Medical Cannabis - Review of Risks and Benefits

MEDICAL CANNABIS - REVIEW OF RISKS AND BENEFITS

INTRODUCTION

Medical cannabis, or medical marijuana, refers to the use of the cannabis plant and its constituents (cannabinoids, terpenes, flavonoids) to treat disease or improve symptoms. Cannabis was used for its medicinal qualities by most of ancient civilizations, with first documented use in Ancient China dating back to 2737 BC. As a mainstay of the American Pharmacopeia, cannabis extract was used to relieve symptoms of over 100 medical conditions from 1851 until 1941. In the next 55 years, it was banned due to political reasons, against the advice of the American Medical Association. Cannabis returned to its due place of being a medicine in the United States in 1996, when the Californian law allowed the use of cannabis by patients. At present, 41 states have reenacted their medical cannabis laws, along with many other countries in the world.

The first active constituents of cannabis, cannabinoids THC and CBD, were discovered in the early 1960s. Further research led to an even more important discovery of the Endocannabinoid System in the early 1990s. This system includes internally produced cannabinoids and their receptors, which are present in almost every organ and tissue of the human body. Over 22,000 studies performed to date helped to reveal numerous important physiological roles of the endocannabinoids, which control not only how the human body operates under normal conditions but also in the disease.

This also helped us understand why cannabis has so many medicinal qualities. It works through interaction of the phytocannabinoids (plant cannabinoids) with our own endocannabinoid system, by acting through its receptors, by helping to restore the normal function of the cells and systems, and most importantly by helping to maintain homeostasis - the inner balance of the human body and mind.

THC (Tetrahydrocannabinol) THC is the most studied cannabinoid. It works by interacting with the endocannabinoid system’s CB1 (cannabinoid-1) and CB2 receptors. It provides many of the medicinal properties of cannabis (see table below). THC Effect analgesic reduces pain neuropathic pain (resistant to regular analgesics) reduces pain originating from damaged nerves antiemetic reduces nausea and vomiting orexigenic stimulates appetite muscle relaxant and anti-spasmotic helps to relieve muscle spasms and spasticity bronchodilation helps to open narrowed airways and breathe better anti-pruritic helps to relieve itching anti-cholestatic helps to relieve bile retention anti-proliferative inhibits cancer cell growth anti-inflammatory has considerable anti-inflammatory effect antioxidant protects cells from oxidative damage antiepileptic relieves or reduces seizures neuroprotective slows nerve cell degeneration, promotes new cell growth glaucoma lowers intraocular pressure and protects retinal neurons peptic ulcers helps to heal peptic ulcers multiple sclerosis protects neurons and improves symptoms Alzheimer’s disease protects neurons and improves symptoms

THC is also responsible for most of psychoactive effects of cannabis, including euphoria, transient changes in short-term memory, sense of space and time, heightened sensory perception (five senses). Finding an individual dose of THC which produces therapeutic benefits without affecting activities of daily living is the goal for most of patients. It is recommended not to use high-THC strains, especially in the beginning of the treatment.

CBD (Cannabidiol) CBD produces the majority of therapeutic effects of cannabis. It has numerous mechanisms of action in the body that do not involve CB1 and CB2 receptors, though it has been shown to modify the effects of other substances at these receptors, including its close relative THC.

CBD Effect analgesic reduces pain levels antiepileptic relieves or reduces seizures antiemetic reduces nausea and vomiting anti-inflammatory has considerable anti-inflammatory effect antibiotic treats bacterial infection, effective against MRSA antifungal treats fungal infection anti-proliferative inhibits cancer cell growth anxiolytic relieves anxiety antidepressant relieves symptoms of depression antipsychotic treats psychosis/hallucinations anti-addiction treats addiction antispasmotic reduces spasms, including bowel contractions vasorelaxant reduces vascular tension/blood pressure anti-psoriatic treats psoriasis anti-diabetic reduces blood sugar levels anti-ischemic reduces risk of artery blockage bone stimulant promotes bone growth immunosuppressant helps to treat autoimmune conditions neuroprotective slows nervous system degeneration (e.g., Multiple Sclerosis, ALS, Parkinson’s disease, Spinal Cord Injury) glaucoma protects retinal neurons antioxidant protects cells from oxidative damage increases levels of Anandamide main endocannabinoid with THC-like properties balances effects of THC lowers psychoactive effects of THC*

*CBD is considered a “non-psychoactive” cannabinoid, although it can alter one’s consciousness to some extent. Combining CBD and THC decreases the psychoactivity and other side effects of THC, while enhancing some of THC’s benefits. At the ratio of CBD and THC as 1:1, the psychoactive effects of THC start to diminish. At the ratio of 2:1 or more with CBD predominance, psychoactive effects of THC are minimal to none.

ROUTES OF ADMINISTRATION

INHALATION (vaporizer) Pros Cons 1.The most rapid onset of action (0.5-2min), may 1. The shortest duration of effects (1-3 hours) provide quick relief for breakthrough symptoms 2.Easy to titrate the dose needed for relief of symptoms 2. Less economically friendly - 85% of each dose is (another puff may be taken in 10 min if needed) lost with exhalation 3. Requires equipment (e.g., vaporizer or vape-pen) 4. May irritate the airways, induce cough or mucus

Vaporization - is a lower temperature process (180-195 C), compared to smoking (600 C), and produces a smaller amount of toxic by-products, while the subjective effects and blood concentrations of cannabinoids are similar to those obtained by smoking cannabis. Heating the plant to 180 C makes cannabinoids activated and volatile. Unlike burned material with smoking, vaporized cannabis may be effective with repeated use.

Note: Smoking cannabis is not a recommended route of administration, and especially should be avoided in patients with cardiovascular and pulmonary disease. Although it was not shown to increase the risk of lung cancer, cannabis smoke is known to contain up to 3 times the amount of carcinogens of the tobacco smoke (tobacco smoke is known to increase the risk of lung cancer by up to 55 times).

TINCTURE (also known as extract or drops)

Pros Cons 1. Faster onset of action (10-45 min) than oral route 1. Longer onset of action than inhalation 2. Longer duration of effects (2-6 hrs) than inhalation 3. Does not require additional equipment 4. 4x times more economically friendly than inhalation 5. Easy to titrate the dose (amount of drops needed) 6. Does not have smell, easy to carry and use discreetly

Note: For a quicker onset of action, it is best to put the drops under the tongue and keep them in the mouth for 1-2 minutes before swallowing. This helps to facilitate absorption through capillaries directly into the bloodstream. Alcohol-based tincture may cause irritation of the oral mucosa. Diluting it in 1-2 oz of water can prevent irritation. Oil-based extract does not cause irritation and can be applied directly into the mouth. Note: Please remember, Extracts are not the same as Concentrates (hash, keef, dabs, shatter, RSO), which contain high concentration of cannabinoids and are not recommended for inexperienced users. ORAL (capsules, edibles)

Pros Cons 1. Longest duration of effects (4-8 hrs), may be 1. Longest onset of action (30min-2hrs). To avoid especially helpful for chronic, constant symptoms overdosing, wait for 2 hours before taking more 2. Absorption is more erratic, some patients do not reach peak concentration for as long as 6 hours, some may have more than one peak of concentration 3. Oral cannabis may be more psychoactive than inhaled (due to x3 higher levels of 11-hydroxy-THC which is one of the initial metabolites of THC in the liver known to be more psychoactive than THC)

Note: Because absorption rate is less with oral intake than with inhalation, equivalent dose is 2.5 times higher for oral intake. For example, 1 mg of inhaled THC is equal to 2.5 mg of oral THC.

TOPICAL (salves, lotions, creams, oils)

Pros Cons 1. May be helpful for localized areas of pain, 1. Limited amount of research data on this route of inflammation, itching, or skin cancer administration 2. Unless used in significant quantities, systemic absorption and effects are minimal to none

RAW CANNABIS (juicing, unheated edibles)

Raw cannabis mostly contains cannabinoids in their acid form - THCA, CBDA, etc. With heating, the acid form of each cannabinoid is converted to alcohol form - THC, CBD (more active form). THCA does not produce psychoactive effects of THC. Both THCA and CBDA were shown to have anti-inflammatory, anti-nausea, and anti- seizure properties (they can be effective against resistant seizures even when THC and CBD are not effective).

DOSING Start Low - Go Slow approach is recommended in all patients, and the correct dose is the lowest dose that produces a therapeutic benefit. It is important to understand that cannabis is not a standardized medicine with a single isolated molecule but rather a medicinal plant with various constituents (over 800 are known to date). It is best to start with very small doses of cannabis, i.e. not more than 1-2 mg of total cannabinoids per dose. Then gradually increase the dose, if needed, by 1 puff of vapor or 1-2 drops of tincture at a time. Write down both wanted and unwanted effects for each dose (and each strain) and try to grade these effects on a scale from 1 to 10. Observe your response after each new dose and try to find the minimal dose that has the most beneficial effects on you. This strategy helps you find the right dose, the right strain, and minimize side effects, which are also dose-dependent.

Less Cannabis Is More - is another very important principle to remember. For the majority of patients, smaller doses of cannabis have the best effect on relieving their symptoms. Although there are no official guidelines created to date for exact dosing range and dose per condition, it is important to know that many of the effects of cannabis are biphasic and dose-dependent. Low to medium doses may show improvement in symptom control, whereas higher doses may worsen the same symptom. This was demonstrated in multiple patient studies, including studies of pain, glaucoma, anxiety, and depression.

INTERACTIONS WITH MEDICATIONS/HERBS/FOODS

Cannabis can interact with many medications and herbs (over 400 known to date) most of which require monitoring while using cannabis - only five medications do not. Some medications may increase or decrease concentration and effects of cannabis. Cannabis in its turn may increase or decrease concentration and effects of other medications. Grapefruit and chocolate (especially dark chocolate) may increase concentration and effects of cannabis (especially THC). Bitter orange and caffeine may potentiate transient elevation of heart rate induced by cannabis, which is most noticeable with inhaled THC.

TOLERANCE/DEPENDENCE/OVERDOSE

Tolerance - is a person's diminished response to a medicine over time. Although tolerance to cannabis is not common, it can develop just after a few doses, and disappears rapidly after stopping it. Two clinical studies with the spray of cannabis extract (Sativex) failed to show dose escalation within the combined 3 years of treatment. Monitoring of dispensed doses among 5,540 registered cannabis patients in Holland over 8 years showed no signs of tolerance or dose escalation.

Dependence - is an appearance of physical or mental symptoms of withdrawal if medicine is stopped abruptly. Risk of dependence to cannabis is low (9% of users) and is similar to caffeine (9%). In comparison, dependence rate of alcohol is 15%, nicotine - 32%. Mostly described by chronic, heavy users of cannabis, withdrawal symptoms may appear in 1-2 days after stopping it and usually resolve within a few days. Symptoms resemble caffeine withdrawal and may include headache, irritability, restlessness, sleep difficulties, decreased appetite.

Overdose - is an appearance of unwanted side effects when too much of a medicine is consumed at once. Most of ER visits related to cannabis overdose were seen in inexperienced users after intake of large quantities of edible products without waiting for 2 hours. Symptoms of overdose may include nausea, vomiting, numbness, irregular heartbeat, drowsiness, hacking cough, anxiety/panic attack, and in rare cases psychosis/hallucinations. It is important to understand that cannabis is non-toxic and non-lethal. Even though taking too much of cannabis at once may produce unpleasant symptoms, these symptoms are transient and usually disappear within hours. Trying to relax, drinking plenty of water, consuming lemon zest, chamomile tea, or using other relaxing techniques is usually all that is needed. If symptoms are intolerable, a patient must be transported to the nearest ER for evaluation and supportive treatment. There are no documented fatalities exclusively attributable to cannabis overdose in almost 5,000 year-history of its use. CB1 receptors are now known to be the most prevalent receptors in the brain. They are 10 times more prevalent than opioid receptors, but unlike the latter,

Copyright ©2016 REN Health, LLC. All Rights Reserved. Page 4 of 6 cannabinoid receptors are not present in the medulla oblongata - the part of the brain that controls vital functions including breathing and circulation. Presently, every 19 minutes someone dies from a medication overdose in the United States. A recent study (2016) showed that in 17 studied medical cannabis states, the number of prescription doses decreased by almost 5,000 per doctor per year (40% of them were analgesics).

OTHER CONSIDERATIONS

Driving and performance of hazardous tasks - Patients must not drive or operate heavy machinery or involve in any activity that may put others or oneself at risk while under the influence of cannabis. Impairment of mental alertness and physical coordination resulting from the use of cannabis may decrease ability to perform such tasks. By law, anyone who drives while impaired can be arrested and prosecuted.

Alcohol - Using cannabis together with alcohol is not recommended. Side effects of both cannabis and alcohol can become more pronounced.

Patients with severe cardiovascular disease should not use cannabis. One of the most common effects of cannabis is the transient increase of heart rate (especially with inhaled THC-rich strains). Similarly to the effect of caffeinated products, this may put predisposed individuals to an increased risk of a heart attack or stroke. Both increase or decrease of heart rate and/or blood pressure were described with cannabis use.

Cannabis should be used with caution in patients with severe kidney or liver disease. The products of cannabis metabolism are removed from the body mostly by liver (2/3) and kidney (1/3). Stimulation of CB1 receptor by THC was shown to have pro-cirrhotic effects, whereas CBD shows anti-cirrhotic (liver protective) effects.

Cannabis should not be used in patients with schizophrenia. Although incidence of psychosis/hallucinations due to cannabis use is relatively rare (1 : 2,800 in heavy users and 1 : 10,000 in light users), cannabis may exacerbate schizophrenia in diagnosed patients, or uncover it in predisposed individuals. Cannabis should be used with caution in patients with a family history of schizophrenia.

Other psychiatric ailments (including Anxiety, Depression, Bipolar disorder). Cannabis may be quite helpful in controlling anxiety and depressive symptoms, especially when these symptoms are triggered by other medical conditions. However, it should be used with caution by patients with diagnosed anxiety, depression, or bipolar disorder as response may vary among different individuals, different doses, and different strains of cannabis.

Cannabis is not recommended for women who are pregnant, planning pregnancy, or breastfeeding. Cannabinoids pass through the placenta and were shown to slow the fetal growth. Cannabinoids accumulate in the breast milk and were associated with a decrease in infant motor development. Mothers who use cannabis out of medical necessity should avoid breastfeeding.

Sexual function and fertility - Cannabis can affect sexual function, often helping relieve stress, focus on the present moment, enhance erection, intensify five senses, and increase the enjoyment of sexual activity. The effects of cannabis on sexual function and behavior appear to be dose-dependent. For both women and men, intake at low to moderate doses may facilitate sexual desire and activity. At higher doses or with more frequent or chronic use cannabis may decrease libido in both genders, as well as erectile function in men. A few days or weeks after stopping regular use, erectile function returns to normal. Animal and human studies also point to differences amongst genders, with females more consistently stimulated by cannabinoids, and males sometimes stimulated and sometimes inhibited. Cannabis can dry vaginal secretions so cannabis users may benefit from added lubrication. Cannabis use may decrease fertility in both genders, especially in people with decreased fertility at baseline. Couples pursuing fertility treatment are advised to avoid cannabis use for at least six months before starting the treatment.

Cannabinoid Hyperemesis Syndrome - is a condition observed with chronic, daily use, however, it was also described with acute use of large doses. It is characterized by episodes of severe nausea and vomiting accompanied by abdominal pain. Hot water bathing or showering typically relieve the symptoms. Treatment includes anti-nausea medications, rehydration, and cessation of cannabis use.

Amotivational Syndrome - some investigators described this condition in heavy, chronic users of cannabis who may exhibit apathy, lack of motivation, social withdrawal, narrowing of interests, lethargy, impaired memory/concentration/occupational achievement, disturbed judgement. Two studies described that stopping cannabis use results in resolution of symptoms.

Cancer - Cannabis was shown to have both cancer-preventing and cancer-fighting properties through five different mechanisms. Multiple studies demonstrated that both THC and CBD are able to kill cancer cells in vitro. On the other hand, increased testicular tumor risk was linked to cannabis use, especially in patients with first use during adolescence: 2.8-fold (age <18 years at onset of use), compared to 1.3-fold increase (age >/= 18 years at onset of use). Even though it is one of the least aggressive types of cancer (5-year survival rate is 95-99%), testicular cancer is the most common type of cancer in young men aged 20-39. Does cannabis cause weight gain? - Despite of well-known appetite stimulating effect of cannabis and beneficial effects on body weight in clinical disorders, a number of studies have failed to find an association between overweight/obesity and consumption of cannabis in the general population. In fact, the prevalence of obesity is significantly lower (30%) in cannabis users than in non-users, and the proportion of obese individuals decreases with frequency of cannabis use, according to three large (> 50,000 people) U.S. epidemiological studies.

SIDE EFFECTS

The profile of side effects of cannabis is generally safe and is favorable in comparison to almost any prescription medication available, including prescriptions of synthetic THC (Dronabinol and Nabilone). Based on the systematic review of many clinical studies with different forms of cannabis, the most common side effects encountered by patients are:

Dizziness, dry mouth, headache, euphoria ("high"), nausea, decreased concentration/attention, fatigue, anxiety, confusion, sedation/somnolence, heightened sensory perception, decreased short-term memory, fragmentation of thoughts, distortion of space and time sense, disorientation, lightheadedness, redness of eyes, increased appetite, palpitations/increased heart rate, imbalanced gait, suspiciousness, throat irritation, eye irritation, blurred vision, altered taste, vomiting, low blood pressure, feeling intoxicated, strange thoughts/abnormal thinking, impaired judgement.

Disclaimer: The data provided in this brochure is primarily based on the review of over 1000 pre-clinical (animal model of the disease) and clinical studies (patients and healthy volunteers). Additional risks and benefits of cannabis are possible. Most of the cannabis studies conducted to date had certain limitations and the information provided above should be treated as a review of relevant scientific data rather than guidelines for treatment. This document should not be construed as expressing conclusions from REN Health about the appropriate use of cannabis for medical purposes. It is also not meant to be comprehensive and should be used as a complement to other reliable sources of information.

References - The main sources of information used to create this review were “Information for Health Care Professionals - Cannabis (marihuana, marijuana) and the cannabinoids” prepared by Health Canada, and the cannabis monograph created by the American Herbal Pharmacopoeia “Cannabis Inflorescense”. For additional sources of information used in preparation of this review, please refer to REN Health's website www.ren- health.com/resources/medical marijuana.