physical function and overall quality of life across interventions. V1: Baseline (pre-CBD phase), V2: Post-CBD phase (2-month follow-up), V3: Post-CBD plus multi-modal exercise phase (4-month follow-up). a, d: CIPN neurotoxic symptoms assessed by the Functional Assessment of Cancer Treatment/Gynecological Oncology-Neurotoxicity subscale (FACT-Ntx); b, e: Perceived physical function assessed by FACT-Trial Outcome Index (FACT-TOI); c, f: Overall quality of life assessed by the FACT-GOG-Total score (FACT-G). Group means calculated through estimated marginal means for V1: n = 27, V2: n = 21, and V3: n = 13

Comparing baseline with 4-month follow-up (CBD + MME phase), CMIs were experienced by 77% of participants for the FACT-Ntx, by 92% for FACT-TOI, and by 83% for overall QoL (FACT-G). A large and large to very large effect size was observed for CIPN neurotoxic symptoms (Cohen’s d 0.862, CI 0.67–1.55) and perceived physical function (Cohen’s d 1.03, CI 0.30–1.74). A medium to large effect size was also found for overall QoL mean scores (Cohen’s r 0.447, CI 0.15–0.67) (data not shown).

According to the painDETECT questionnaire, at 4-month follow-up, only 15% of participants experienced neuropathic pain as compared to 37% at baseline. In contrast, the percentage of participants with nociceptive pain increased from 22% at baseline to 54% at the 4-month follow-up (Fig. 3). Medium and large to very large important differences were noted between baseline and 4-month follow-up (Cohen’s d 0.526, CI -0.15–1.19) and between 2- and 4-month follow-ups (Cohen’s d 1.03, CI 0.28–1.75).

Fig. 3.

Quality of pain assessed by painDETECT score (nociceptive, unclear/mixed, or neuropathic pain) at study visits. V1: Baseline (pre-CBD phase), V2: Post-CBD phase (2-month follow-up), V3: Post-CBD plus multi-modal exercise phase (4-month follow-up)

Functional tests

After 2 months of CBD, there was a medium to large effect size in HGS (Cohen’s r 0.401, CI 0.13–0.61). In comparison to baseline, at the 4-month follow-up, medium effect sizes were observed in 9-HPT (Cohen’s r 0.339, CI 0.03–0.59), gait speed (Cohen’s r 0.389, CI 0.08–0.63), and 5 × STS tests (Cohen’s d 0.548, CI -0.16–1.3). A medium to large effect was shown for the 5 × STS test (Cohen’s d 0.631, CI -0.11–1.36) between 2-month and 4-month follow-ups. No important differences were found for the timed up and go (TUG) between baseline and follow-up visits for both interventions.

Discussion

This interventional, open-label study provides proof of concept for the impact of CBD alone and in combination with MME to treat CIPN in cancer survivors. It revealed the following preliminary findings: (1) CBD alone may improve CIPN neurotoxic symptoms and perceived physical function, (2) CBD + MME can also improve overall QoL and pain scores, (3) upper body strength and manual dexterity may also be positively impacted by these interventions, and (4) moderate to high levels of adherence and compliance were registered for both CBD and MME in this patient population.

Almost 2/3 of our patients experienced clinically meaningful improvements in CIPN neurotoxic symptoms (FACT-Ntx) and perceived physical function (FACT-TOI), with medium to large effect sizes recorded for both scores, after CBD alone. The therapeutic role of cannabinoids for taxane and/or cisplatin-related CIPN has been previously suggested either to prevent CIPN [11] or to treat it in patients undergoing active cancer treatments [12]. Nielsen et al. [11] reported that oral CBD (300 mg/day) was able to attenuate early symptoms of CIPN in cancer survivors compared with untreated controls. More recently, 135 mg/day of CBD was reported to reduce numbness/tingling and improve sensory function in patients with cancer in a randomized placebo-controlled clinical trial [12]. Our study confirmed similar CBD effects in cancer survivors.

Large improvements in CIPN neurotoxic symptoms, perceived physical function, overall QoL, and painDETECT scores were observed after combining CBD with MME. These improvements were also clinically meaningful in over 70% of the patients. After CBD + MME intervention, most patients experienced nociceptive pain as compared to neuropathic pain. CBD interacts with the ECS to exert anti-inflammatory and neuroprotective activity [36, 37]. MME, on the other hand, has been hypothesized to help counteract CIPN symptoms by (1) improving sensorimotor function, (2) increasing vascular function and metabolic activity (supply of glucose and oxygen to mitochondria) of peripheral nerves, (3) upregulating neurotrophic factors, (4) releasing endogenous opioids to manage neuropathic pain, and (5) reducing chronic inflammation [38, 39]. Exercise and the ECS also seem to be strongly related; during exercise, the ECS stimulates the peripheral nervous systems via transient receptor potential channels and various cannabinoid and non-cannabinoid receptors, reducing pain sensation and chronic inflammation [19]. In rodent models of CIPN, a decrease in circulating endocannabinoid levels has been observed [40]. It was demonstrated that 30 min of moderate exercise alone could increase the circulating concentration of endocannabinoid AEA [41]. Thus, through the ECS, exercise may increase the role of the brain in modulating pain, CIPN symptoms, and functional capacities via enhancing dopaminergic and serotoninergic pathways, neurogenesis, neuroplasticity, and brain-derived neurotrophic factors [19]. The increased adherence and, thus, stimulation of the ECS by CBD + MME may explain the beneficial effects on overall QoL and pain scores in our study group.

After CBD alone, we could observe a moderate to large effect size on muscle strength. It has been previously reported that sensory and motor nerve damage due to CIPN can negatively affect physical function, including muscle strength, gait speed, proprioception, and balance function in patients with cancer [42]. A recent meta-analysis revealed that CIPN has a greater influence on distal rather than on proximal muscle strength, suggesting that grip strength (i.e., distal muscle strength) is a highly suitable method to test overall strength/functional ability in CIPN patients [42]. Weak hand grip strength has been associated with impaired health-related quality of life in cancer survivors [43]. Kilgour et al. directly linked muscle strength with function. They found that the weakest HGS percentile group of patients with advanced cancer also experienced worse survival along with other clinical and functional impairments [44].

A moderate effect size of CBD + MME on gait speed, 5 × STS test, and finger dexterity was observed. A clinically meaningful improvement for gait speed was observed in 52% and 62% of participants after CBD-alone and after CBD + MME interventions, respectively. Previous studies have found that patients with CIPN have muscle atrophy in their lower extremities [42]. The loss of sensation and proprioception in the lower extremities can result in impaired dynamic balance, which may lead to a higher risk of falling, limitations in mobility and poor quality of life. Our findings are consistent with a recent study which demonstrated the positive effect of MME on balance and strength in cancer survivors suffering from CIPN [45].

Despite longer TUG times observed in patients with CIPN, none of our patients experienced an impaired TUG status (> 10 s) at any study observation [46].

The main limitations of our study include open-label design, a small sample size, and several dropouts at V2 and V3. Without a control group, a placebo effect cannot be ruled out for the improvements observed in both the subjective and objective outcomes. Because of the small sample size of our study, we have focused primarily on effect size calculations, and all data points collected (including the dropout ones) were used for our analyses.

Major strengths of this study are (1) combination of CBD and MME in one intervention, (2) concurrent evaluation of subjective and objective measurements, (3) focus on effect sizes and clinically meaningful improvements, and (4) close monitoring of patients during each study phase. The latter characteristic allowed for precise calculations of adherence/compliance rates, which further documented our interventions’ feasibility. Finally, we considered multiple cancer types and chemotherapy agents, providing a consistent proof of concept that CBD with or without MME may be effective for CIPN across different clinical settings.

Conclusions

This study provides a proof of concept supporting the use of CBD and multi-modal exercise (MME) to relieve CIPN in patients who are cured from cancer. Within the limitations of an observational study, our data suggest that 4 months of oral administration of CBD (up to 300 mg/day) in combination with 2 months of MME may provide clinically relevant improvements in CIPN-neurotoxic symptoms, neuropathic pain, QoL, and perceived physical function. CBD with or without MME may also positively affect functional capabilities such as muscle strength, gait speed, and manual dexterity, which are often impaired because of CIPN. Future randomized studies are needed to replicate our findings and confirm the causal effects of CBD and MME on CIPN, and to replicate our findings.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MariaLuisa Vigano, Sarah Kubal and Sarah Habib. The first draft of the manuscript was written by MariaLuisa Vigano and all authors commented and contributed to the manuscript. All authors read and approved the final manuscript.

Funding

This research was funded by the Rossy Cancer Network’s Cancer Care Quality & Innovation Program Research Fund 2021 (RF-2021). The work of S. K. and S. H. was supported in part by the Cedars Cancer Foundation. The funders had no role in the collection and analysis of the data, and in the decision to publish the study results.

Data availability

No datasets were generated or analysed during the current study.

Code availability

Not applicable.

Declarations

Ethics approval

This study was approved by the Institutional Review Board of McGill University Health Centre (approval number: 2022–8570; date of approval: 7 September 2022).

Consent to participate

All patients provided written informed consent prior to participating.

Consent for publication

All patients provided written informed consent to the eventual publication of results from the anonymous data collected.

Competing interests

The authors declare no competing interests.