What’s the Buzz?

Good morning. My name is Barbara Phillips. Today, I’d like to give a cannabis update, an update on the use of medical marijuana.

There are many different types of marijuana plants. The two that are most used for medical uses are Cannabis sativa and Cannabis indica. It’s an extremely complex plant with over 500 chemicals. Over 80 of them are cannabinoids. These are the chemicals that will work in the brain. The most common one is tetrahydrocannabinol, and there are 11 types of this. These are found in no other types of plants. They’re considered phytocannabinoids. These work in the central nervous system because there is an intrinsic endocannabinoid system. It is involved with the most abundant G-coupled receptors in the brain.

There are two receptors that are involved with cannabis use: the CB1 receptor which is in the hippocampus association cortices, basal ganglia, cerebellum, dorsal root ganglion and peripheral nerves. The CB2 receptors are in other parts of the body: lymphatic tissue, hematopoietic and immune cells, pancreas, intestine and retinae. There is a low concentration in the CNS.

There is an intrinsic endocannabinoid system in the brain. These involved are the most abundant G coupled receptors in the brain. G proteins are attached to receptors and they modify their firing and, therefore, affect the effect in the brain. The two main ones are CB1 receptors in the hippocampus association cortices, basal ganglia, cerebellum, dorsal root ganglion and the peripheral nerves. CB2 receptors are in other parts of the body predominantly: lymphatic tissue, hematopoietic and immune cells, pancreas, intestine and retinae. There are low concentrations in the CNS.

The brain makes endogenous cannabinoids including anandamide and 2-Arachidonoylglycerol. The metabolism in the brain indicates that they are neuromodulators. They are rapidly synthesized and then rapidly degraded. They are synthesized by neurons after depolarization and increase in intracellular calcium. It is released into the cleft and travels retrograde, binding at the CB1 receptor in the presynaptic neuron. The effect is inhibitory. It inhibits neurotransmitter release opening potassium channels and closing calcium channels. It also inhibits adenylyl cyclase and stimulates the kinase enzymes.

The history of cannabis in western medicine dates back to the 1800s. It has been documented to be used long before that, at least 5,000 years ago. In the late 1800s, a famous paper by Drs. Reynolds and Gower documented a patient who was controlled on bromides which was the major anticonvulsant at the time. He recurred when he stopped taking his bromides. Eventually, with his noncompliance, he stopped responding, even when bromides were reintroduced. The seizures were controlled again with the addition of cannabis oil, which they had been using as an adjunct to bromides in seizure treatments. Unfortunately, he remained noncompliant and was poorly controlled and eventually lost to followup.

In the last one hundred years, the use has been documented in glaucoma, nausea, vomiting, cachexia related to HIV, insomnia, tremors, multiple sclerosis-related spasms, cancer and multiple sclerosis pain as well as HIV-associated painful sensory neuropathy.

The volume of research has exploded in the last twenty years, especially as it’s been used and noted to be effective in the treatment of certain types of seizures. As it’s been more widely used, side effects have been documented, including low testosterone and erectile dysfunction in men. There have been concerns about promoting heart disease and cancer; although that has not been proven to this point. There has also been a recent paper regarding a presentation of increasing numbers of patients to emergency rooms with acute gastrointestinal pain related to marijuana use.

The main chemical is delta-9-tetrahydracannabinol. In the brain, this is a partial agonist at both the CB1 and CB2 receptors. It is only one of three chemicals that work via this intrinsic endocannabinoid system. The other two are cannabinol and THCV, tetrahydrocannabivarin. THC is the principle psychoactive component responsible for the feelings of being high when taking marijuana. With respect to seizures, it has a mixed result. Most people feel that their seizures have been reduced when using this chemical. Others experience a worsening of seizures.

The second most prevalent chemical is cannabidiol. It is the major nonpsychoactive chemical in marijuana. It has a low affinity for CB1 and CB2 receptors in the brain. It is an indirect antagonist of CB receptors and decreases the effect of CB1 activation. It’s a partial agonist of serotonin receptors. It allosterically modifies some opioid receptors. It consistently has anticonvulsant effects when tested.

In looking at preclinical evidence studies involving animal species, THC showed an overall improvement in seizures in 61 percent; whereas 10 percent of the subjects experienced increased seizures. Cannabidiol had twenty-one studies with two species, and 81 percent showed an anticonvulsant effect with no proconvulsive results. Specifically with CB1 receptor agonists, there were fifty-five studies with two species; 73 percent were anticonvulsant and 2 percent were proconvulsant. CB1 receptor antagonist studies involved only five studies with two species; 9 percent were anticonvulsant and 30 percent were proconvulsive. However, that was a small number of studies.

In humans, the studies are limited and mainly anecdotal and retrospective. The products used are varied. There are varied benefits and side effects noted in these studies. It was found that the results tended to be expectation-dependent. That is, if people expected that they would get better, they were more likely to, or if they expended more effort in trying to get the medication, they were more likely to feel that it was effective rather than not effective. I’ll conclude with the statement that more work needs to be done.

A study done in Colorado, “Parental Reporting of Response to Oral Cannabis Extracts for the Treatment of Refractory Epilepsy” in Epilepsy and Behavior in 2015, documented 75 children given oral cannabinoids; this was cannabinoid oil. Fifty-seven percent showed improved control and 33 percent was the responder rate. The responder rate indicates the percentage of patients that get at least a 50 percent improvement in seizures. Only two patients were seizure-free. It was found that if the family moved to Colorado for treatment, the responder rate was 47 percent versus 27 percent for those who were already residents of Colorado.

The responder rate also varied based on the syndrome being studied. Lennox-Gastaut Syndrome patients experienced an 89 percent responder rate. Patients with Dravet Syndrome experienced a 23 percent responder rate, but no patients with Doose Syndrome experienced improvement at that level. Eight responders had EEGs but none of them showed improvement in the baseline EEG. The parents reported a third of the patients improving with respect to behavior and alertness. Eleven percent were reported to improve in their ability to use language, and 11 percent were reported to improve in their motor skills. Eleven of the patients, 15 percent, were discontinued due to lack of efficacy. Adverse events were fairly common at 44 percent. Thirteen percent of the patients had worsened seizures or developed a new seizure type. Twelve percent reported fatigue. Eleven percent had GI side effects. Rarely, there were reported developmental regression, a new type of movement disorder, transient hemiparesis or focal weakness, cholecystitis, opisthotonus and status epilepticus with one death. The perceived benefit, again, was higher in those who had moved to Colorado independent of the result.

Devinsky et. al. in 2015, published a study in Lancet regarding cannabidiol in patients with treatment-resistant epilepsy. This was an open label trial with eleven U.S. centers. It was conducted from January 2014 through January 2015. The majority of the patients had Lennox-Gastaut and Dravet syndrome. There were a few other intractable syndromes. This involved 214 patients, ages ranging from 1 to 30. There were two overlapping groups. They utilized purified cannabidiol oil. Median monthly decrease in seizures was reported to be 36.5 percent. Adverse events included 79 percent in the safety group. Twenty-five percent reported somnolence. Nineteen percent had a decreased appetite. Nineteen percent had diarrhea, 15 percent fatigue and five patients, 3 percent, were discontinued. Serious adverse events occurred in 6 percent of the patients. One patient died related to sudden, unexpected death in epilepsy. Upon evaluation, this was deemed to be unrelated to the treatment.

An Israeli study was reported in Seizure in 2016, “Cannabidiol-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.” There were 74 patients aged 1 to 18. They had all failed more than seven anticonvulsants and 49 had also failed the ketogenic diet or vagal nerve stimulation. Eighty-nine percent reported a decrease in seizures, but 7 percent reported an increase in seizures. There have been interactions reported between cannabidiol and some anticonvulsants.

In 2015, Jeffrey et. al. published in Epilepsia, a study of a small number of patients. Thirteen patients were studied who were on both clobazam and cannabidiol. Clobazam is also called Onfi. There was an average increase in clobazam levels of 500 percent, resulting in side effects. Ten of thirteen patients had to reduce or stop the clobazam due to side effects because of this interaction.

There are two commercial preparations available in this country. Marinol, which is dronabinol, and Cesamet which is nabilone. They are approved for chemo-related nausea and vomiting and age-related anorexia and wasting. Other preparations include nabiximols, called Sativex, which is approved in Canada. It is an aerosolized oral mist which has a 1:1 ratio of cannabidiol and THC. This is approved for multiple sclerosis and cancer-related pain. Epidiolex is currently undergoing trials for refractory epilepsy. It is a purified oil of cannabidiol plant extract and contains no THC. It was recently given orphan drug status by the FDA. Synthetic cannabinoids have been available and include brands such as K2 and Spice. They are a thousand times more binding to CBRs than phytocannabinoids. Side effects have included dizziness and altered mental status, but severe side effects have also been reported including strokes and seizures.

Recently, Rimonabant, which is a CB1 receptor blocker, was being developed as a diet drug. The study was stopped due to complications including depression, anxiety, insomnia, anorexia, suicide and homicide. Another experimental preparation, BIA-10-2474, inhibits an enzyme required to break down the endocannabinoids, thereby increasing the length of their effect. It was being developed as a long acting pain reliever. It was stopped due to complications including six subjects becoming severely ill and one becoming brain dead.

In summary, evidence is promising for medical use of marijuana and its chemicals. This is especially true in epilepsy where certain types of seizures have responded well to its use. Pros as well as cons have been documented. More work needs to be done.

Thank you for joining me for this update in the use of medical marijuana.