Abstract. “Cannabinoid” is the collective term for a group of chemical . As a result, patients and caregivers might seek out illegal sources (“street in weight with dronabinol, either alone or in combination. . Furthermore, pharmacies are designed to ensure proper storage and security of medical products. The combination of THC with the nonpsychotropic cannabis constituent CBD has a .. In self-reports of substance use among help-seeking veterans, PTSD Waterfield MR., Waterfield AE., Wright D., Zajicek J. The effect of cannabis on urge. The optimal dose involves the right ratio of CBD to THC in the right quantity for you. of CBD and THC until you find the sweet spot with the right combination of both . Of cancer patients who were not finding pain relief with opiates, the.
Cannabinoid Combo Seeking the Right
Although much is known about botanically sourced thc and cbd , and the pharmaceutical cannabinoid agents, little clinical data on the pharmacology of terpenoids and flavonoids have been published. Adverse outcomes such as psychotomimetic reactions and hypotension are more likely to occur with recreational cannabis because it tends to be preponderant in thc. The Cannabis plant yields inactive acidic forms of thc and cbd , namely thc - a and cbd - a.
The process of decarboxylation, which occurs through thermal treatment heating or combustion , generates the pharmacologically active formats 15 , Although dried botanical cannabis from licensed producers for medical use is not thermally treated, medical cannabis oils contain cannabinoids that have undergone decarboxylation Tweed Inc.
Personal communication, 18 September Generally speaking, higher bioavailability levels are achieved with smoking and vaporization than with oral ingestion.
Peak serum concentrations occur within 2—10 minutes. Absorption of both thc and cbd from the gastrointestinal tract is good, but both molecules undergo extensive first-pass metabolism. Table i summarizes the pharmacokinetic profiles of the various forms of cannabinoid therapies 5 , 17 — As summarized in Table ii , thc and cbd are both processed through the cytochrome P cyp system in the liver 5 , 17 — The effect of cyp 2C9 on thc metabolism is significantly affected by genetic polymorphisms; compared with individuals carrying high-functioning variants, those who carried genetic variants with diminished function experienced a doubling or tripling in thc exposure Furthermore, higher levels of thc and cbd can be observed with concomitant use of strong cyp 3A4 inhibitors.
Although neither thc nor cbd are inducers of cyp enzymes, both are inhibitors of a number of those enzymes, most notably 3A4, the enzyme that has the largest number of commonly used medical drugs as substrates Smoked cannabis has been noted to induce cyp 1A2 Being highly lipophilic, thc and cbd both have a large volume of distribution.
They are also highly bound by serum proteins. Although, theoretically, a high incidence of drug—drug interaction by displacement from protein binding sites might be expected, only one case report to date has described the occurrence of an increased normalized ratio and bleeding complications in a patient who smoked recreational cannabis Although the assessment and treatment of pain and other symptoms in patients with advanced cancers has become a standard of care, many patients still have incomplete symptom control That situation persists despite a plethora of pharmaceutical therapies, including opioid analgesics and adjuvant or targeted therapies for example, antiepileptic and antidepressant therapies.
Many oncology physicians are unaware of the potential medical benefits of cannabis 28 and are unwilling or unable to authorize their use. A selective review of the best-supported treatments follows. Cannabinoids, including herbal cannabis and extracts, have been used for the treatment of pain for centuries. There is evidence in historical texts and ancient pharmacopeia of treatment for various pain syndromes—from menstrual cramps to childbirth to headaches 1 — 3.
In terms of cannabinoid use in the modern era, an emerging literature includes systematic reviews that are showing benefit in several areas, including non-cancer pain 34 , Early studies using dronabinol, nabilone, and levonantradol demonstrated benefit, but their methodologies were not as rigorous as in more recent trials, and so the benefits might have been overestimated The few trials using cannabinoids in acute pain have shown essentially no benefit, and present recommendations are against cannabinoid use in the postoperative setting 37 — Cannabinoid treatments for cancer pain have been studied in a few randomized trials, but the evidence has been less than convincing.
Earlier studies published before , as reviewed by Campbell et al. Comparators such as codeine and secobarbital are not commonly used in patients with severe cancer pain, and so it is difficult to extrapolate the results.
More recently, two placebo-controlled trials using a cannabis extract nabiximols did show modest benefit when used in addition to opioids and other adjuvant pain medications in patients with chronic cancer pain 40 , Chronic neuropathic pain has received the most focus, with studies looking at the use of pharmaceutical cannabinoids and cannabis and its extracts in a variety of settings posttraumatic neuropathies, diabetic neuropathy, aids -related neuropathic pain, and so on.
Two recent publications confirmed the benefit of cannabinoid use, with twenty-nine randomized studies having been examined and included in separate systematic analyses 34 , Cannabinoids were found to be safe, modestly effective, and a reasonable option for treating chronic neuropathic pain. Those data have contributed to the revision, by the Canadian Pain Society, of their consensus statement on the treatment of chronic neuropathic pain to include cannabinoids as third-level therapy Inhaled or vaporized cannabis has also been studied, but, again, few randomized trials have been conducted.
A recently published meta-analysis demonstrated that 1 in 5—6 patients would benefit from the use of inhaled cannabis treatments for neuropathic pain Controlling nausea and vomiting was one of the initial uses of cannabinoids documented in the modern scientific literature.
In , Sallan et al. Since then, several larger-scale studies—including placebo-controlled randomized studies using dronabinol, nabilone, and cannabis extracts—have been completed. At least two systematic reviews on the topic have shown benefit with the use of cannabinoids, especially pharmaceutical cannabinoids, in patients undergoing chemotherapy 45 , When looking at the use of cannabis or extracts to control nausea and emesis, the picture is not quite as clear. Many of the published studies were observational or uncontrolled, and certainly randomized controlled trial data for cannabis use are in short supply 47 , Preclinical research has established animal models for nausea mouse, shrew , which have shown benefit with the use of cbd That benefit has been especially evident in a model of anticipatory nausea, a condition that has been difficult to treat for patients undergoing longer-term chemotherapy Anecdotal reports to us from patients who routinely smoke or vaporize cannabis containing varying amounts of thc and cbd before chemotherapy confirm improvement in their quality of life as measured by the Edmonton Symptom Assessment System and subsequent appetite and food intake.
Although treatment of some specific body areas abdomen, chest, whole brain with radiotherapy can induce nausea, very few reports of cannabinoid use in those situations have been published, and the reports that exist have used mainly pharmaceutical cannabinoids A recently published placebo-controlled study demonstrated that quality of life for patients with head-and-neck cancers undergoing radiotherapy is not improved with the use of nabilone The authors postulated that nabilone on its own is not potent enough to affect symptoms.
Another recently published study surveyed 15 patients with previously treated head-and-neck cancer about their use of medical cannabis, and all respondents endorsed the benefits of cannabis in the treatment of the long-term residual effects of radiation The data supporting cannabis and cannabinoid use in appetite stimulation is less conclusive than it is in pain or nausea. When used in cancer patients with cachexia, cannabinoids appear to be only modestly effective.
A study from the North Central Cancer Trial Group compared the use of an oral cannabinoid dronabinol with oral megestrol acetate and with the two drugs together. Final results did not show any statistical improvement in weight with dronabinol, either alone or in combination A Swiss-led study using cannabis extract in cancer patients also did not show benefit in terms of appetite or weight gain, and the trial was closed early after a mandated review A small Canadian study using oral dronabinol in advanced cancer patients demonstrated improved sense of taste and subsequent increased protein consumption.
That change did not translate to weight gain, but patients did express improvement in quality of life measurements More promising results were seen in studies of the non-cancer population. A study of response to smoked cannabis, dronabinol, or placebo in patients with aids demonstrated that the patients using smoked cannabis experienced the greatest weight gain 3. An earlier study in patients with dementia treated with either dronabinol or placebo documented an increase in appetite, increased weight gain, and modulated aggressive behaviour Although the main use of cannabinoids in patients with cancer and palliative patients has been symptom management, there could be other roles for these molecules in the treatment of malignancies.
In one of the first reports of cannabinoids having antitumour effects, extracts of cannabis were shown to inhibit the growth of lung adenocarcinoma cells in vitro An in vivo mouse model produced similar results. Preclinical studies have investigated cannabinoid activity in several malignancies lung, glioma, thyroid, lymphoma, skin, pancreas, endometrium, breast, prostate 59 — 61 , demonstrating antiproliferative, anti-metastatic, antiangiogenic, and proapoptotic effects reviewed by Velasco et al.
Cannabis has not been studied clinically as a treatment for malignancy. The only clinical study published to date that used cannabinoids enrolled patients with glioblastoma multiforme and was based on extensive preclinical work by the same investigators Their small study 9 patients showed the safety of intracranial administration of thc and demonstrated antiproliferative effects in some of the patients.
All patients eventually progressed and died, but not because of any effects of the extract. The investigators are actively continuing their clinical and research work, focusing on tumours of the central nervous system Oncologists might be concerned that cannabinoids could reduce the effectiveness of established chemotherapy agents. Several authors have investigated cannabis extracts used in tandem with a variety of chemotherapy agents in vitro and in animal models, showing synergism in reducing cell numbers, and no negative effect on anticancer function.
Cell cultures from pancreatic 64 , glioma 65 , gastric 66 , lung 67 , and colon 68 cancers have been investigated using a range of antineoplastic agents, including gemcitabine, temozolomide, paclitaxel, and 5-fluorouracil. Synergism in inducing cancer cell death is a common finding, which bodes well for the possibility of human clinical trials in future Despite the emerging evidence of antineoplastic activity, some older in vitro studies demonstrated cancer cell proliferation and loss of immune-mediated cancer suppressor activity after treatment with cannabinoid preparations 58 , Some studies have even shown discordant results depending on the concentration of cannabinoids: Thus, conflicting evidence points to the need for sober second thought before outright recommendations of cannabinoids for cancer patients can be made.
But again, mice and rats are not people, and what is observed in vitro does not necessarily translate into clinical medicine.
The preclinical evidence that cannabinoids might have direct anticancer activity is provocative as well, but more research is warranted. Currently, several clinical studies using cannabinoids in cancer therapy are registered at http: When a patient is referred to our outpatient clinic with a request for medical cannabis, several questions come to mind:.
Most of our patients have either tried medical cannabis or read about its role in symptom control. Those who have tried it recreationally or for medical purposes can accurately reflect on the benefits or the adverse effects experienced, which makes the discussion somewhat easier. Those who have little knowledge and less experience require a complete discussion with respect to the benefits, the possible adverse effects, the process of application and authorization, and the cost which is borne by the patient, because it is not covered by provincial or private medical insurance.
Table iii lists our contraindications to authorization, which are similar to those published by Health Canada 70 , the College of Family Physicians of Canada 71 , and the Canadian Medical Protective Association It should be noted that no special license or additional certification is necessary to authorize the use of medical cannabis, but a working knowledge of cannabis as already presented is helpful for oncology professionals who are considering a patient request.
Once the decision is made to support authorization, the choice of which licensed producer and product to use can be somewhat difficult for some patients. The more than 30 licensed producers list more than products for sale, which can be a problem for those who do not have experience with cannabis or patients who might be elderly or excessively fatigued. We do not advise that patients smoke the dried product; rather, they should vaporize, which is likely safer in the long run We also advise neophytes to choose a product that has a balanced thc: Cannabinoid proportions can be guided by available efficacy data summarized in Table iv.
Once patients have started to use the product and document the effects, the thc: Conditions potentially responding to cannabinoid therapies 74 — Titration of dose should follow the effect on the symptom in question for example, pain reduction, nausea control. Follow-up with patients is essential to determine benefits and any adverse effects, questions about use or strain selection, and outcomes. Certainly, if the adverse effects are not tolerable, then an alternative therapy should be considered.
If the patient is not getting the desired symptom control, then some dose modification might be necessary. Discontinuation of cannabis should be considered if an adequate trial does not result in the desired outcome as determined by the treating team or the patient.
Inter-professional collaboration is the new paradigm under which modern health care operates Research has demonstrated that inter-professional collaboration is enabled and promoted by inter-professional education, especially at the undergraduate level 79 , Although physicians ultimately authorize and prescribe cannabinoid therapies, valuable insights and inputs about achieving optimal patient outcomes can be derived from other members of the health care team, including nurses, social workers, rehabilitation therapists, and pharmacists.
Furthermore, pharmacies are designed to ensure proper storage and security of medical products. Pharmacists are also well positioned to comprehensively counsel patients and caregivers on the optimal methods of opioid and by extension, cannabis storage and disposal so as to limit diversion and unintentional exposure Moreover, given the emergence of cannabinoids as a novel therapeutic class, cannabinoid education for medical professionals as well as for patients and caregivers should be conducted per the principles of inter-professional education Industrialized countries are experiencing exponential increases in the utilization of opioids 84 , Major public health issues are emerging as a result, not the least of which relate to drug diversion, opioid addiction, and death from opioid overdose 84 , Currently, opioids remain the mainstay of cancer pain management, and increased cancer survival translates into patients using opioids for longer periods of time High-dose and long-term opioid therapy in cancer patients is becoming a concern, given observed risks such as poly-endocrinopathy, osteoporosis, and immunosup-pression Preclinical studies have demonstrated that certain opioids—such as codeine, morphine, methadone, and remifentanil—are associated with increased morbidity and mortality attributable to worsening of cancer and infections Opioid-induced hyperalgesia syndrome is also being reported with increased incidence, especially in patients with advanced cancer and escalating pain Thus, it behooves physicians to explore options that will allow for improved overall pain relief while curbing the overuse of opioids.
Observational studies in advanced cancer cohorts have demonstrated that cannabinoid therapies are associated with opioid-sparing and improved analgesia Published data on the addiction potential for recreational cannabis reflects a risk of 9.
Finally, a British study showed that the overall harm score for user and society for recreational cannabis score: Because medical cannabis generally tends to have a higher ratio of cbd to thc , it would be expected to be associated with a lower predilection to diversion, less addiction potential, and lower overall harm scores than those for recreational cannabis The integration and broader utilization of cannabinoid therapies within the domain of oncology including palliation carries the potential not only for improved health care outcomes for patients but also for economic savings and greater safety for society 90 , Patient reports of improvement in quality of life, especially for those undergoing intensive treatment regimens, could be key to patients continuing with lifesaving or life-prolonging therapies.
Cannabinoids might be able to help patients throughout their disease trajectory, but evidence about the ideal timing for cannabinoid initiation is lacking. More research will guide oncology and palliative care teams in their pursuit of excellence in cancer and symptomatic care.
VM has presented educational activities supported by Tweed, Bedrocan, and Mettrum. National Center for Biotechnology Information , U. Journal List Curr Oncol v. Published online Dec Find articles by P. Author information Copyright and License information Disclaimer. Copyright Multimed Inc. This article has been cited by other articles in PMC.
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Glioblastoma is the primary brain tumour with the worst prognosis: median survival is only 12 months despite the use of the most advanced. Epidiolex is the first cannabis-based drug ever approved by the FDA. especially in combination with other drugs given to epileptic patients, such as clobazam. will entice many parents who already use CBD to seek out a prescription. they have an exclusive right to CBD-based therapies for Dravet and. When these drugs are combined, particularly at high doses, the effects of both drugs are enhanced, and this can lead to some significant.