By Lowell Quenemoen M.D., Neurology(ret)
Growing up in the “Age of Aquarius”, the culture of sandals, beads and “grass”, many Americans have continued their interest in “weed” as a recreational product and more recently as a medicinal product. A Gallop poll in 2013 reveals that 38% of Americans have tried marijuana at some point in their
lives and 7% continue to do so. The highest use is in the 56-‐65yo group at 32% of the total users and the second highest is in the under 25yo group at 25%.
Increasingly there has been pressure to legalize recreational marijuana (currently legal in
Colorado, Washington, Oregon and Alaska as well as the District of Columbia but commercial sales are banned there.) Medical marijuana is legalized in 20 states and Guam. The US federal government continues to list it as a Schedule 1 substance and is therefore outlawed. In Kentucky, a non legalized state, the possession and/or sale of less than 8 oz is a misdemeanor as is the cultivation of less than 5 plants but more than that is a class D felony. Medical marijuana is licensed in Israel, Canada and the Netherlands.
The use of marijuana for medical purposes has largely been anecdotal since it was made illegal in 1970 with the passage of the Controlled Substances Act and research has been restricted. Negative side effects including addiction potential, impact on neurocognitive performance, mood disorders, psychosis, cardiovascular, pulmonary and the potential for accidental overdose have continued to temper trials and acceptance.
The medicinal use of cannabis dates back to 2700 BC in China and it was used as an analgesic in the West in the late 1800s. Of note, it was sold as an OTC until 1937 when the Marijuana Tax Act was enacted.
Cannabis includes two species, C. sativa which is psychotropic and stimulating and C .indica, the more sedating. Although more than 100 compounds are found in cannabis the two most studied are THC (Delta-‐9-‐tetrahydrocannabinol) which is psychoactive and CBD (Cannabidiol) which is not. In recreational use, product with higher THC levels have been promoted with an average concentration in 1996 0f 2.2% and in 2008 was 9.9%. CBD has been selectively reduced from .24% down to .08%. Efforts
have been made to synthesize cannabis derivatives and two are currently available in the US, Dronabinal (Marinol), a synthetic THC, and Nabilone (Cesamet). In the UK Nambiximols (Sativa) is available and contains a THC:CBD ratio of 1:1. Recently Epidolex, a 98% CBD compound has been developed in the UK. Pharmacologically, cannabinoids work through the endocannabinoid system which is spread through the brain and the spinal cord. CB-‐1 receptors are located in central terminals (hippocampus, basal ganglia and cortex) and peripheral nerves and CB-‐2 receptors in immune cells and lymph tissue. The CB-‐! receptors inhibit neurotransmitter release while the CB-‐2 receptors influence cytokine release
and cell migration.
In 2014 Koppel et al reviewed multiple articles (1948-‐2013) looking at the use of cannabis in multiple neurologic diseases ie.MS, movement disorders and epilepsy. Thirty four studies were looked
at and the effectiveness of oral cannabis extract(OCE), Nambiximol and THC evaluated.
In MS, spasticity and central pain were effectively treated with OCE with the other two
compounds being probably effective. Bladder dysfunction had a positive benefit with Nambiximol. but no benefit with the others. No clear benefit was seen in L-‐Dopa induced dyskinesias, Touretts tics,
cervical dystonia or epilepsy.
In 2015 Knezevich et al did a meta-‐analysis of 7 published articles using cannabis in the
treatment of refractory epilepsy. The controlled trials were randomized but small, averaging 9 patients. Standard doses of 200 mg of CBD were used in aerosol. Statistical benefit was not demonstrated. More recent studies published by Devinsky et al report success using Epidolex with reduction of more than 60% refractory seizures in Dravet and Lennox-‐ Gastaut syndromes.
Application of cannabis to headache was studied by Napchan et al in the journal Headache in 2011. They reviewed the pathophysiology of migraine and cluster headache and speculated on a deficiency in the endocannabinoid system since anadamide, an endogenous CB receptor active compound was present in reduced levels in the CSF. This in turn activated the trigemino-‐vascular nucleus triggering headache. A number of case reports and anecdotal studies have claimed success with cannabis for the refractory headache.
Cannabinoids have been used to treat glaucoma since it has been shown to reduce intraocular pressure. The benefit of one cigarette lasts about 4 hours and therefore requires multiple doses leading to cognitive changes. In addition arterial hypotension may be induced putting the optic nerve at risk.
Cannabinoid’s effects on the CB-‐2 receptors are thought to have an anti-‐inflammatory effect leading to trials in ulcerative colitis and other inflammatory GI disease. Positive results have been claimed for fibromyalgia but no benefits in rheumatological diseases proven.
Recent studies suggest relief of chronic neuropathic pain and, for patients on chronic opiates, the possibility of reducing doses with the addition of cannabis. The AMA has supported the use of cannabinoids in spasticity reduction in MS, in appetite stimulation, in reduction of nausea and vomiting
and for pain relief.
In psychiatry, a recent Cochran review suggests that CBD has some antipsychotic value and may be helpful in chronic anxiety states and possibly PTSD.
All things considered, the future role of medical marijuana depends on more Class 1 studies using rigorous methodology with adequate numbers of study patients. Cannabinoids will need to be more refined to facilitate standardized dosing and placebo effects related to psychotropic elements minimized. Physician willingness to prescribe is only going to follow if clear benefit is shown and the agents are no longer outlawed at the federal as well as the state level. A recent case in Colorado, a marijuana legal state, involving a quadriplegic Dish employee using medical marijuana for severe spasms, resulted in his losing his job after testing positive in a work mandated drug screen. Again there may be medical benefit realized but zero tolerance policies will dissuade many from using it because of legal and economic risks.
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By Danesh Mazloomdoost, M.D.
Since the early 1990s, scientific publications on medical cannabis have increased from 70 per year to over 1000 per year. As medical interest in the endocannabinoid system has evolved, so have political and financial interests in order to fast-track legalization, thus trumping the rigorous methodology of studying a drug and its adverse effects. Raw opium, coca leaves, and mustard gas all have derivatives that are prescribed with medical benefit but they rarely, if ever, prescribed in raw form. Similarly, cannabinoids have potential benefits but, unrefined, may also pose significant public harm.
Marijuana is composed of 500 different compounds, of which over 60 are considered active ingredients1. Two have been the focus of research, Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (d9THC). CBD demonstrates medical interest and is being studied in seizure disorders, pain, inflammation, dementia, and cancer treatment. d9THC, on the other hand is psychoactive with limited medicinal use. Often the ratio of d9THC to CBD is used to determine the recreational versus medicinal property of a crop, but even when maximizing CBD, crops still carry half to equal ratios of d9THC2. The concentration and bioavailability of these compounds also vary from one plant to the next, among different plant generations, and with altered delivery methods. Therapeutic effects are additionally complicated with dose-dependent effects that may contradict each other3. Furthermore, without regulation, pesticides, synthetic fertilizers, additives, and microbes could all be present within distributed medical products without clinician or patient awareness.
The media often sensationalizes failures in conventional medicine as a rational for legalization. Even though these cases evoke sympathy, they are not representative of the average medical marijuana recipient. Following legalization in California, the average recipient was a 32 year old white male, of whom 50% had a life-time prevalence of cocaine use and 75% of methamphetamine use4. Vague diagnoses such as “chronic pain” are most commonly cited as the rationale for use5. In Colorado, 50% of the entire state’s medical marijuana scripts were generated by 1% of prescribing physicians6. Ill-defined diagnoses coupled with a few physicians prescribing high quantities are conditions similar to the opiate epidemic and pill mills seen in Kentucky.
The benefits of marijuana legalization are often touted as both good for local tax revenue and cost-cutting because of decriminalization. However, in the context of currently legal substances such as alcohol and tobacco, the evidence conflicts with theory. In Wisconsin, the revenue collected from alcohol and tobacco tax averaged to $700 million per year, while the costs (motor vehicle accidents, hospital admissions, fetal effects and treatment, arrests, and addiction treatment) totaled $11.3 billion, a 16-fold difference7.
In the criminal justice system, there is an impression that prisons are overflowing because of marijuana incarcerations. These statistics can be misleading. Any charge (e.g. rape, murder, robbery) that also includes a marijuana charge may be quoted as a marijuana-related offense, thus inflating the numbers. In reality, only 0.1% of state prisoners are incarcerated for marijuana possession while drug traffickers encompassed 99.8% of federal drug charges8. Most possession charges are directed to drug courts for rehabilitation services. Legalization could actually increase marijuana-related charges for the same reasons that alcohol, a legal substance, outnumbers marijuana arrests by 4:19,10. For example, Washington State saw a sizeable increase in marijuana-related DUI arrests following legalization11.
Legalization normalizes, and consequently increases, marijuana demand12. Terming marijuana medicine further connotes harmless and beneficial attributes. Lobby interests often marginalize the many adverse effects of marijuana. While the spectrum of effects from each individual active ingredient is undergoing investigation, the meta-effect of raw marijuana shows detrimental effects on memory, coordination, substance abuse, and mental health, particularly for vulnerable populations such as adolescents.
Memory and IQ are proportionally affected in correlation to age of onset, duration of use, and frequency of exposures to marijuana13-17. This effect is particularly harmful to adolescents, who irreversibly lose an average of 8 IQ points, theoretically because of inhibited synapse formation18. These effects are even more pronounced in utero even at low doses and infrequent exposure19.
Adverse effects continue throughout life. Marijuana smokers show higher rates of industrial accidents, injuries, and absenteeism20. Heavy users share lower income, greater welfare dependence, unemployment, and low life satisfaction21-23. Kentucky already ranks among the nation’s highest rates of disability24; legalizing marijuana risks increasing its availability and indirectly raising disability rates further.
Proponents of marijuana often deny adverse psychoactive properties, such as addiction and psychosis, citing anecdotal cases. Similarly, one may argue not everyone who tries alcohol becomes addicted. Yet, marijuana addiction rates among adults average 10%, while teens show higher rates at 20%, and daily users at 40%25-27; all are higher rates than alcohol use disorder28. Signs of physical addiction noted by Marijuana Anonymous participants include insomnia, depression, vivid nightmares, anger/irritability, headaches, and anorexia29. Because of marijuana’s lipid solubility, symptoms may take weeks to develop following abstinence and last up to 3 months. In addition to addiction, there are indeed notable risks for psychosis. The variables contributing to an individual’s vulnerability to schizophrenia are undergoing investigation. However, those who have genetic propensity to schizophrenia show 6-fold higher rates of psychotic breaks with marijuana use, and teen exposure has the greatest risks30-32.
While marijuana has active ingredients with therapeutic potential for the endocannabinoid system, it currently has ill-defined therapeutic ranges, adverse effects, or contra-indications. Consider the impact opiates had in devastating Kentucky communities. In evolving this epidemic, the medical community caved to the soft science presented by special interests on its safety profile and efficacy. Marijuana has the potential for similar problems if distribution circumvents vetted scientific processes and overlooks the harms of unintended consequences. Ultimately, liberalization of marijuana under the guise of medicine conveys a message of safety and endorsement that defies the objective scrutiny engendered in medicine. As practitioners, we must maintain our professional standards for all substances.
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