Cannabis for Chronic Pain: Mechanistic Insights and Therapeutic Challenges

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors provided a comprehensive review of the literature on the issue of chronic pain treatment. The manuscript is well-written, it is very easy to read and easy to follow the text from chapter to chapter, although each chapter is a topic of its own. Precisely because the authors have dealt with each aspect of the issue separately, briefly but in sufficient detail to understand, the work forms a cohesive whole: mechanism of pain, cannabis, cannabinoids, clinical trials, and possible limitations of medical cannabis regarding potential interactions, and finally constructive conclusion in the form of solving current problems concerning gaps in knowledge, public opinion on cannabis and regulation related to clinical policies and practices.

Author Response

7^th January 2025

 

Dear Editor,

Thank you for your letter and the constructive comments regarding our manuscript entitled "Cannabis for Chronic Pain: Mechanistic Insights and Therapeutic Challenges" (Manuscript ID: stresses-3372630). We greatly appreciate the reviewers' valuable feedback, and all suggestions have been thoroughly considered. The revisions made in response to the comments are highlighted in yellow in the revised manuscript to facilitate the review process. We believe these changes have significantly enhanced the quality of the manuscript, and we hope it now meets the high standards of your journal. Below, we provide a summary of the main corrections and our point-by-point responses to the reviewers' comments:

 

Reviewer #1

Comments and Suggestions for Authors

The authors provided a comprehensive review of the literature on the issue of chronic pain treatment. The manuscript is well-written, it is very easy to read and easy to follow the text from chapter to chapter, although each chapter is a topic of its own. Precisely because the authors have dealt with each aspect of the issue separately, briefly but in sufficient detail to understand, the work forms a cohesive whole: mechanism of pain, cannabis, cannabinoids, clinical trials, and possible limitations of medical cannabis regarding potential interactions, and finally constructive conclusion in the form of solving current problems concerning gaps in knowledge, public opinion on cannabis and regulation related to clinical policies and practices.

Author’s reply:

We sincerely thank the reviewer for recognizing the merit of our work and for approving the acceptance of our research paper.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors reviewed evidences on cannabis in chronic pain. A large number of reviews is available on cannabis and pain. To be competitive, this review would need to be more complete and put forward new hypotheses. Insofar, a clear analgesic effect of cannabis has not been demonstrated. However, chronic pain patients may benefit from medical cannabis from other mechanisms of action. For example, anxiolytic, antidepressant and antistress (the journal is Stresses..!!!) (DeVuono  et al., 2024; Halman et al., 2024; Sultan et al., 2024) effects of medical cannabis could explain the relatively minor analgesic activities of cannabis and a clear effects in a subset of chronic pain patients. In my opionion, authors should report and discuss studies on the effects of cannabis on stress, depression and pain.

Line 251: hyperalgesia and allodynia are typical of neuropathic rather than chronic pain per se or, of chronic pain with neuropathic symptoms.

Lines 319-334: The “ladders” for nociceptive and for neuropathic pain differ (Bates et al., 2019). Treatment guidelines for neuropathic pain include andepressants (ie, TCA and SNRIs) and/or anticonvulsivants (ie, GBP and PGB) as a first step therapy.

Line 338: cannabinoids are seldom included in guidelines as third or fourth line therapy for chronic pain. Please report guidelines you are referring to. Ref. 86 is not very clear.

Line 419: those results should not be overstated ((ie, THC:CBD compared with placebo (improvement of -1.37 vs. -0.69 NRS), whereas the THC group showed a nonsignificant change (-1.01 vs. -0.69)); in addition, there was no change in median dose or in mean number of doses for breakthrough pain, which means that analgesic effects of THC:CBD were pretty mild (Häuser   et al.2023). Please include THC and CBD doses and NRS numbers.

Please include and discuss Van Dam et al, 2024; Purohit  et al, 2024; and Choi et al., 2021. 

Patient and study selection is important. In Table 2, please report whether these adverse events were observed in clinical pratice and trials or for non medical cannabis. Acute intoxication is an issue (Leen et al., 2024). However, I doubt that long term memory problems can be ascribed to medical cannabis (Kuharic et al., 2021; Leen et al., 2024; Marques  and Campos, 2024; Halman et al., 2024). The same holds true for the cardiovascular problems. How many of these reports are from medical cannabis studies?

In people taking long-term high doses of cannabis under medical control, side effects are almost negligible (Shukla et al., 2025; Seffah et al, 2023). Patient taking non medical cannabis can to have been exposed to other agents (ie, alcohol, amphetamines, nicotine, non medical opioids etc).  Therefore, when reporting side effects, the two conditions (ie, medical, physician-controlled cannabis vs non-medical/recreational/tradional use of cannabis) should not be lumped. Also, given the current evidence, side effects of medical cannabis are not (and should not be) the major determinants for the use of medical cannabis in selected patients. I do not agree with statements in the Abstract at lines 27-30.

 

In a recent review Cerina Lee  wrote “…this systematic review indicates that there is minimal high-quality evidence to support medical cannabis as a first line treatment at the population level. However, there may be circumstances where certain patients or small subgroups of patients may benefit from using medical cannabis synergistically with other pain medications to alleviate their LBP. Robust RCTs are needed to investigate the safety and efficacy profile of medical cannabis’s prolonged use..”

I completely agree. However, expensive RCTs are unliked to be carried out because the available data on a non-patentable treatment are not encouraging.

Author Response

7^th January 2025

 

Dear Editor,

Thank you for your letter and the constructive comments regarding our manuscript entitled "Cannabis for Chronic Pain: Mechanistic Insights and Therapeutic Challenges" (Manuscript ID: stresses-3372630). We greatly appreciate the reviewers' valuable feedback, and all suggestions have been thoroughly considered. The revisions made in response to the comments are highlighted in yellow in the revised manuscript to facilitate the review process. We believe these changes have significantly enhanced the quality of the manuscript, and we hope it now meets the high standards of your journal. Below, we provide a summary of the main corrections and our point-by-point responses to the reviewers' comments:

 

Reviewer #2

Comments and Suggestions for Authors

The authors reviewed evidences on cannabis in chronic pain. A large number of reviews is available on cannabis and pain. To be competitive, this review would need to be more complete and put forward new hypotheses. Insofar, a clear analgesic effect of cannabis has not been demonstrated. However, chronic pain patients may benefit from medical cannabis from other mechanisms of action. For example, anxiolytic, antidepressant and antistress (the journal is Stresses..!!!) (DeVuono  et al., 2024; Halman et al., 2024; Sultan et al., 2024) effects of medical cannabis could explain the relatively minor analgesic activities of cannabis and a clear effects in a subset of chronic pain patients. In my opionion, authors should report and discuss studies on the effects of cannabis on stress, depression and pain.

Author’s reply:

First, we would like to thank the Reviewer for the comments and suggestions that helped to improve the quality of the manuscript.

 

In response to this pertinent observation, we acknowledge that long-term studies to date reveal a lack of consistent evidence and some contradictory findings. This discussion has been addressed in the newly added subtopic "6.3. Long-Term Usage", as outlined below:

“The use of cannabis for the treatment of chronic pain has shown mixed results, particularly with long-term use. Halman et al (2024) investigated the efficacy of cannabinoid-based medications for the treatment of pain, mental health and sleep disorders over a 12-month period and found significant benefits, particularly within the first 6 months. Patients reported reduced pain severity, improved mental health (particularly anxiety and depression), better sleep quality and reduced reliance on other medications, improving overall quality of life. However, the therapeutic effects, particularly for pain and medication reduction, waned after six months, possibly due to receptor desensitization or disease progression. While improvements in mental health and sleep were sustained, some patients experienced a decline in perceived benefits [183]. These findings are consistent with other studies that have shown initial efficacy of medical cannabis, but overall mild to modest long-term improvement in pain and associated symptoms over 12 months [184,185]. In contrast, a real-world analysis of the efficacy and safety of oral medical cannabis in 3,961 cannabis-naive patients demonstrated rapid and significant improvement in all measured patient and clinically reported validated outcomes that were maintained for over two years [186]. Although short-term benefits are evident for many patients, the long-term efficacy of cannabis in managing chronic pain remains inconclusive. While some patients report consistent improvements, others may not experience the same benefits or may even experience adverse effects, underscoring the complexity of the mechanisms by which cannabis relieves pain and regulates emotional states.

The variability in responses to cannabis use for chronic pain may be closely related to its role in modulating anxiety, stress and depression. Chronic pain is often associated with psychological conditions that amplify pain perception, such as anxiety and stress, which activate the hypothalamic-pituitary-adrenal (HPA) axis and increase cortisol release. Chronic pain is influenced by pain-related fears and cognitive distortions, integrating neural, psychological, and physiological mechanisms in brain regions (e.g., amygdala, hippocampus, and prefrontal cortex) associated with stress and pain modulation. Acute stress exacerbates threat memory encoding, further perpetuating the fear-avoidance cycle in chronic pain [187]. The endocannabinoid system plays a critical role in modulating stress response, anxiety, and associated behaviors through the regulation of two key endocannabinoids, AEA and 2-AG. AEA constrains stress responses via CB₁ receptor signaling, but its FAAH-mediated reduction promotes ex-citatory glutamate release in the hypothalamus and amygdala and disinhibits stress pathways in the prefrontal cortex, heightening stress susceptibility, anxiety, and glucocorticoid levels. Conversely, stress-induced glucocorticoid feedback enhances 2-AG synthesis and CB1 activation, which can restore stress resilience [188].”

Comments and Suggestions for Authors

“Line 251: hyperalgesia and allodynia are typical of neuropathic rather than chronic pain per se or, of chronic pain with neuropathic symptoms.”

Author’s reply:

The sentence was corrected. Thank you.

 

Comments and Suggestions for Authors

“Lines 319-334: The “ladders” for nociceptive and for neuropathic pain differ (Bates et al., 2019). Treatment guidelines for neuropathic pain include andepressants (ie, TCA and SNRIs) and/or anticonvulsivants (ie, GBP and PGB) as a first step therapy.”

Author’s reply:

We appreciate the reviewer’s valuable input and have addressed the issue raised, as detailed below:

“Although adjuvants are coadministered with analgesics, they are indicated as a first-line treatment option for treating specific pain conditions. Tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances are recommended as firstline therapy for management of neuropathic pain [85].”

 

Comments and Suggestions for Authors

“Line 338: cannabinoids are seldom included in guidelines as third or fourth line therapy for chronic pain. Please report guidelines you are referring to. Ref. 86 is not very clear.”

Author’s reply:

We thank the reviewer for this comment. The sentence was rewritten and the reference was replaced by a more suitable one, as follows:

“Cannabinoids are included in guidelines as fourth line therapy for chronic pain. The guidelines report that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, with chronic non-cancer pain, and with chronic non-cancer, non-neuropathic pain, but with some caveats [86]. However, there are authors who argue that there is sufficient evidence of the quality of medicinal cannabis to support its use as a first-line treatment for pain, as an adjuvant or alternative to opioids [87].”

References:

86. Banerjee, S.; McCormack, S. Medical Cannabis for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jul 24. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546424/
87. Lee, C.; Danielson, E.C.; Beestrum, M.; Eurich, D.T.; Knapp, A.; Jordan, N. Medical Cannabis and Its Efficacy/Effectiveness for the Treatment of Low-Back Pain: a Systematic Review. Curr Pain Headache Rep. 2023, 27(12), 821-835.

 

Comments and Suggestions for Authors

“Line 419: those results should not be overstated ((ie, THC:CBD compared with placebo (improvement of -1.37 vs. -0.69 NRS), whereas the THC group showed a nonsignificant change (-1.01 vs. -0.69)); in addition, there was no change in median dose or in mean number of doses for breakthrough pain, which means that analgesic effects of THC:CBD were pretty mild (Häuser et al.2023). Please include THC and CBD doses and NRS numbers.”

Author’s reply:

We agree with the reviewer, and the complementary data has been incorporated as suggested, along with the proposed reference, as follows:

“A multicenter, double-blind, randomized scientific study published in 2009 aimed to evaluate the efficacy of an extract containing 2.7 mg of ∆⁹-THC and 2.5 mg of CBD, compared to a pure ∆⁹-THC extract (2.7 mg) and a placebo in relieving pain in patients with advanced cancer. This clinical trial was carried out on 177 patients with moderate to severe pain (on a 0-10 mean pain Numerical Rating Scale (NRS)>4) despite being treated with opioids. The study concluded that after two weeks of treatment with a THC:CBD extract, there was a higher reduction in pain intensity (NRS changed from 5.68 to 4.31) compared to the placebo group (NRS decrease from 6.05 to 5.38) and the ∆⁹-THC-only group (NRS reduction from 5.67 to 4.66). These results highlight a synergy between ∆⁹-THC and CBD and lead to the conclusion that CBD can enhance the analgesic power of ∆⁹-THC through a strong inverse antagonism on CB2 receptors, which can produce anti-inflammatory effects and inhibit the migration of immune cells. In addition, CBD can modulate the undesirable effects of ∆⁹-THC by antagonizing CB1 receptors, potentially providing a better safety profile for this extract in chronic use. However, there was no change in median dose or mean number of doses for break-through pain, meaning that THC: CBD analgesic effects were pretty mild [108].”

Comments and Suggestions for Authors

“Please include and discuss Van Dam et al, 2024; Purohit  et al, 2024; and Choi et al., 2021.^”

Author’s reply:

As recommended by the reviewer, we have included and discussed the study by Van Dam et al. (2024), in which fibromyalgia patients were randomized to receive oxycodone, inhaled cannabis, or a combination of both over a six-week period, as outlined below. Additionally, we are prepared to include the studies by Purohit et al. (2024) and Choi et al. (2021), should the reviewer consider their inclusion relevant to the manuscript.

“However, a recent review of five double-blind randomised controlled trials involving 1539 participants with moderate-to-severe pain unresponsive to opioid therapy found moderate-certainty evidence that oromucosal nabiximols (∆⁹-THC and CBD) and ∆⁹-THC alone offered no clinically relevant benefits. Meta-analysis of four studies with 1333 participants revealed no significant improvement in patient-reported global impression of change or reductions in pain intensity compared to placebo [109].

Van Dam et al (2024) evaluated whether adding inhaled cannabis containing 6.3% ∆⁹-THC and 8% CBD to oxycodone for chronic non-cancer pain management could reduce adverse effects while maintaining analgesia. Fibromyalgia patients were randomized to receive oxycodone, inhaled cannabis, or a combination of both for six weeks. No differences were observed in composite adverse event scores across groups. Hence, this study shows the results with cannabis are not superior to opioids in con-trolling pain in fibromyalgia patients. Nevertheless, the study has several limitations: it did not assess the intensity of adverse events for participants who remained in the study; the high dropout rate among cannabis users could bias results; the absence of a placebo control limits baseline comparisons, and the study population was predominantly female fibromyalgia patients, restricting generalizability beyond this demo-graphic [110].”

Comments and Suggestions for Authors

Patient and study selection is important. In Table 2, please report whether these adverse events were observed in clinical pratice and trials or for non medical cannabis. Acute intoxication is an issue (Leen et al., 2024). However, I doubt that long term memory problems can be ascribed to medical cannabis (Kuharic et al., 2021; Leen et al., 2024; Marques  and Campos, 2024; Halman et al., 2024). The same holds true for the cardiovascular problems. How many of these reports are from medical cannabis studies?

Author’s reply:

Thank you for your insightful feedback. In response to your comment on patient and study selection, we have revised Table 2 to clearly indicate whether the reported adverse events were observed in clinical practice, clinical trials, or associated with non-medical cannabis use. We agree that this distinction is essential for accurately contextualizing each adverse effect, and we believe the updated table now provides improved clarity regarding the sources and populations analyzed.

Furthermore, as the reviewer rightly noted, attributing long-term memory deficits specifically to medical cannabis remains challenging. To better align with the existing evidence, we have adjusted the terminology to “memory deficits,” which we believe offers a more precise and balanced description.

With respect to cardiovascular issues, we concur that many reported cases are more strongly associated with recreational cannabis use rather than medical applications. To address this, we have made the distinction clearer in the revised Table 2 to minimize the risk of misinterpretation.

Comments and Suggestions for Authors

In people taking long-term high doses of cannabis under medical control, side effects are almost negligible (Shukla et al., 2025; Seffah et al, 2023). Patient taking non medical cannabis can to have been exposed to other agents (ie, alcohol, amphetamines, nicotine, non medical opioids etc).  Therefore, when reporting side effects, the two conditions (ie, medical, physician-controlled cannabis vs non-medical/recreational/tradional use of cannabis) should not be lumped. Also, given the current evidence, side effects of medical cannabis are not (and should not be) the major determinants for the use of medical cannabis in selected patients. I do not agree with statements in the Abstract at lines 27-30.

Author’s reply:

We agree with the reviewer’s perspective that the adverse effects of medicinal cannabis should not be the primary determinants of its clinical use. Indeed, we have emphasized that “the majority of adverse effects are mild to moderate in intensity, dose-dependent, and transient.” However, approximately 20% of patients have discontinued treatment due to side effects, even when under medical supervision (doi: 10.1016/j.ejim.2018.01.023). In line with the reviewer’s suggestion, we have revised the Abstract to more clearly emphasize the most significant limitations, as outlined below:

“However, the full integration of medical cannabis into clinical practice faces significant obstacles, including the need for standardized dosing, long-term safety data, and regulatory frameworks. These issues, alongside concerns over adverse effects and drug interactions, must be addressed to unlock the full therapeutic potential of cannabinoids, particularly for chronic pain patients, who endure both physical suffering and the added burden of stress.”

 

Comments and Suggestions for Authors

In a recent review Cerina Lee  wrote “…this systematic review indicates that there is minimal high-quality evidence to support medical cannabis as a first line treatment at the population level. However, there may be circumstances where certain patients or small subgroups of patients may benefit from using medical cannabis synergistically with other pain medications to alleviate their LBP. Robust RCTs are needed to investigate the safety and efficacy profile of medical cannabis’s prolonged use..”

I completely agree. However, expensive RCTs are unliked to be carried out because the available data on a non-patentable treatment are not encouraging.

Author’s reply:

The authors would like to thank you for your comment. The text has been amended and the suggested reference has been included.

Author Response File: Author Response.pdf