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Medical Cannabis for Healthcare Professionals

Medical Cannabis for Healthcare Professionals

What is Medical Cannabis?

Medical cannabis is a plant product of Cannabis sativa L., Cannabis indica or hybrid plant varieties, either obtained as raw or dried or as an extract for medical use. Cannabinoids are naturally occurring compounds of cannabis. The joint compound of medical cannabis includes delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). All cannabinoids are reported to be psychoactive; however, THC is reported to be the only cannabinoid that causes intoxication​1​.

Mechanism of Action of Medical Cannabis

The exact mechanism of action of medical cannabis is not understood correctly. Cannabis comprises three bioactive molecules called terpenoids, flavonoids, and cannabinoids. Δ9-tetrahydrocannabinol (THC) is the most well-studied cannabinoid. In addition to THC, cannabis also has concentrations of Cannabidiol (CBD). Cancer treatment using medical cannabis uses the various ratios of THC and CBD. Medical cannabis functions by binding to specific receptors known as cannabinoid receptors, which make up the endogenous cannabinoid system. These receptors, called cannabinoid receptors 1 and 2 (CB1 and CB2), work as G-protein coupled receptors, inhibiting calcium channels and adenylate cyclase and activating the potassium channels. CB1 receptors are located throughout the body, with the highest concentration of receptors observed in the central nervous system. CB2 receptors are highly expressed in the immune system, where the highest expression of the receptors is observed in B-lymphocytes, involved in cell migration induction and immune suppression. The mechanism of action of Cannabidiol is not clearly understood; however, it is reported to modify the effects and metabolism of THC while acting as an antagonist of CB1 and CB2 receptors due to its low binding affinity. Cannabidiol is also reported to be a potent anti-inflammatory agent​2​.

Uses of Medical Cannabis in Cancer Patients

  • Chemotherapy-Induced Nausea and Vomiting

Medical cannabis finds great importance in medical treatment for its antiemetic properties, for which it finds great importance in treating chemotherapy-induced nausea and vomiting. It has been reported that THC helps treat nausea via the emetic reflex pathways in which it acts at receptors located in the nucleus tractus solitarii at the level of the area postrema. THC is also reported to reverse the effects of 5-HT3 receptor agonists, which induce vomiting.

Medical cannabis is effective in suppressing anticipatory nausea. Studies have reported that medical cannabis helps suppress anticipatory nausea better than 5-HT3 receptor antagonists. Various studies have reported that combining other antiemetics with THC derivatives works best for nausea​3​.

  • Cancer-Associated Pain

Cannabinoids were also reported to have analgesic properties in cancer-associated pain, particularly neuropathic pain. CB1 receptors in the central nervous system are observed to be in high concentrations in brain regions. Cannabinoids are also reported to act on mast cell receptors, inhibiting the release of inflammatory substances and boosting the release of analgesic opioids to prevent inflammation. Cannabinoids also found their uses in treating neuropathic pain by preventing the acute pain response in C-fibers​4​.

  • Medical Cannabis as an Antitumor Agent

Evidence suggesting the use of cannabis as a potential chemotherapeutic treatment is reported. Endocannabinoid signalling is observed to increase in some human tissue malignant neoplasms compared to noncancerous tissue, specifically in highly invasive cancers, thus reporting the role of endocannabinoids in tumour growth. Cannabinoids are reported to induce apoptotic cancer cell death through cellular signalling pathways. A study reported that Cannabinoids might be essential in preventing cancer metastasis​5​. In another study by Guzman et al., it was reported that cancer treatment with THC decreased tumour progression and growth, as assessed by biomarker expression and magnetic resonance imaging. Cannabis research proposed that cannabinoids can prevent tumour growth through several mechanisms, including suppression of cell proliferation and increased cellular apoptosis​6​.

  • Medical Cannabis for reduced anxiety and increased sleep

Studies have suggested that medicinal cannabis may help enhance sleep and post-traumatic stress disorder; however, the number of such evidence is low. CBD is used by cancer patients, often in low doses, to manage self-perceived stress, anxiety, sleep, and other symptoms, and these patterns differ by demographic characteristics. Further research is needed to understand CBD's dose-dependent effect in reducing mental health symptoms such as anxiety, stress and sleeping problems.

Studies on the efficacy of medical cannabis on cancer treatment

Due to various legal issues surrounding medical cannabis, there are minimal studies of medical cannabis and its anticancer effects on humans, although many have reported animal studies.

A 2019 review of in vivo and in vitro studies on pancreatic cancer reported that cannabinoids could help reduce tumour growth, slow tumour invasion, and stimulate tumour cell death. However, research focussing on the effectiveness of different dosing, formulations, and the exact mode of action lacks​7​.

A 2019 study reported that CBD could induce cell death and make the glioblastoma cells more sensitive to radiation therapy without affecting healthy cells​8​.

Noyes et al. studied the effect of medical cannabis on advanced cancer patients and reported a significant correlation between higher doses of THC and increased pain relief.

Portenoy et al. reported that compared to the placebo, low and medium medical cannabis doses significantly reduced average daily pain​9​.

In another study by Noyes et al., conducted on advanced cancer patients' a significant difference in pain reduction was observed between placebo and 20 mg THC.

Dosage of Medical cannabis and THC: CBD ratio

There are no legalized medical or recreational ratios of THC: CBD in drafted regulations. Therefore, Healthcare providers must to understand the medical impacts of cannabis and the interactions among various ratios of THC and CBD before it is prescribed in a medical setting.

The Food and Drug Administration (FDA) has approved low-dose THC (initial oral dose 0.04 mg/kg b.i.d.) for treating nausea/vomiting associated with cancer chemotherapy for non-responders.

Previous studies have reported various therapeutic dosages of medical cannabis for cancer treatment. Wide variations in the therapeutic doses were reported where the dosage of 0.5 mg/day THC: 10 mg/day CBD to 100 mg/day or 50 mg/day combined THC and CBD to 40 mg/day THC and 600 mg/day CBD was observed. Dosage forms were also found to vary greatly, with sublingual oil reported being the most common form of medical cannabis administration among children while vaporization being the most common dosage form among adults for the maximum conservation of cannabidiols and cannabinoids​10​.

In a study on brain cancer patients, a CBD: THC ratio of 1:1 was found to be effective in improving the functional and physical capabilities and sleep qualities of cancer patients compared to using a CBD: THC ratio of 1:4​11​.

Approval by Regulatory Bodies

The AYUSH Ministry in India permits using the Vijaya or cannabis extract for medical purposes. Both CBD and THC are permitted to be used for treatment. The mention of ingredients on the box of medical cannabis-based medicines is at the manufacturer's or distributor's discretion. The Narcotic Drugs and Psychotropic Substances Act, 1985 (NDPS Act) prohibits the recreational use of cannabis; however, it does not apply to the seeds or leaves of the plant. Besides, the medicinal use of medical cannabis is encouraged once proper regulations and licenses are obtained​12​.

After Effects of Medical Cannabis

Several after-effects have been reported after the intake of medical cannabis and cannabinoids. Some may benefit cancer patients, such as sedation and mood enhancement. Some of the common side effects include:

  • Alteration of mood (dysphoria as well as euphoria)
  • Dry mouth
  • Anxiety and paranoia
  • Depression
  • Hallucinations
  • Sensation of depersonalization
  • Memory impairment
  • Dizziness
  • Blurred vision

Medical cannabis in cancer treatment may potentially be used for managing refractory cancer pain, reducing chemotherapy-induced nausea and vomiting anticipatory and as an antitumor agent. Currently, medical cannabis is not the primary means of treatment for any cancer type or treatment related to adverse effects; however, it can be used as an alternative medicine in cancer treatment.

CBD

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Ingredients and Quality requirements

Approximately 560 different substances have been identified in Cannabis sativa so far. Around 120 of these are cannabinoids, which are unique to this plant genus and are responsible for its pharmacological effects. Cannabinoids are a heterogeneous group of substances. They include Phyto cannabinoids and synthetic cannabinoids found in plants and endocannabinoids, which are messenger substances produced naturally in the body. Delta-9-tetrahydrocannabinol (THC) is the most psychoactive of the plant's 100 or so cannabinoids, 21-carbon–containing terpene phenolic compounds.  Several other cannabinoids are also thought to be medicinally beneficial. Cannabidiol (CBD), for example, is believed to be analgesic and anti-inflammatory while being non-psychoactive. The most critical Phyto cannabinoids are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their inactive precursors delta-9-tetrahydrocannabinol acid (THC-A) and cannabidiolic acid (CBD-A). The concentration of cannabinoids varies depending on the plant drug (flowers or leaves) and the method of preparation. Most are found in essential oil, which is obtained by distilling flowers or resin.

This essential oil should not be confused with hemp oil, derived from cannabis seeds and does not contain significant amounts of cannabinoids as edible oil. Marijuana's effects also differ depending on how marijuana compounds enter the body. Marijuana is most commonly used in food (edible marijuana) and by smoking or vaping it (inhaled marijuana): When marijuana is consumed orally, such as in  drinks,cooking oils (beer, soda, vodka), baked goods (cookies, brownies,), and candy, the THC is poorly absorbed and can take hours to be interested. Once absorbed, the liver processes it, producing a second psychoactive compound (a substance that acts on the brain and changes mood or consciousness) that has a different effect on the brain than THC. It's critical to understand that THC amounts in marijuana-infused foods are frequently unknown, and consuming too much THC may result in overdose symptoms enters the bloodstream and quickly travels to the brain when marijuana is smoked or vaporized. Because the second psychoactive compound is produced in small quantities, it has a minor effect. Marijuana inhaled has a shorter duration of action than marijuana taken orally.

Does the mode of administration (inhalation vs. oral consumption) make a difference?

When Cannabis is inhaled, whether as combusted or vaporized plant matter, the peak THC concentration occurs in 2 to 5 minutes, followed by a rapid drop-off. The kinetics of inhaled oils, such as those found in portable electric devices, may not yet be fully understood. The oral bioavailability is low and variable when taken orally, ranging from 5% to 20% of the ingested dose. In studies, the peak plasma concentration of THC taken orally reached 2.5 hours and declined much more slowly. Orally ingested THC has a terminal half-life of 25 to 30 hours, and when delta-9-THC passes through the liver, it is metabolized into a psychoactive 11-hydroxy-THC, which may be even more psychoactive than delta-9-THC.

Mechanism of action

The endocannabinoid system and its receptors mediate many of the effects of herbal and synthetic cannabinoids in the human body. So far, cannabinoid receptors refer to two types of cell membrane receptors: CB1 and C2. Both CBS are inhibitory G-protein-coupled receptors that inhibit adenylate cyclase, resulting in decreased intracellular second messenger substances. CB1 receptors are abundant in the cortex and hippocampus, as well as the basal ganglia and cerebellum. They are thus found in areas related to mental performance and motivation and movement coordination, spatial orientation, and sensory perception. CB1s protect the central nervous system through presynaptic inhibition by compensating for the over-or under-activity of many transmitter systems. CB2s are found on nearly all immune system cells and microglial cells in the central nervous system. They have a mild anti-inflammatory effect, modulating both acute and chronic inflammatory processes. Anandamides, which are arachidonic acid derivatives and are referred to as endocannabinoids, are natural ligands for both receptor types. Tetrahydrocannabinol is a cannabinoid receptor partial agonist at both cannabinoid receptors. Its psychotropic effects are primarily due to CB1 activation.

This applies to both therapeutically desirable effects on pain, nausea, and appetite, as well as motor function, and therapeutically undesirable effects such as dysphoria, hallucinations, reduced thinking and memory capacity, dizziness, and vegetative symptoms.CBD, in contrast to THC, only weakly binds to cannabinoid receptors. CBD, as an allosteric modulator of CB1, reduces THC binding and activation (25). CBD is thought to have anti-epileptic properties because it inhibits anandamide degradation by the fatty acid amide hydrolase (FAAH.

Cancer symptoms are influenced by marijuana.?

Several small studies on smoked marijuana discovered that it could help treat nausea and vomiting caused by cancer chemotherapy. A few studies have found that marijuana inhaled (smoked or vaporized) can help treat neuropathic pain (pain caused by damaged nerves). Certain cannabinoids have also been shown in animal studies to slow the growth and spread of certain cancers. There have been some preliminary clinical trials of cannabinoids in cancer treatment in humans, and more research is being planned. While research has shown that cannabinoids are safe for use in cancer treatment, there is no evidence that they help control or cure the disease. Relying solely on marijuana as a treatment for cancer while avoiding or delaying conventional medical care may have serious health consequences (Dariš et al., 2019).

Cannabinoid drugs

In the United States, two chemically pure drugs based on marijuana compounds have been approved for medical use.

1.Dronabinol (Marinol®) is a gelatin capsule containing delta-9-tetrahydrocannabinol (THC) that has been approved by the US Food and Drug Administration (FDA) for the treatment of vomiting and nausea caused by cancer chemotherapy, as well as weight loss and poor appetite in AIDS patients.

2.Nabilone (Cesa met®) is a synthetic cannabinoid that functions similarly to THC. It can be taken orally to treat vomiting and nausea caused by cancer chemotherapy when other medications have failed.

Frequently asked questions for healthcare professionals

  • Can any doctor prescribe medical cannabis?

No, not any doctor can prescribe medical cannabis. Only the specialist can apply to the government for approval to prescribe medicinal cannabis for any medical condition.

  • What approvals are needed to access medical cannabis products?

TGA approval is required for the supply and importation of the medicinal cannabis product and is through the TGA Special Access Scheme or Approved Prescriber Scheme, both of which allow access to unapproved therapeutic goods.

  • What type of medical cannabis available in India?

The  purified and standardized form of medical cannabis is available in India.

  • Are there any clinical trials on medical cannabis?

Over the last few years, doctors have launched small-scale CBD studies and CBD clinical trials to find other potential uses for the compound.

  • How can medical cannabis help cancer growth?

Medical cannabis does not help in cancer growth.

  • How can medical cannabis prevent stress and anxiety?

Tetrahydrocannabinol (THC)  appears to decrease anxiety at lower doses and increase anxiety at higher doses. CBD appears to decrease anxiety at all doses that have been tested.

  • Is it safe to recommend medical cannabis to advanced-stage cancer patients?

Yes, it is to recommend medical cannabis to advanced-stage cancer patients. A number of small studies found that it can be helpful in treating nausea and vomiting from cancer in chemotherapy during advanced stages of cancer.

  • Is brand substitution of medical cannabis products permitted?

Pharmacists are only able to substitute medicinal cannabis products provided the active ingredients, concentration, quantity and any other specifications (i.e. dosage form) are the same, and the prescriber has not indicated that brand substitution is not permitted.

  • Is it possible to get addicted to medical cannabis?

 While most people who use medical cannabis occasionally, they do not develop an addiction.

  • What are cannabinoids?

Cannabinoids are the type of chemical in marijuana that causes drug-like effects all through the body, including the central nervous system and the immune system.

  • What is the recommended CBD:THC ratio of medical cannabis for cancer treatment?

The recommended concentration of CBD is in the ratio CBD:THC ratio of 1:1

  • What is the best method to administer medical cannabis?

The most efficient administration route of medicinal cannabis is by inhalation.

  • Do regulatory bodies approve medical cannabis for treatment?

The federal government still considers it illegal, but some states allow it to treat specific health problems. The FDA, the U.S. agency that regulates medicines, has approved one cannabis-derived drug product cannabidiol to treat certain seizure disorders.

  • Is it possible to have an adverse effect due to an overdose of medical cannabis?

Yes, it is possible to have an adverse effect due to an overdose of medical cannabis. It impacts mentally, heart related and leads to pale skin.

  • What are the health risks of using medical cannabis?

The health risks of using medical cannabis includes impaired driving, increased risk of stroke and testicular cancer, brain changes that could affect learning and memory, and a particularly consistent link between cannabis use and mental illnesses involving psychosis.

  • Can medical cannabis be prescribed for patients undergoing chemotherapy or radiation therapy treatment?

Yes, medical cannabis is prescribed for patients undergoing chemotherapy or radiation therapy treatment as it is  helpful in treating nausea and vomiting from cancer chemotherapy and radiation therapy.

  • At what stage of cancer medical cannabis is usually recommended to patients?

Medical cannabis is usually recommended to the patients at any stage of cancer. It is recommended with the cancer treatment to get relief from the side effects.

References

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    Bridgeman M, Abazia D. Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting. P T. 2017;42(3):180-188. https://www.ncbi.nlm.nih.gov/pubmed/28250701
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    Wilkie G, Sakr B, Rizack T. Medical Marijuana Use in Oncology. JAMA Oncol. They were published online on May 1, 2016:670. doi:10.1001/jamaoncol.2016.0155
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    Himmi T, Dallaporta M, Perrin J, Orsini JC. Neuronal responses to Δ9-tetrahydrocannabinol in the solitary tract nucleus. European Journal of Pharmacology. Published online October 1996:273-279. doi:10.1016/0014-2999(96)00490-6
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    Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for managing acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257. doi:10.2174/157015906778019527
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    Qamri Z, Preet A, Nasser M, et al. Synthetic cannabinoid receptor agonists inhibit tumour growth and metastasis of breast cancer. Mol Cancer Ther. 2009;8(11):3117-3129. doi:10.1158/1535-7163.MCT-09-0448
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    Di M, Bifulco M, De P. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771-784. doi:10.1038/nrd1495
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    Sharafi G, He H, Nikfarjam M. Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer. J Pancreatic Cancer. 2019;5(1):1-7. doi:10.1089/pancan.2018.0019
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    Ivanov V, Wu J, Wang T, Hei T. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells. Oncotarget. 2019;10(8):825-846. doi:10.18632/oncotarget.26582
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    Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial. The Journal of Pain. Published online May 2012:438-449. doi:10.1016/j.jpain.2012.01.003
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    Zeyl V, Sawyer K, Wightman R. What Do You Know About Maryjane? A Systematic Review of the Current Data on the THC: CBD Ratio. Substitute Misuse. 2020;55(8):1223-1227. doi:10.1080/10826084.2020.1731547
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    Schloss J, Lacey J, Sinclair J, et al. A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas. Front Oncol. Published online May 21, 2021. doi:10.3389/fonc.2021.649555
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    General Guidelines for Drug Development of Ayurvedic Formulations. Central Council for Research in Ayurvedic Sciences Ministry of Ayush, Government of India. Published 2018. Accessed March 2022. https://www.ayush.gov.in/docs/guideline-drug-development.pdf
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