Download MEDICAL CANNABIS - REVIEW OF RISKS AND

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
neuropathic pain (resistant to regular analgesics)
antiemetic
orexigenic
muscle relaxant and anti-spasmotic
bronchodilation
anti-pruritic
anti-cholestatic
anti-proliferative
anti-inflammatory
antioxidant
antiepileptic
neuroprotective
glaucoma
peptic ulcers
multiple sclerosis
Alzheimer’s disease
reduces pain
reduces pain originating from damaged nerves
reduces nausea and vomiting
stimulates appetite
helps to relieve muscle spasms and spasticity
helps to open narrowed airways and breathe better
helps to relieve itching
helps to relieve bile retention
inhibits cancer cell growth
has considerable anti-inflammatory effect
protects cells from oxidative damage
relieves or reduces seizures
slows nerve cell degeneration, promotes new cell growth
lowers intraocular pressure and protects retinal neurons
helps to heal peptic ulcers
protects neurons and improves symptoms
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.
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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
analgesic
antiepileptic
antiemetic
anti-inflammatory
antibiotic
antifungal
anti-proliferative
anxiolytic
antidepressant
antipsychotic
anti-addiction
antispasmotic
vasorelaxant
anti-psoriatic
anti-diabetic
anti-ischemic
bone stimulant
immunosuppressant
neuroprotective
glaucoma
antioxidant
increases levels of Anandamide
balances effects of THC
Effect
reduces pain levels
relieves or reduces seizures
reduces nausea and vomiting
has considerable anti-inflammatory effect
treats bacterial infection, effective against MRSA
treats fungal infection
inhibits cancer cell growth
relieves anxiety
relieves symptoms of depression
treats psychosis/hallucinations
treats addiction
reduces spasms, including bowel contractions
reduces vascular tension/blood pressure
treats psoriasis
reduces blood sugar levels
reduces risk of artery blockage
promotes bone growth
helps to treat autoimmune conditions
slows nervous system degeneration (e.g., Multiple
Sclerosis, ALS, Parkinson’s disease, Spinal Cord Injury)
protects retinal neurons
protects cells from oxidative damage
main endocannabinoid with THC-like properties
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.
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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
1. Faster onset of action (10-45 min) than oral route
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
Cons
1. Longer onset of action than inhalation
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
1. Longest duration of effects (4-8 hrs), may be
especially helpful for chronic, constant symptoms
Cons
1. Longest onset of action (30min-2hrs). To avoid
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
1. May be helpful for localized areas of pain,
inflammation, itching, or skin cancer
2. Unless used in significant quantities, systemic
absorption and effects are minimal to none
Cons
1. Limited amount of research data on this route of
administration
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 antiseizure properties (they can be effective against resistant seizures even when THC and CBD are not effective).
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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,
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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.
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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.renhealth.com/resources/medical marijuana.
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