By: Katharine Cimmino, Editor-in-Chief

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Marijuana, also known as “grass,” “pot,” “joint,” “weed,” “reefer,” “hashish,” and “Mary Jane,” is a very popular illicit drug.¹ According to the National Survey on Drug Use and Health, “In 2012, 5.4 million persons aged 12 or older used marijuana on a daily or almost daily basis in the past 12 months (i.e., on 300 or more days in that period), which was an increase from the 3.1 million daily or almost daily marijuana users in 2006.”² In addition, Colorado and Washington have both legalized recreational marijuana, although currently Colorado is the only state to sell it.³ Although marijuana is an illicit drug, it has been shown to offer many therapeutic benefits. If scientists can determine how to harness the desirable effects and eliminate the harmful addictive ones, then marijuana can be a viable and safe treatment alternative.

U.S. Federal and New York Law

The federal government regulates drugs through the Controlled Substance Act. They classify marijuana as a Schedule I drug, or a drug that is highly addictive and has no medical value. The federal government has the constitutional authority to prohibit marijuana for any and all purposes. This power was affirmed by the Supreme Court case Gonzales v. Raich (2005).  Therefore, even if a citizen resides in a state that allows for the use of marijuana, he or she can still be prosecuted under federal law for growing, selling, or using this drug. However, the Supreme Court ruling and the law still reside in a grey area. Currently, there are statutory mandatory minimum sentences, which say that there is a 5-year minimum jail sentence for growing 100 plants or for possession of 100 kilograms of marijuana. The jail time dramatically increases if someone grows more plants, or if they have prior convictions. In states that allow patients to grow their own plants, citizens are often restricted to growing far below the statutory mandatory minimum amount. The laws and ruling passed by the Supreme Court say nothing about prosecuting patients using medicinal marijuana. Also, the current rulings do not say that any of the state laws are unconstitutional.⁴ Because of this fact, many states are beginning to pass laws allowing for the use of medical marijuana.

Currently, there are 21 states that have passed laws legalizing medical marijuana: Alaska, Arizona, California, Colorado, Connecticut, Delaware, Hawaii, Illinois, Maine, Maryland, Massachusetts, Michigan, Montana, Nevada, New Hampshire, New Jersey, New Mexico, Oregon, Rhode Island, Vermont, Washington, and the District of Colombia.⁵ On January 9^th, 2014, Governor Andrew Cuomo of New York took administrative action that allowed for the medical use of marijuana.^6-8 The Governor is able to pass this by relying on a provision of the Public Health Law, the Antonio G. Olivieri Controlled Substance Therapeutic Research Program, which allows for controlled substances to be used for “cancer patients, glaucoma patients and patients afflicted with other diseases as such diseases are approved by the commissioner.”⁹

In his 2014 State of the State Address, Governor Cuomo talked about the medical marijuana pilot program in which 20 hospitals can provide medical marijuana to patients being treated for serious illnesses. According to the policy, “This program will allow qualified eligible participants to seek relief for their symptoms in a safe and legal manner, while also evaluating the effectiveness and feasibility of a medical marijuana system.”⁷ The plan calls for the State Department of Health to set the standards for using marijuana. The Department would decide which hospitals would be able to dispense the drug, how it could be used, and what procedure needs to be followed to dispense it.⁶ The findings from this program will help to create future policy.⁷

It is important to note that this is an administrative action. There is no actual legislation as of yet to legalize medical or recreational marijuana in New York.⁶ In the past, New York has tried to enact legislation to authorize the sale of medical marijuana, but the state’s Senate has blocked it. However, administrative officials do believe that the marijuana policy in New York would be more restrictive than in other states, such as Colorado and California.⁸ While Governor Cuomo’s action will allow an infrastructure to be set up to use marijuana in hospitals, there is no telling when the drug will be available for patients. Officials still need to select which hospitals can dispense marijuana to allow for regional diversity. Finally, the program states nothing about growing marijuana, which means that New York will have to turn elsewhere for its source.⁶ This begs a bigger issue; if New York receives its medical marijuana from an out-of-state source, it could possibly open itself up to federal intervention.

Pharmacology of Marijuana

Marijuana generally refers to the unpurified plant extracts. The active component, tetrahydrocannabinol (THC), is found in the flowering shoots and leaves of the plant. The effects of THC occur when it binds to a cannabinoid receptor, a G protein-coupled receptor, which causes the release of GABA, an inhibitory neurotransmitter. There are two subtypes of cannabinoid receptors: CB1, found mainly in the brain, and CB2, found in immune cells.^{10 (p.195-196)}

Generally, people either ingest or inhale marijuana. Ingestion results in a slower onset of action, approximately 0.5-1 hour, while inhalation is rapid and occurs in a matter of minutes. The drug is highly lipophilic, which results in a large volume of distribution and long half-life of approximately 7 days.  This property explains why chronic users can test positive after 8 weeks.¹⁰

The psychological effects of THC are due to the high abundance of CB1 receptors in the brain, and the effects include euphoria, increased sensory perception, and relaxation.^{10 (p.196)} Some people may also experience depersonalization, changes in body image, disorientation, panic reactions, and severe paranoia.^{10 (p.197)} THC also decreases memory function^{10 (P. 197) -11 (p.53)} and concentration.¹ Smoking marijuana impairs motor skills, which can make driving dangerous.^{10 (p. 197)}

Other effects may include blood-shot eyes, dry mouth, increased heart rate and blood pressure, bronchodilation, and bronchial irritation or bronchospasm.¹ THC also increases conjunctival injection, which decreases intraocular pressure.^{10 (p.196)} This explains why marijuana is helpful in alleviating symptoms of glaucoma. Long term use of cannabinoids, especially THC, can change the function of immune cells, either by the activation or deactivation of the immune system. It is important to note that this finding was only based on extrapolated studies done on acute exposure in animals, and is likely attributed to the CB2 receptors found on numerous immune cells.^{11 (p.53)}

In addition, chronic long-term use of marijuana can cause people to exhibit withdrawal symptoms and the drug can be addictive.^{10 (p.197)} These people can develop tolerance to the drug and physical dependence.^{11 (p.56)}

Therapeutic Uses of Marijuana

Currently, there is a cannabinoid derivative in clinical use. Dronabinol (Marinol^®), a synthetic form of THC, is FDA approved for the treatment of nausea and vomiting associated with cancer chemotherapy. It is also approved as an appetite stimulant for patients with acquired immunodeficiency syndrome (AIDS). However, the nontherapeutic effects, or unwanted side effects, are still the same as marijuana. Patients still run the risk of experiencing anxiety, delusions, depersonalization, euphoria, and more.¹⁰

According to the Institute of Medicine, conditions where patients used marijuana for relief included: HIV (to control nausea, increase appetite, combat wasting, and relieve GI distress caused by antiretroviral therapy), cancer, chronic pain (including back pain), musculoskeletal diseases (including MS and arthritis), glaucoma, seizures, migraines and cluster headaches, terminal cancer, gastrointestinal disorders, neurological disorders (epilepsy, Tourette’s syndrome, brain trauma), and mood disorders.^{11 (p.22)}

Cannabinoids can be used as analgesics and are often used in patients with chronic pain. A randomized, controlled crossover trial was conducted where 23 adults with post-traumatic or postsurgical neuropathic pain were assigned into four different potency groups. Of these, 21 patients completed the trial and average daily pain scores were measured for the four doses of 0%, 2.5%, 6% and 9.4% THC. The study found that the higher inhalation dose of 9.4% THC helped with the intensity of pain, improved sleep, and was overall well tolerated. However, long-term efficacy and safety could not be measured so further investigation would have to be conducted.¹²

Medical marijuana can also be used to treat multiple sclerosis, specifically the symptom of spasticity. In a placebo-controlled, crossover trial involving adult patients with multiple sclerosis, 37 patients were either given a cigarette which contained cannabis or a control cigarette which contained a placebo. After a washout period of 11 days, participants were crossed over to the opposite group. Both change in spasticity and pain scale was measured in the 30 patients that completed the trial. The trial found that smoking cannabis was superior to placebo in both reducing spasticity and pain; however, the patients who smoked cannabis experienced cognitive impairment.¹³

Migraines are another serious health problem and although there are several treatment options, many patients still suffer from painful and sometimes chronic headaches. Depending on the severity of the migraine, patients can often miss work or school, causing a huge economic loss. Another problem with chronic migraines is rebound headaches, which can be triggered by medication overuse. Although the 5-HT_1D or “triptan” drugs are good abortive drugs for migraines, some patients cannot tolerate the side effects such as chest or throat tightness, tingling, and anxiety. In addition, these drugs have variable oral absorption and if not taken quickly enough, will not prevent a migraine. Therefore, patients often look for alternative therapies for migraine relief.¹⁴ Many different drugs have been used for migraine relief and doctors will often create regimens that are patient specific. A review article examined five case studies of patients who experimented with cannabis to relieve migraines. Three patients with chronic headaches found that smoking cannabis was comparable and even superior to aspirin and ergotamine tartrate therapy.¹⁴ It is important to note that with most of these case studies, patients have exhausted all other measures and found little relief with conventional agents.

Safety and Efficacy Concerns

Although marijuana has been used as an herbal remedy prior to the 20^th century, experts are skeptical of its use as a drug because of safety and efficacy concerns.^{11 (p.19)} According to the report published by the Institute of Medicine in 1999, “…cannabinoid drugs might offer broad-spectrum relief not found in any other single medication.”^{11 (p.R8)} Although the report discusses benefits of this drug, it also cautions against the harmful substances that marijuana smoke can deliver. The report concludes that the answer is not necessarily medical marijuana, but harnessing the effects of the chemical THC to help these patients. Overall, the Institute of Medicine asks that more research be conducted so that the effects of marijuana and THC an be understood, safer and more reliable delivery systems can be found, and that the negative psychological adverse effects be weighed against the medical benefit when using this drug.^{11 (p.1-4)}

Since this report, numerous studies on the use of medical marijuana have been conducted, yet professionals remain skeptical about the risks vs. benefits of the drug. Perhaps the best solution is to not use a current drug available, but to look for other biochemical and biopharmaceutical options. Most of these patients have debilitating chronic conditions, and the last thing we, as professionals, should do is add to the patient’s disease burden by giving drugs with unwanted side effects.

A Hope For A Safer “High”

A study published in Science showed how a natural chemical, pregnenolone, can stop the “high” effect of marijuana. In the study, the French scientific team gave rats and mice enough active ingredients of cocaine, morphine, nicotine, alcohol, and marijuana so that the drugs intoxicated the animals. According to Dr. Pier Vincenzo Piazza, neurobiologist and principle author of the study, “We have this built-in negative feedback mechanism, a brake,” on THC intoxication.¹⁵ The study found that THC increased pregnenolone levels in the brain by 1500%, which was 50 times greater than any other drug used in the study.¹⁵

After this was discovered, the scientists decided to experiment further. They used two groups of rodents, one sober and one under the influence of marijuana. They injected the rodents with stimulators and inhibitors of the CB1 receptor and found that pregnenolone levels rose and fell, respectively, in both groups. Next, scientists injected the intoxicated rodents with an inhibitor of pregnenolone only to discover that they became more inebriated. The sober rodents showed no effect. The scientists therefore discovered that pregnenolone, a substance that was once thought to only be a precursor for other steroid hormones, could actually suppress THC intoxication.¹⁵

At normal levels, when someone smokes cannabis, THC binds to the CB1 receptor and induces intoxication. The study also discovered that when abnormally high levels of cannabis were consumed, much higher than what the average smoker consumes, the body began to produce pregnenolone. Pregnenolone binds to the CB1 receptor, but at a different point of the receptor.¹⁶ Essentially, pregnenolone is an allosteric modulator of the CB1 receptor. This study found that at a cellular level, pregnenolone only partially reverses or prevents the binding of THC.¹⁷

By pregnenolone binding to the receptor, THC binds less effectively and the effects of cannabis intoxication are blocked.¹⁶ High rodents injected with pregnenolone appeared to have decreased memory loss. In addition, pregnenolone also counteracted the increased appetite caused by marijuana. However, this is not beneficial for patients taking the drug hoping to increase their weight (e.g. HIV and cancer patients). Lastly, pregnenolone was also shown to reduce the addictive behavior of rodents taking marijuana.^{15, 17}

While the study did aid in identifying the cellular pathway of pregnenolone and its binding site on CB1 receptors, its clinical role is still unclear. Pregnenolone is orally unstable and only remains in the brain for a short time.¹⁵ It is quickly metabolized into other steroids.¹⁷ Dr. Piazza states, “Pregnenolone cannot be used as a drug by itself.”¹⁵ So instead, other pregnenolone derivatives need to be synthesized that stay attached to the CB1 receptor and are not metabolized to other products. These are the drugs that should be tested in humans and on which more studies must be done.¹⁷

What This All Could Mean

Further research must be conducted, but if a suitable drug can be found to stop the negative effects of a high, medical marijuana can be a safe alternative to patients with many of these chronic and debilitating conditions. Until then, healthcare professionals can give marijuana to those who have no other option while weeding out ones who are just addicted to a high.

SOURCES:

1. Drug abuse. New York Times web site. http://www.nytimes.com/health/guides/specialtopic/drug-abuse/overview.html?inline=nyt-classifier. 2013. Accessed January 10, 2014.
2. Results from the 2012 national survey on drug use and health: summary of national findings. U.S. Department of Health and Human Services. http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresults2012.htm#ch2.13. 2012. Accessed January 10, 2014.
3. Sanchex R, Martinex M. Colorado pot law called springboard for other states. CNN web site. http://edition.cnn.com/2014/01/03/us/marijuana-laws-united-states/index.html. January 7. 2014. Accessed January 10, 2014.
4. Federal marijuana law. Americans For Safe Access web site. http://www.safeaccessnow.org/federal_marijuana_law. 2013. Accessed January 10, 2014.
5. Legal information by state and federal law. Americans For Safe Access web site. http://www.safeaccessnow.org/state_and_federal_law. 2013. Accessed January 10, 2014.
6. Craig S, McKinley J. New York State is set to loosen marijuana laws. New York Times web site. http://www.nytimes.com/2014/01/05/nyregion/new-york-state-is-set-to-loosen-marijuana-laws.html?_r=0. January 4, 2014. Accessed January 10, 2014.
7. Cuomo A. Governor Cuomo outlines agenda for 2014. Governor’ Press Office web site. http://www.governor.ny.gov/press/01082014-agenda-outline-for-2014. January 8, 2014. Accessed January 10, 2014.
8. The Associated Press. NY set to allow limited use of medical marijuana. NPR web site. http://www.npr.org/templates/story/story.php?storyId=259767549. January 4, 2014. Accessed January 10, 2014.
9. 3397-C – Antonio G. Olivieri controlled substances therapeutic research program established; participation. Laws.com web site. http://statutes.laws.com/new-york/pbh/article-33-a/3397-c. 2013. Accessed January 10, 2014.
10. Barile FA. Clinical Toxicology, Principles and Mechanisms. 2^nd Ed. Taylor & Francis US; 2010.
11. Medicine IO. Marijuana and medicine, assessing the science base. National Academies Press; 1999. http://www.nap.edu/openbook.php?record_id=6376. Accessed January 10, 2014.
12. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694-701. http://www.ncbi.nlm.nih.gov/pubmed/20805210. Accessed January 10, 2014.
13. Corey-bloom J, Wolfson T, Gamst A, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ. 2012;184(10):1143-50. http://www.ncbi.nlm.nih.gov/pubmed/22586334. Accessed January 10, 2014.
14. Russo, E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. http://www.maps.org/mmj/russo_98_migraine_pain.pdf. January 26, 1998; 76 (3-8). Accessed January 10, 2014.
15. Mohan G. Natural brain chemical could harsh the high of marijuana. Los Angeles Times web site. http://www.latimes.com/science/sciencenow/la-sci-sn-brain-chemical-marijuana-20131231,0,1308382.story#axzz2pZvMBqbn. January 2, 2014. Accessed January 10, 2014.
16. Piazza V. Pregnenolone can protect the brain from cannibus intoxication [Video]. Youtube. http://www.youtube.com/watch?v=kF_Wi73gbQM&list=UUlJjbr5Jwnbdh6-sQ8euKRg&feature=c4-overview. January 7, 2014. Accessed January 10, 2014.
17. Piazza V. Pregnenolone can protect the brain from cannibus intoxication [Video]. Youtube. http://www.youtube.com/watch?v=DGwu1wSp9jY&list=UUlJjbr5Jwnbdh6-sQ8euKRg. January 7, 2014. Accessed January 10, 2014.

Published by Rho Chi Post