By Dr. Donal Marks Harvey
What is medical marijuana?
The marijuana plant contains more than 100 cannabinoids, which is a general term for chemicals that may help treat a wide range of illnesses and symptoms. Cannabinoids are chemicals related to delta-9-tetrahydrocannabinol (THC), marijuana’s main mind-altering ingredient that makes people "high." There are at least two active chemicals in marijuana that researchers think have medicinal applications : cannabidiol (CBD), which has CNS pharmacologic properties excluding mood elevation “high”, and tetrahydrocannabinol (THC), which is analgesic “pain relief” but can also produce the euphoric “high”.
Tetrahydrocannabinol THC, is one of at least 113 cannabinoid compounds identified in cannabis. THC is the principal psychoactive (acts directly on the brain) constituent of the cannabis plant product. The chemical name trans-Δ⁹-tetrahydrocannabinol also can be used to refer to cannabinoid isomers (chemically and structurally similar compounds). Dronabinol, a synthetic form of THC approved by the FDA, is an appetite stimulant for people with AIDS and also an antiemetic, both are properties which can be helpful for people receiving chemotherapy. The pharmaceutical formulation dronabinol is an oily resin provided in capsules available by prescription in the United States, and a growing list of other countries, including Canada, Germany, and New Zealand.
Mass 314.47 g·mol
Cannabinol, a dreivitie of THC, is a non-psychoactive (doesn’t act directly on the brain cells) cannabinoid found only in trace amounts in Cannabis. It is mostly found in aged Cannabis. Pharmacologically relevant (compunds that can have direct effect on the brain) quantities are formed as a metabolite of THC.
Molar mass: 310.4319 g/mol
The term medical marijuana refers to using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illness and other conditions.
Scientific study of the chemicals in marijuana, called cannabinoids, has led to two FDA-approved medications that contain cannabinoid chemicals in pill form. Continued research may lead to more medications. Dronabinol is a synthetic form of THC approved by the FDA as an appetite stimulant for people with AIDS and antiemetic for people receiving chemotherapy. The pharmaceutical formulation dronabinol is an oily resin provided in capsules available by prescription in the United States, Canada, Germany, and New Zealand.
● US: C (Risk not ruled out)
8–10% (Relatively low risk of tolerance)
Oral, local/topical, transdermal, sublingual, inhaled
● AU: S8 (Controlled)
● CA: Schedule II
● UK: Class B
10–35% (inhalation), 6–20% (oral)
Mostly hepatic by CYP2C
1.6–59 h, 25–36 h (orally administered dronabinol)
65–80% (feces), 20–35% (urine) as acid metabolites
Products from the marijuana plant such as leaf products for smoking and for inclusion in consumables, such as food products.
Demonstrated or Purported medical benefits of Marijuana
An estimated 45 to 61% of patients with cancer will experience chemotherapy-induced nausea and vomiting (CINV). This is caused by chemotherapeutic agents and/ or their metabolites activating neurotransmitter receptors in the gastrointestinal (GI) tract [e.g., 5-hydroxytryptamine type 3 (5-HT3)] and in the brain [e.g., neurokinin-1 (NK-1)]. When CINV is managed according to published guidelines (such as Roila 2006), the incidence and severity is significantly reduced. In a literature review, Badowski 2017 found that oral cannabinoids have similar or improved efficacy compared with conventional antiemetics for the resolution of nausea and/or vomiting in patients with cancer, and presumably with lesser side effects and cost.
Synthetic pharmaceutical-grade THC (i.e., dronabinol capsules, nabilone capsules, and dronabinol oral solution) is approved in the United States for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who failed to adequately respond to conventional antiemetic therapy.
Synthetic pharmaceutical-grade THC (dronabinol capsules) is also approved for the treatment of anorexia associated with weight loss in patients with AIDS.
On the negative side, oral cannabinoids can be associated with greater incidence of certain adverse effects compared with conventional antiemetic therapy or placebo (e.g., dizziness, hypotension, and dysphoria or depression). This could be due to greater product variability, and active drug availability. Although used for CINV, cannabinoids may themselves cause nausea, a phenomenon termed Cannabinoid Hyperemesis Syndrome : CHS (Nourbakhsh 2018). CHS is characterized by cyclic attacks of nausea and vomiting in chronic cannabinoid users and learned behavior of compulsive hot bathing. Nourbakhsh described the deaths of two to CHS, and stressed the importance of recognizing CHS as a potential cause or contributing factor to death in cannabinoid users.
Pain is classified into Neuropathic and Nociceptice pain. Neuropathic pain is caused by damage or disease affecting the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is commonly seen in cancer as a direct result of cancer’s effect on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy), radiation injury or surgery.
In contrast to neuropathic pain, Nociceptive pain is caused by damage to body tissue and is typically of a sharp, aching, or throbbing nature. This kind of pain can be due to benign pathology; or by tumors or cancer cells that are growing larger and crowding other body parts near the cancer site. Nociceptive pain may also be caused by cancer spreading to the bones, muscles, or joints, or that causes the blockage of an organ or blood vessels.
Häuser 2018 performed a literature review of treatment of chronic pain with cannibus. Out of the 748 papers identified, only 10 met the inclusion criteria chosen, so it was a highly refined and selective and partial report. Inconsistent findings were observed in 4/10 studies on the efficacy of cannabis-based medicines in neuropathic pain and of one study for painful spasms in multiple sclerosis. Insufficient evidence was found of any cannabis-based medicine for pain management in patients with rheumatic diseases and in cancer pain (as opposed to success for CINV). Similar results were obtained in a study by Mucke 2018 (which also included Häuser). Both the Mucke and the Häuser studies were systemic reviews of other studies, and not their own studies. Their lack of direct experience with clinical studies on this issue, and apparently their lack of contact with patients with chronic pain who have successfully treated their pain with marijuana, is surprising. I think that their inability to find supportive date within 748 published reports attests to their experimental design and conceptual bias rather than to a lack of data.
Shleider et al 2018 analyzed 2970 cancer patients treated with medical cannabis between 2015 and 2017. The average age was 59.5, 54.6% were women and 26.7% of the patients reported previous experience with cannabis. The most frequent types of cancer were: breast (20.7%), lung (13.6%), pancreatic (8.1%) and colorectal (7.9%) with 51.2% being at stage 4. The main symptoms requiring therapy were: sleep problems (78.4%), pain (77.7%, median intensity 8/10), weakness (72.7%), nausea (64.6%) and lack of appetite (48.9%). After six months of follow up, 902 patients (24.9%) died and 682 (18.8%) stopped the treatment. Of the remaining, 1211 (60.6%) responded; 95.9% reported an improvement in their condition, 45 patients (3.7%) reported no change and four patients (0.3%) reported deterioration in their medical condition. The researchers concluded that Cannabis as a palliative treatment for cancer patients seems to be well tolerated, effective and safe option to help patients cope with the malignancy related symptoms.
The THC in marijuana mechanism of actions appears to be binding to receptors in the nerves and muscles to relieve pain.
Marijuana may ease painful symptoms of multiple sclerosis, according to a study published in the Canadian Medical Association Journal. Corey-Bloom et al 2012 performed a placebo-controlled, crossover trial involving 37 adult patients with multiple sclerosis and spasticity / painful muscle contractions, of whom 30/37 completed the study. These patients didn't respond to other treatments, but after smoking marijuana for a few days, they reported that they were in less pain. Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Other types of muscle spasms may respond to marijuana as well, for example diaphragm spasms that are untreatable by other, prescribed medications.
Medical marijuana legalization may (per the NIDA) decrease prescription opioid problems, as an indirect conclusion from several studies. Research published in the Harm Reduction Journal found that some people use marijuana as a less harmful substitute for alcohol, prescription drugs, and other illegal drugs. Some of the most common reasons patients make that substitution are that marijuana has less negative side effects and is less likely to cause withdrawal problems. Some people do become psychologically dependent on marijuana, and it is not a cure for substance abuse problems, but from a harm-reduction standpoint, it can help.
Several studies have showed that states that allow medical marijuana have fewer opioid deaths. This effect seems to grow over time, with states who pass these laws seeing a 20% lower rate of opioid deaths in the laws' first year, 24% in the third, and 33% in the sixth. (Bachhuber 2014) It's hard to say that deaths went down because of medical marijuana legalization and not other reasons. But because the effect seems to get stroznger the longer marijuana remains legal, researchers think marijuana is a likely cause of the decline in opioid deaths.
Some studies have shown that CBD seems to help people with treatment-resistant epilepsy. A number of individuals have reported that marijuana is the only treatment that helps control their or their children's seizures. In one child, CBD decreased seizures from 300 to just one every seven days, and forty other children are also showing positive results. The treating physicians think that CBD interacts with brain cells to quiet the excessive activity in the brain that causes these seizures. Regardless, a Florida hospital that specializes in the disorder, the American Academy of Pediatrics, and the Drug Enforcement agency don't endorse marijuana as a treatment for Dravet or other seizure disorders.
Hausman-Kedem 2018 conducted an observational study on the efficacy of medical cannabis for the treatment of refractory epilepsy. Fifty-seven patients (age 1-20 years) with epilepsy of various etiologies were treated with Cannabis oil extract (CBD/THC ratio of 20:1) for at least 3 months (Median follow up time-18 months). Forty-Six Patients were included in the efficacy analysis. Average CBD dose was11.4 mg/kg/d. Twenty-six patients (56%) had ≤50% reduction in mean monthly seizure frequency. There was no statistically significant difference in response rate among various epilepsy etiologies, and cannabis strain used. Younger age at treatment onset (<10 years) and higher CBD dose (>11 mg/kg/d) were associated with better response to treatment. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation. The study concluded that adding CBD-enriched cannabis extract to the treatment regimen of patients with refractory epilepsy may result in a significant reduction in seizure frequency, according to parental reports.
One of the most common reasons that states allow medical marijuana use is to treat and prevent the eye disease glaucoma, which increases pressure in the eyeball, damaging the optic nerve and causing loss of vision. Marijuana decreases the pressure inside the eye, according to the National Eye Institute: "Studies in the early 1970s showed that marijuana, when smoked, lowered intraocular pressure (IOP) in people with normal pressure and those with glaucoma."
For now, the medical consensus is that marijuana only lowers IOP for a few hours, meaning there's not good evidence for it as a long term treatment. Researchers hope that perhaps a marijuana-based compound could be developed that lasts longer.
Researchers know that many cannabis users consume marijuana to relax, but also that many people say smoking too much can cause anxiety. Childs et al 2017 reported that THC at low doses reduced stress, while higher doses had the opposite effect.
Ribeiro 2016 found that not only does marijuana not impair lung function, it may even increase lung capacity. Pletcher et al, looking for risk factors of heart disease tested the lung function of 5,115 young adults over the course of 20 years found that tobacco smokers lost lung function over time, but pot users actually showed an increase in lung capacity.
Chakravarti 2014note that cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. Most studies address CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. They reviewed anti-cancer studies on several cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.
CBD can stop cancer from spreading, at least in cell cultures (Sumida). There is evidence that CBD can turn off the ID-1gene, which is the gene that causes cancer to spread. At that point, the cells stopped spreading and returned to normal. Gurley 2014 marijuana can significantly slow the growth of the type of brain tumor associated with 80% of malignant brain cancer in people.
Eubanks 2006 found that Marijuana may be able to slow the progression of Alzheimer's disease. THC slows the formation of amyloid plaques by blocking the enzyme in the brain that makes them. These plaques kill brain cells and are associated with Alzheimer's.
A synthetic mixture of CBD and THC seems to preserve memory in a mouse model of Alzheimer's disease. Another study suggested that a THC-based prescription drug called dronabinol was able to reduce behavioral disturbances in dementia patients. All these studies are in very early stages, though, so more research is needed.
As pointed out by Müller-Vahl 1999, most hyperkinetic and hypokinetic movement disorders are caused by a dysfunction of basal ganglia-thalamo-cortical loops. It has been suggested that an endogenous cannabinoid tone participates in the control of movements and, therefore, the central cannabinoid system might play a role in the pathophysiology of these diseases. During the last years in humans a limited number of clinical trials demonstrated that cannabinoids might be useful in the treatment of movement disorders. Despite the lack of controlled studies there is evidence that cannabinoids are of therapeutic value in the treatment of tics in Tourette syndrome, the reduction of levodopa-induced dyskinesia in Parkinson''s disease and some forms of tremor and dystonia. It can be speculated that cannabinoid antagonists might be useful in the treatment of chorea in Huntington''s disease and hypokinetic parkinsonian syndromes.
As discussed by Müller-Vahi, Central cannabinoid receptors are densely located in the output nuclei of the basal ganglia (globus pallidus, substantia nigra pars reticulata), suggesting their involvement in the regulation of motor activity. Furthermore, there is evidence that endogenous cannabinoid transmission plays a role in the manipulation of other transmitter systems within the basal ganglia by increasing GABAergic transmission, inhibiting glutamate release and affecting dopaminergic uptake.
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