Marijuana was listed as a Schedule 1 drug in 1970. At the time it was considered to have no medicinal purpose; as the discovery of the first cannabinoid receptor wouldn’t occur until the 1980’s. Due to governmental suppression of illicit marijuana use, research into its medicinal use was discontinued.  Recent debates over legalizing marijuana coupled with new understanding of the cannabinoid receptor system in the human body has renewed investigation into the development of pharmaceutical therapeutic alternatives. The alternatives include receptor-based drugs, inhibitors of enzymes that break down endogenous cannabinoids, and synthetic compounds that can modulate how cannabinoids bind to their receptors. Ideally, alternatives should have improved efficacy, potency, duration of action, safety, and the beneficial properties of marijuana, but without the harmful side effects.

However, In January of this year a man died as a result of participating in a clinical trial in Rennes, France. He was part of a Phase I drug trail investigating the safety, adversity, and therapeutic dose range, of a potential new drug, BIA 10-2474. The drug acts on the same receptors as marijuana and was supposed to relieve nerve pain. Although early test in animals proved safe, some very unexpected and severe side effects became apparent when tested in humans.

Six healthy men in total were subjected to the highest dosage in the trial, and whereas 128 other healthy men and women had no major complications, these several were hospitalized for neurological damage. Of the 6, Guillaume Molinet was the only one pronounced brain-dead after experiencing blurry vision, headaches, and suffering a stroke like incident. The other 5 may suffer some irreversible or long-lasting damage.

History of Marijuana/Cannabis

Marijuana has been grown for centuries, and used in the production of hemp fiber for making paper, rope, and canvas. Hempseed are also derived from the same plant, and hemp oil is used to make paint and soaps. It has also been cultivated for use medicinally and recreationally.

Marijuana comes from the leaves, stem, and seeds of the Indian hemp plant, Cannabis Sativa. It is indigenous to India and certain parts of Asia, but has been cultivated in various other parts of the world. As such, it is known by a multitude of names: weed, pot, sinsemilla, hemp, and hashish. It grows best in tropical regions, but also thrives in temperate climates; though the potency of the herb decreases when grown in temperate climates making tropical cultivars more desirable.

Medicinal Marijuana

Phytocannabinoids and Synthetic Cannabinoids. Marijuana contains a variety of chemicals known as phytocannabinoids. Over 60 of these structurally diverse compounds have been identified, and not all of them are psychoactive. Most notable however, are delta-9-trans-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD).The most  active of these are THC.

The drug is obtained from the flowering part of the plant which yields up to 20% of the active compound. THC acts on two cannabinoid receptors in the brain known as CB1 and CB2, where they elicit psychoactive, analgesic, and antiemetic effects. For this reason, THC  has been used to alleviate the nausea and vomiting associated with cancer chemotherapy treatment. Marijuana is also known to increase ones appetite; cannabinoids are therefore used in the management of AIDS related anorexia.

Dronabinol (Marinol), Nabilone (Cesamet), and Levonamtradol are cannabinoids approved for clinical therapeutic use. When used therapeutically, these drugs are administered in pill form, as oral administration offers the greatest absorption into the body. When ingested as much as 90% of the drug is absorbed, whereas only up to 10% is absorbed via inhalation – inhalation does offer the fastest rate of absorption – but much of the drug is lost to pyrolysis (burning in cigarette form).

Additonally, Medicinal marijuana is used as an anticonvulsant in the treatment of epilepsy, as an anti-inflammatory agent in the treatment of glaucoma (it relieves pressure build-up in the eye), and in managing pain and spasticity associated with multiple sclerosis.

 

When smoked THC is absorbed through the lungs into the bloodstream, rapidly entering the brain. Present in the brain, blood vessels and heart are the THC receptor CB1 and CB2. Receptor CB1 is primarily found in the central nervous system but is also present in the lungs, kidneys, and liver. Also expressed in the brain, CB2 receptors are mostly present in the immune system; on red and white blood cells. This accounts for why the main target organs for toxicity by Marijuana are the brain and the heart.

THC and other cannaboids are highly lipid soluble, meaning they accumulate in fat. Being sequestered in fatty tissue, they stay in the body for a long time, continuing to be released slowly back into the bloodstream. And because they are excreted mainly into the gut, they are again reabsorbed, taking up to a month to be completely eliminated. So, attempts to flush the drug from ones system, by taking diuretics are not effective.

Adverse Effects

Unfortunately medicinal phytocannabinoids and synthetic cannabinoids have the same psychotropic effects as marijuana. Though many, few cannabinoids have been approved for therapeutic use. Some synthetic cannabinoid-like chemicals (chemo-types) were  effective, but that they unintentionally resulted in new drugs of illicit use, such as “spice”. This unfortunately led to  some of these compounds being banned and loosing favor amongst researchers as potential therapeutic agents.

CNS. Marijuana impairs ones motor-sensory coordination, sense of time, causes short-term memory loss, and impairs learning. Regular users experience alterations to their mood that result in laziness and lack of motivation. . High doses can cause hallucinations and delusions. It has also been associated with increased risk of schizophrenic episodes.

Cardiovascular. Smoking marijuana can severely affect the cardiovascular system. It causes urinary retention which can affect blood pressure, and increased heart rate, and cause angina. Risk of heart attack is significantly increased in the moment’s right after smoking.

Fertility. Chronic marijuana use can impair fertility by decreasing both male (testosterone) and female hormones (follicle-stimulating hormone/luteinizing hormones. Additionally abnormalities in appearance, motility, viability, and production of sperm are seen.

Pulmonary. As with cigarettes, marijuana contains the same hazardous compounds and carries the same ill effects. Acutely, smoking marijuana irritates the bronchial tract causing cough, wheezing, and phlegm. Chronic users experience bronchitis, emphysema, and may even develop mouth, throat, and nasal cancer. Lung function decreases with continued use.

Endogenous Cannabinoids – Fatty Acid Amides. As it turns out, humans  naturally produce cannabinoids. Although chemically different from cannabis, Anandamide and 2-arachidonyl glycerol are endogenous compounds that bind to the same receptors as phytocannabinoids. They are derivatives of arachidonic acid known as fatty acid amides. These enodcannabinoids are produced by the body on demand for the relief of inflammation and pain, but have a limited timeframe of action. The discovery and synthesis of these compounds in the lab have renewed investigation of cannabinoids, cannabinoid-like compounds, and molecules that act on the endocannabinoid system, for their medicinal use.

FAAH Inhibitors

Fatty acid amides have the same beneficial effects as marijuana and synthetic cannabinoids, but do not possess the same psychotropic response. Since they have a short duration of action, increasing their supply by decreasing their catabolism would make them effective “in-house” therapeutic targets for CB1/CB2 receptors. Enhancing the levels of fatty acid amides in the CNS requires blocking the enzyme responsible for their degradation; fatty acid amide hydrolase (FAAH). This is where fatty-acid amide hydrolase inhibitors come into play. FAAH inhibitors are potentially safe and effective small molecules that elevate brain levels of endocannabinoids.

The experimental drug that caused the death of Guillaume Molinet was a FAAH inhibitor. The drug trial was started in July of 2015, and was conducted by a French company named Biotrial, for the Portuguese pharmaceutical, Bial. The company is said to have conducted its trial according to regulations, and  the outcome of the study was unexpected. Sadly in this case, investigators gave an unnecessary high dose of a drug that was not very effective at blocking pain in the first place, and it resulted in a  toxic response. As it turns out the drug was safe at lower doses, and none of the patients in the other treatment groups experienced any adverse outcomes. Essentially, at very high doses  a toxic build-up  occurs, leading to neurological damage.

All FAAH inhibitors are not alike, and their efficacy and safety vary. Many FAAH inhibitors and synthetic cannabinoids have been investigated for use as new drugs in the management of pain and inflammation associated with such diseases as: Epilepsy, Diabetes, Atopic Dermatitis, Alzheimer’s disease, and Multiple Sclerosis. Some promising compounds have even advanced to phase II clinical trials.