A selective review of medical cannabis in cancer pain management
Contributions: (I) Conception and design: A Blake, E Chow, S O’Hearn; (II) Administrative support: BA Wan, L Malek, P Diaz; (III) Provision of study materials or patients: N Lao; (IV) Collection and assembly of data: A Blake, BA Wan, L Malek, S O’Hearn; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Ms. Alexia Blake, MSc. MedReleaf Corp, Markham Industrial Park, Markham, Ontario, Canada. Email: [email protected] .
Abstract: Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic options. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7–43.2 mg/day THC and 0–40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7–10.8 mg THC in combination with 2.5–10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neuropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.
Keywords: Medical cannabis; cancer; pain
Submitted Jul 04, 2017. Accepted for publication Aug 03, 2017.
Cancer patients often present with chronic pain, which may stem from direct tumour involvement, or present as a side effect of cancer treatment (1). As pain negatively impacts the physical, functional, and emotional domains of life, effective pain management strategies are essential for restoring and maintaining quality of life of cancer patients (2). Unfortunately, the current standard treatment regimens for chronic or neuropathic pain in end-stage cancer patients rely heavily on opioid analgesics, which are problematic for some patients (3,4). This can be due to a combination of factors, including differences in individual responses to these drugs, and the presence of serious side effects such as severe constipation, that may prevent the administration of sufficient doses for pain relief (3). In addition, imprudent dosing runs the dangerous risk of patients developing dependency, or overdosing on opioids (4). Therefore, identifying alternative classes of analgesics that can effectively manage pain in cancer patients is of great importance.
Alternative pharmacological interventions include prescription medications such as acetaminophen, or nonsteroidal anti-inflammatory drugs like ibuprofen (5). Non-medicated approaches include therapies such as acupuncture, physical therapy, in addition to psychological or behavioural approaches (6). In addition to the management strategies listed above, compounds derived from the plant species Cannabis Sativa L. have demonstrated the potential to alleviate pain. The most commonly studied examples include tetrahydrocannabinol (THC), and cannabidiol (CBD) from the family of compounds known as cannabinoids (7). These compounds are commonly administered via inhalation, orally as oils or oil-filled capsules, or oromucosally via sprays containing either THC alone, or a combination of THC:CBD (8). Several pre-clinical studies have been conducted in animal models, investigating the mechanism of cannabinoid modulation of pain pathways (9,10). One of the identified mechanisms is the interaction of these compounds with one of the body’s endogenous signalling systems, known as the “endocannabinoid” system (11). This system acts independently of the opioid pathway to control pain signalling, immune activation, and inflammation (11). While there is an abundance of existing anecdotal evidence of the analgesic properties of medical cannabis, its efficacy has not yet been validated through high-quality clinical studies that provide strong evidence supporting its utility in the clinical setting (12).
This selective review is an overview of clinical studies conducted historically and up until the present day that aimed to investigate the efficacy of medical cannabis in managing pain in advanced cancer patients.
A search of literature published on Medline between 1975 and 2017 through using key words including “cannabis”, “THC”, “CBD”, “Nabiximol”, “cancer”, and “pain” was conducted. Five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain were evaluated for a selective review. Information regarding the study population, interventions, pain response, and side effects was reviewed and summarised.
Patient populations and selection criteria
Five studies were selected based on their evaluation of cannabinoids to manage chronic pain in advanced cancer patients. An early pilot study conducted in 1975 by Noyes et al. assessed pain in ten advanced cancer patients (eight women and two men, average 51 years old) (13). In a similar pain management study, Noyes et al. compared the effects of THC and codeine in 36 cancer patients (consisting of 26 women and 10 men) (14). Non-study medications were withheld from patients from both studies by Noyes et al. during the study period (13,14). Johnson et al. conducted a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of nabiximols and THC in patients with intractable cancer-related pain, using a well-distributed population of 177 advanced cancer patients, who recorded non-study breakthrough analgesics (15). In this study, the mean age, gender, primary disease sites, and pain classification were distributed similarly between the three treatment arms; THC, nabiximols, and placebo (15). In 2012, Portenoy et al. conducted a randomized, placebo-controlled, graded-dose trial involving 360 patients with advanced cancer, looking at the efficacy of THC or nabiximols. Patients were chosen based on having previously responded poorly to opioid analgesics, but were allowed to take breakthrough opioid analgesics as required (16). Patients who had received long-term methadone treatment for pain were excluded. Pain characteristics were categorized as mixed (48%), bone (24%), visceral (15%), and neuropathic (11%), and were distributed approximately equally across the study arms. Finally, Lynch et al. conducted a double-blind, placebo-controlled, crossover pilot trial including 16 cancer patients who had persistent neuropathic pain 3 months after their cancer treatment (17). These patients had an average 7-day pain intensity ≥4 on 0–10 NRS, stable concurrent analgesic treatment for 14 days prior to study initiation, and were not taking breakthrough analgesics.
Evaluation of pain
In the clinical studies of cannabinoids for cancer pain management included in this review, several methods of measuring changes in pain intensity were employed. Early studies by Noyes et al. used a 4-point pain scoring system in which 0= absent, 1= mild, 2= moderate, and 3= severe (13,14). Since then, many studies have employed the numerical rating scale (NRS) to evaluate pain on a 0–10 scale, with “0” representing “no pain” to “10” representing “pain as bad as you can imagine”. Patients with neuropathic pain studied by Lynch et al. completed the NRS at baseline, and the last day of each week of dosing (17). The change in NRS score from baseline to the week in which a stable dose was reached was used as the primary endpoint in determining cannabis efficacy. In the study by Johnson et al., patients used the NRS in addition to recording their long-term and break-through pain medications in a pain diary (15). Portenoy et al. asked patients to report their average pain on the brief pain inventory (BPI), as well as through an interactive voice recording system (16). The two remaining studies used the BPI to assess change in pain as the primary endpoint (18,19).
Efficacy of interventions
Overall, four out of the five studies found that cannabis was significantly associated with a decrease in cancer-associated pain. Table 1 presents a summary of the efficacy of THC or CBD on cancer pain.
Table 1 An overview of randomized controlled trials (RCTs) involving medical cannabis for cancer pain
THC oil capsules and THC, CBD oromucosal sprays
Studies included in this review assessed the efficacy of THC oil capsules, and oromucosal sprays containing THC extract, or THC:CBD extract, also known as nabiximols. Since nabiximols have CBD in addition to THC, they may potentially target more pain pathways when compared to THC extract alone.
Two early clinical studies on the efficacy of THC extract in sesame oil capsules were published by Noyes et al. in 1975 (13,14). The first was a pilot study that identified a correlation between higher doses of THC and increased pain relief (P<0.001) (13). The second study found a significant difference in pain reduction between placebo and 20 mg THC (P<0.05), in favour of THC treatment (14).
Oromucosal sprays have been a common method of administration for cannabinoid-based medicines in clinical investigations, to date (12). Both THC extracts and nabiximols, administered oromucosally, were studied by Johnson et al. (15). They did not observe a significant change in mean pain score from baseline for THC spray compared to placebo, but did report a statistically significant change in favour of nabiximols treatment compared to placebo (P=0.024). In addition, they reported that patients taking nabiximols required significantly fewer doses of breakthrough pain medications when compared to placebo (P=0.004). Portenoy et al. found that compared to placebo, nabiximols were significantly more effective for reducing average daily pain when comparing scores from baseline to the end of the study period (P=0.038) (16). These findings are in contrast with the study by Lynch et al. in which there was no statistically significant difference between placebo and nabiximols treatment groups amongst the 16 patients experiencing cancer-related neuropathic pain (17).
Studies assessed the efficacy of different doses of medication, or allowed patients to self-titrate up to a maximum dose, as dictated by study protocols.
Evaluation of the effect of 5, 10, 15, and 20 mg of THC in oil capsules by Noyes et al. found that the amount of pain relief increased with dose (13). Out of 10 patients in each cohort, 5 received substantial relief from 15 mg, and 7 patients received substantial relief from 20 mg. In the second study by Noyes et al., two different THC doses of 10 and 20 mg were compared to placebo and 60 mg codeine (14). A 60 mg dose of codeine is a standard daily opioid analgesic regimen used in the management of many pain types, including cancer pain (20). A significant difference in pain reduction was observed with the administration of 20 mg THC when compared to placebo (P<0.05). Additionally, no significant difference in pain relief was observed when comparing the 10 mg THC cohort to those receiving 60 mg codeine (P<0.05). This suggests the non-inferiority of 10 mg of THC in comparison to a commonly used opioid treatment.
Evaluation of the efficacy of THC oromucosal spray by Johnson et al. followed a self-titration method of dosing (15). Patients who used THC sprays used an average of 8.3 sprays/day, corresponding to 22.5 mg of THC/day following dose titration up to a ceiling dose of 48 sprays/day. Patients were considered to have reached their optimal dose upon experiencing relief of pain, or the development of side-effects. The authors found the optimal dose of THC reached across patients provided greater pain relief compared with placebo as measured by the average NRS pain score reduction (THC −1.01 vs. placebo −0.69) however, statistical significance was not reached (P=0.245).
In the three studies on nabiximols included in this review, self-titration was recommended up to a maximum dose of 8 sprays/3-hour period (15), and 11–16 sprays/day (16,17). In one of the studies, patients were divided into three dose groups categorized by titration ranges of mild (1–4 sprays/day, or 2.7–10.8 mg THC, 2.5–10.0 mg CBD), moderate (6–10 sprays/day, or 10.8–16.2 mg THC, 10.0–15 mg CBD), and high (11–16 sprays/day, or 29.7–43.2 mg THC, 27.5–40 mg CBD) (16). The doses found to produce significant pain relief include an average of 8.75 sprays/day (15), 1–4 sprays/day (16), and 6–10 sprays/day (16). It was observed that the high dose group of patients who utilised 11–16 sprays/day did not experience significant pain relief compared to placebo. Similarly, Lynch et al. found that at a high dose of an average of 8 sprays/day there was no significant pain relief observed in comparison to placebo (17).
Side effects and adverse events
Side effects reported in studies included in this review were consistent with those reported in literature investigating the use of cannabinoid-based therapies for several other indications (7). Table 2 summarises the five most commonly reported side effects of the five studies. In both studies by Noyes et al., side effects of 15 and 20 mg of THC included mental clouding (60–70%), drowsiness (70–100%), and euphoria (40–50%) (13,14). Not all side effects were experienced by all patients, and side effects tended to become more prevalent with higher doses.
Common treatment-related adverse events reported by Johnson et al. include somnolence (nabiximols 13%, THC 14%, placebo 10%), dizziness (nabiximols 12%, THC 12%, placebo 5%), confusion (nabiximols 7%, THC 2%, placebo 2%), nausea (nabiximols 10%, THC 7%, placebo 7%), and hypotension (nabiximols 5%, THC 0%, placebo 0%) (15). These were reportedly more frequent in patients receiving the nabiximols extract and the THC only extract, when compared with placebo. The adverse events identified by Portenoy et al. were significantly more frequent in the higher nabiximols dose group, whereas little difference was observed between the low dose and placebo groups (17). Lynch et al. identified fatigue (nabiximols n=7, placebo n=0), dry mouth (nabiximols n=5, placebo n=1), dizziness (nabiximols n=6, placebo n=0), and nausea (nabiximols n=6, placebo n=1) to be the most common side effects, which were more often observed in the treatment arm compared to placebo, although the significance of this difference was not assessed. However, patients also reported that the majority of side effects were transient and mild, and could be reduced through adjusting treatment dose. Side effects did not lead to any study drop-outs (13-17).
The paucity of clinical data available on medical cannabis for treatment of cancer pain is partly due its classification as a schedule I agent by the Controlled Substances Act in 1970, which restricted its investigation as a potential medical product (8). However, the few studies that were produced on the use of medical cannabis for cancer pain management have results that suggest it does possess therapeutic potential, and is at least worthy of further investigation.
There is a lack of dosing guidelines for the use of cannabinoid-based therapies in clinical practice. The ideal dosage would be one that provides effective pain management, but does not produce intolerable side effects. However, there are challenges in establishing this optimal dose in the advanced cancer patient population. One of these is inter-patient variability, in keeping with results from studies on narcotics and other prescription analgesics. As optimal doses were found to vary from patient to patient, physicians need to understand how to determine the correct dosage when prescribing to a new patient. In addition, advanced cancer patients are likely to present with complex symptomologies that make it difficult to accurately assess side effects derived from cannabis treatments, and are often taking multiple concurrent medications. That said, a number of these studies reported that observed side-effects tended not to be treatment-limiting, and could be controlled through dose titration, with pain relief in as little administration of 2.7–10.8 mg THC in combination with 2.5–10.0 mg CBD (17). This highlights the importance of establishing and validating a titration protocol that will allow researchers to identify effective and tolerated dosages in a safe and controlled manner.
Several studies presented in this review were underpowered due to small sample sizes, with three out of the five studies reviewed enrolling less than 50 patients. Therefore, the generalizability of the results may be limited, and future studies on medical cannabis are warranted to establish its efficacy and side effect profile in the cancer pain population. This includes additional efforts to identify the efficacies of specific cannabis compounds and their combinations, as well as ideal methods of administration through the assessment of relevant endpoints. Subsequent clinical trials should also consider the differences in cannabinoid pharmacokinetics and pharmacodynamics among individuals. Moreover, standardized and validated evaluation and reporting of cannabis-associated side effects is warranted in order to enable more accurate comparisons across studies. Ultimately, this will contribute to the development of clinical guidelines for the dosing and administration of cannabis as a pain medication for the large population of cancer patients in need of pain management, particularly those for whom alternative analgesics are insufficient, intolerable, or unsafe.
Current research shows that there is a potential role for medical cannabis in cancer pain management. However, the scale and quality of studies conducted to date are somewhat limited (12). Therefore, further research is needed to establish the efficacy of medical cannabis, either as an alternative to opiates or as an adjunctive therapy, and to identify the most appropriate methods of administration to achieve optimal therapeutic efficacy with minimal side effects.
We thank the generous support of Bratty Family Fund, Michael and Karyn Goldstein Cancer Research Fund, Joey and Mary Furfari Cancer Research Fund, Pulenzas Cancer Research Fund, Joseph and Silvana Melara Cancer Research Fund, and Ofelia Cancer Research Fund. This study was conducted in collaboration with MedReleaf.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S. A selective review of medical cannabis in cancer pain management. Ann Palliat Med 2017;6(Suppl 2):S215-S222. doi: 10.21037/apm.2017.08.05
Cannabis, CBD oil and cancer
Cannabis is a plant and a class B drug. It affects people differently. It can make you feel relaxed and chilled but it can also make you feel sick, affect your memory and make you feel lethargic. CBD oil is a chemical found in cannabis.
- Cannabis has been used for centuries recreationally and as a medicine.
- It is illegal to possess or supply cannabis as it is a class B drug.
- Research is looking at the substances in cannabis to see if it might help treat cancer.
- There are anti sickness medicines that contain man-made substances of cannabis.
What are cannabis and cannabinoids?
Cannabis is a plant. It is known by many names including marijuana, weed, hemp, grass, pot, dope, ganja and hash.
The plant produces a resin that contains a number of substances or chemicals. These are called cannabinoids. Cannabinoids can have medicinal effects on the body.
The main cannabinoids are:
- Delta-9-tetrahydrocannabinol (THC)
- Cannabidiol (CBD)
THC is a psychoactive substance that can create a ‘high’ feeling. It can affect how your brain works, changing your mood and how you feel.
CBD is a cannabinoid that may relieve pain, lower inflammation and decrease anxiety without the psychoactive ‘high’ effect of THC.
Different types of cannabis have differing amounts of these and other chemicals in them. This means they can have different effects on the body.
Cannabis is a class B drug in the UK. This means that it is illegal to have it, sell it or buy it.
CBD oil, cannabis oil and hemp oil
There are different types of oil made from parts of the cannabis plant. Some are sold legally in health food stores as a food supplement. Other types of oil are illegal.
CBD oil comes from the flowers of the cannabis plant and does not contain the psychoactive substance THC. It can be sold in the UK as a food supplement but not as a medicine. There is no evidence to support its use as a medicine.
Cannabis oil comes from the flowers, leaves and stalks of the cannabis plant. Cannabis oil often contains high levels of the psychoactive ingredient THC. Cannabis oil is illegal in the UK.
Hemp oil comes from the seeds of a type of cannabis plant that doesn’t contain the main psychoactive ingredient THC. Hemp seed oil is used for various purposes including as a protein supplement for food, a wood varnish and an ingredient in soaps.
Why people with cancer use it
Cannabis has been used medicinally and recreationally for hundreds of years.
There has been a lot of interest into whether cannabinoids might be useful as a cancer treatment. The scientific research done so far has been laboratory research, with mixed results, so we do not know if cannabinoids can treat cancer in people.
Results have shown that different cannabinoids can:
- cause cell death
- block cell growth
- stop the development of blood vessels – needed for tumours to grow
- reduce inflammation
- reduce the ability of cancers to spread
Scientists also discovered that cannabinoids can:
- sometimes encourage cancer cells to grow
- cause damage to blood vessels
Cannabinoids have helped with sickness and pain in some people.
This means a cannabis based product used to relieve symptoms.
Some cannabis based products are available on prescription as medicinal cannabis. The following medicines are sometimes prescribed to help relieve symptoms.
Nabilone is a drug developed from cannabis. It is licensed for treating severe sickness from chemotherapy that is not controlled by other anti sickness drugs. It is a capsule that you swallow whole.
Sativex is a cannabis-based medicine. It is licensed in the UK for people with Multiple Sclerosis muscle spasticity that hasn’t improved with other treatments. Sativex is a liquid that you spray into your mouth.
Researchers are looking into Sativex as a treatment for cancer related symptoms and for certain types of cancer.
How you have it
Cannabis products can be smoked, vaporized, ingested (eating or drinking), absorbed through the skin (in a patch) or as a cream or spray.
CBD oil comes as a liquid or in capsules.
Prescription drugs such as Nabilone can cause side effects. This can include:
- increased heart rate
- blood pressure problems
- mood changes
- memory problems
Cannabis that contains high levels of THC can cause panic attacks, hallucinations and paranoia.
There are also many cannabis based products available online without a prescription. The quality of these products can vary. It is impossible to know what substances they might contain. They could potentially be harmful to your health and may be illegal.
Research into cannabinoids and cancer
We need more research to know if cannabis or the chemicals in it can treat cancer.
Clinical trials need to be done in large numbers where some patients have the drug and some don’t. Then you can compare how well the treatment works.
Many of the studies done so far have been small and in the laboratory. There have been a few studies involving people with cancer.
Sativex and temozolomide for a brain tumour (glioblastoma) that has come back
In 2021, scientists reported the final results of a phase 1 study to treat people with recurrent glioblastoma (a type of brain tumour that has come back). The study looked at Sativex in combination with the chemotherapy drug temozolomide.
Researchers found that adding Sativex caused side effects, which included, vomiting, dizziness, fatigue, nausea and headache but patients found the side effects manageable.
They also observed that 83 out of 100 people (83%) were alive after one year using Sativex, compared to 44 out of 100 people (44%) taking the placebo.
However, this phase 1 study only involved 27 patients, which was too small to learn about any potential benefits of Sativex. The study wanted to find out if Sativex and temozolomide was safe to take by patients.
Researchers have now started a larger phase 2 trial called ARISTOCRAT, to find out if this treatment is effective and who might benefit from it. Speak to your specialist if you want to take part in a clinical trial.
Sativex and cancer pain
There are trials looking at whether Sativex can help with cancer pain that has not responded to other painkillers.
The results of one trial showed that Sativex did not improve pain levels. You can read the results of the trial on our clinical trials website.
Cancer and nausea and vomiting
A cannabis based medicine, Nabilone, is a treatment for nausea and vomiting.
A Cochrane review in 2015 looked at all the research available looking into cannabis based medicine as a treatment for nausea and sickness in people having chemotherapy for cancer. It reported that many of the studies were too small or not well run to be able to say how well these medicines work. They say that they may be useful if all other medicines are not working.
A drug called dexanabinol which is a man made form of a chemical similar to that found in cannabis has been trialled in a phase 1 trial. This is an early trial that tries to work out whether or not the drug works in humans, what the correct dose is and what the side effects might be. The results are not available yet. You can read about the trial on our clinical trials database.
Word of caution
Cannabis is a class B drug and illegal in the UK.
There are internet scams where people offer to sell cannabis preparations to people with cancer. There is no knowing what the ingredients are in these products and they could harm your health.
Some of these scammers trick cancer patients into buying ‘cannabis oil’ which they then never receive.
You could talk with your cancer specialist about the possibility of joining a clinical trial. Trials can give access to new drugs in a safe and monitored environment.
The science blog on our website has more information about cannabis and cancer.
The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation
This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immuno-regulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic.
Keywords: Bone marrow transplantation, cancer, cannabidiol, cannabinoid receptor 2, cannabinoids, cannabis, endocannabinoid, immunotherapy, tumor, Δ9-tetrahydrocannabinol
CANNABIS AND CANCER
Cancer is one of the most prevalent and devastating diseases in the modern world. Its treatments are often highly toxic to healthy tissues, causing severe side effects. In the course of treatment, both curative and palliative care will be administered either exclusively or in combination. As a result of the disease and its curative treatments, patients experience nausea, vomiting, loss of appetite, and pain. These symptoms greatly reduce their quality of life, and first-line palliative interventions are often insufficient for symptom control.
Cannabis and cannabinoids are known for their analgesic and anti-emetic effects, and therefore their application has increased for chemotherapy-induced nausea, vomiting, and chronic pain. 1 Whether cannabinoids have an anti-cancer affect is yet to be determined. Recent studies suggested that some cannabinoid-based treatments might have anti-tumor properties. 2 – 5 Cannabinoids were found to modulate key cell signaling pathways involved in the control of cancer cell proliferation and survival. 6 – 8 However, most of these studies utilized in vitro methods, a few were done in immune-competent animal models, and the data from human patients are anecdotal. In addition, the heterogeneity of endocannabinoids and their receptors in different tumor types raises the possibility that specific cannabinoid compositions should be used to treat differing cancer subtypes. 3 , 9 , 10
CANNABIS AND IMMUNITY IN CANCER PATIENTS
The tumor microenvironment is a complex ecosystem, comprising blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, hormones, and other factors. The different elements of the tumor microenvironment contribute to cancer progression. In particular, it is now evident that the immune system plays a key role in the development and progression of cancer. 11 – 13 Immune cells possess the ability to eradicate cancer. However, in cancer patients the anti-tumor immune response is insufficient. In recent years, immunotherapy has revolutionized cancer treatment, restoring tumor-induced immune deficiency in the tumor microenvironment and modulating immune responses against cancers. 14 Allogeneic hematopoietic stem cell transplantation (HSCT), which is usually performed for patients with hematologic malignancies, is another treatment that aims to induce anti-tumor immunity by targeting minor histocompatibility antigens on residual cancer cells. Any treatment with immune-suppressive properties may reduce the efficacy of such therapies.
The immune-regulatory properties of cannabis and cannabinoid-based treatments were demonstrated in various preclinical and clinical studies. 15 – 17 It is therefore important to investigate the effects of cannabinoid-based treatments on the immunity of cancer patients and on the efficacy of immune-related therapies. With a greater understanding of cannabinoid-based treatment effects on the immune system we will be able to appropriately apply them to treatment of cancer patients in combination with existing therapies. Unfortunately, the basic and medical research dedicated to this subject is currently lacking.
McKallip et al. demonstrated, in a murine model of breast cancer, that the phyto-cannabinoid Δ9-tetrahydrocannabinol (THC) promotes growth of cancer cells and metastasis by suppression of the anti-tumor immune response. 18 One group demonstrated enhanced tumor growth in THC-treated immune-competent mice but not in immune-incompetent mice in models of lung cancer, 19 while another group showed inhibition of tumor growth by synthetic cannabinoid receptor agonists in both immune-competent mice and immune-incompetent mice, in a model of melanoma xenograft. 20 In an ex vivo experiment, Zgair et al. showed that both phytocannabinoids cannabidiol (CBD) and THC have anti-proliferative effects on peripheral blood mononuclear cells (PBMC) isolated from patients on chemotherapy regimens to treat non-seminomatous germ cell tumors, which were comparable to the effect on PBMCs from healthy volunteers. 16
Only one study has investigated the interaction between phyto-cannabinoids and immunotherapy with checkpoint inhibitors. In this retrospective, observational study in kidney cancer and melanoma patients, Taha et al. demonstrated an inverse relationship between cannabis use and the response to treatment with nivolumab, without affecting progression-free survival or overall survival and without relation to specific phyto-cannabinoid composition. 21
CANNABIS AND IMMUNITY IN HEMATOPOIETIC STEM CELL TRANSPLANTATION
In allogeneic HSCT the propensity of the grafted immune cells to eliminate residual tumor cells is also responsible for rejection of host tissues and the development of graft versus host disease (GVHD). 22 In addition, slow, impaired, or dysregulated reconstitution of donor-derived immune cell populations, together with GVHD and other post-transplant complications, causes susceptibility to both common and rare infections. The early post-engraftment period is characterized by a progressive recovery of cell-mediated immunity; however, full immune reconstitution may take years. 23
In our recently published research, 17 we compared the consequences of treatment with THC and CBD in vitro and in murine bone marrow transplantation (BMT) models. Since it has been suggested that the combination of cannabinoids with other active molecules in the plant may achieve better clinical results than pure cannabinoids (known as the entourage effect), 24 we also examined the differences between the effects of the pure cannabinoids and high THC/high CBD cannabis extracts. Cannabis extracts with a high content (20%–30%) of CBD or THC were named CBD botanical drug substance (BDS) or THC BDS, respectively.
To investigate the effect of THC, CBD, and cannabis extracts on hematopoiesis after BMT in vivo, we utilized a syngeneic transplantation model ( Figure 1A ). Mice underwent lethal whole-body irradiation and were reconstituted with donor bone marrow cells. The cannabinoid treatments were administered intraperitoneally (IP) from the day of transplantation, every other day, for 2 weeks. Once a week, blood was collected for complete blood counts. Surprisingly, all treatments—and especially THC—inhibited lymphocyte reconstitution after transplantation ( Figure 1B ). Only the high-THC extract improved platelet rehabilitation ( Figure 1C ). Indeed, using knockout mice as donors, we have demonstrated that the cannabinoid receptor 2 (CB2), known to be activated by THC, has an inhibitory effect on post-transplant recovery of blood lymphocytes ( Figure 2 ).
Cannabis/Cannabinoids Administration to Syngeneic Bone Marrow Transplantation Model.
A: Recipient C57BL/6 mice (R) received lethal whole-body irradiation and were reconstituted with 8×10 6 donor C57BL/6 (D) bone marrow cells. Cannabis/cannabinoids were administered IP every other day, for 2 weeks from the day of transplantation. Blood samples for complete blood counts were obtained once a week. B: Lymphocyte counts (day 21 after transplantation) in pure cannabinoid-treated groups (left) and BDS-treated groups (right) are presented. C: Platelet counts in pure cannabinoid-treated groups (left) and BDS-treated groups (right), day 14 after transplantation. * PPP
BDS, botanical drug substance; BMT, bone marrow transplantation; IP, intraperitoneally; THC, Δ9-tetrahydrocannabinol.