The recent legalization of cannabis in Canada has changed the landscape for us. Claims of the beneficial effects of cannabis increase every day. It has been used with chemotherapy to reduce nausea, and it may actually be a cure for cancer. It has been used to treat pediatric seizures and it may eventually be used to treat brain damage from strokes. But those unfamiliar with the toxic effects of this drug are ending up in the emergency ward at ever increasing rates.
Is this drug the next best thing, or a dangerous and lethal chemical?
In this article, I will share with you what I have learned. It is a fascinating drug that works on many of our bodies most vital systems. To help you navigate the complexities of this class of drug, I’ll present some of the more important information in the following manner:
Pharmacodynamics (the effect of the drug and mechanism of action)
Interactions with other drugs
Why do substances from the cannabis plant such as THC and CBD have such a profound effect on the human body? The surprising answer is that our body produces a group of ‘cannabis-like’ chemicals called endogenous cannabinoids, or endocannabinoids. Together, the endocannabinoids regulate many bodily functions, such as sleep, blood pressure, thermoregulation, immune responses, bone growth, and even female reproduction. When endocannabinoids work the way they are supposed to, they promote health. However, it is becoming increasingly clear that an unbalance in endocannabinoid activity is involved in many disease processes.
Dozens of substances in the cannabis plant mimic these naturally occurring cannabinoids but the two that have been most studied are TCH and CBD. These chemicals interact with two important receptors in the endocannabinoid system, CB1 and CB2. CB1 receptors are primarily in the brain but they are also located in smaller amounts throughout the body. CB1 receptors can be found in our endocrine glands, leukocytes, spleen, heart and parts of the reproductive, urinary and gastrointestinal tracts. CB2 receptors are found in the peripheral nervous system and are present in high numbers on immune cells. THC, which is the psychoactive ingredient in cannabis, stimulates both CB1 and CB2 receptors in much the same way as the naturally occurring cannabinoids do but in a more intense fashion.
CBD works a little bit differently. Technically, CBD does not bind directly to cannabinoid receptors. Instead, CBD works by inhibiting an enzyme that degrades something called anandamide. When this enzyme is inhibited, it cannot break down anandamide normally and this leads to increased levels of anandamide in the body. Anandamide is the most important endocannabinoid (or naturally occurring) cannaboid in the body. Slightly elevated levels of anandamide are associated with feelings of well being and may even be responsible for increased health.
When a person ingests marijuana, THC overwhelms the endocannabinoid or ‘EC’ system, quickly attaching to cannabinoid receptors throughout the brain and body. This interferes with the ability of natural cannabinoids to do their job of fine-tuning communication between neurons, and can throw the entire system off balance.
Because cannabinoid receptors are in so many parts of the brain and body, the effects of THC are wide-ranging: It can slow down a person’s reaction time (which can impair driving or athletic skills), disrupt the ability to remember things that just happened, cause anxiety, and affect judgment. THC also affects parts of the brain that make a person feel euphoric—this is what gives people the feeling of being “high.” But over time THC can change how the EC system works in these areas of the brain, which can lead to problems with memory, addiction, and mental health.
Cannabinoids are pretty amazing and interact with many important neurotransmitters and neuromodulators. Here is a short list of them and how the function inside us:
- Acetylcholine, the chief neurotransmitter of the parasympathetic nervous system
- Dopamine, the neurotransmitter associated with pleasure
- GABA, the neurotransmitter associated with calming and preventing seizures
- Histamine, a compound which is released by cells in response to injury and in allergic and anaphylactic reactions.
- Serotonin, which is a neurotransmitter involved in a variety of bodily functions. These include; mood, sexual desire and sexual function, appetite, sleep, memory and learning, and even temperature regulation.
- Glutamate, the most abundant excitatory neurotransmitter in our body. It is involved in learning and memory. High levels of glutamate are actually responsible for cellular death.
- Norepinephrine, which increases heart rate, blood pressure, arousal and alertness. It also enhances formation and retrieval of memory.
- Prostaglandins, which are powerful locally acting vasodilators. Prostaglandins are also involved in inflammation. They are synthesized in the walls of blood vessels and prevent needless clot formation. They even regulate the contraction of smooth muscle such as the uterus during labour.
- Opioid peptides, there is increasing evidence that the reward pathways related to opioid actions are also influenced by the endocannabinoid system.
A number of the pharmacological effects of cannabis can be explained by how they interact with these neurotransmitters. For example, tachycardia and hyposalivation (or dry mouth) are mediated by the effect of THC on acetylcholine. Antiemetic (or anti-vomiting) properties of cannabinoids may be based on interactions with serotonin. The therapeutic effects that are seen in treating seizure or spastic disorders are probably mediated by the GABA, glutamine and dopamine systems. Cannabinoids influence the activity of most neurotransmitters in a complex manner, which sometimes may result in contradictory effects. In other words, external cannabinoids may either suppress or intensify symptoms such as pain, hunger or nausea. Interactions of cannabinoids with other neurotransmitter systems may cause unexpected effects. THC interacting with the Circulatory System can induce tachycardia and increase cardiac output with increased myocardial oxygen demand. It can also produce peripheral vasodilation and orthostatic hypotension. (1)
One important physiological role of endocannabinoids is neuroprotection. Ischemia and hypoxia in the CNS induce abnormal glutamate hyperactivity and other processes that cause neuronal damage. These processes also play a role in chronic neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease and multiple sclerosis. Clinical studies are under way to investigate the therapeutic potential of a derivative of THC to treat brain injuries. So far, these trials have shown positive results. (1)
Cannabinoids also seem to help with pain relief, muscle relaxation, immunosuppression, inflammation, allergies, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, seizure control and bronchodilation.
But the list is even longer:
- Preliminary observations show that endocannabinoids seem to stimulate bone formation
- Cannabinoid agonists inhibited human breast cancer cell proliferation
- THC was shown to modulate the immune response in a complex manner. In seems that THC is effective in treating inflammation caused by multiple sclerosis and Crohn’s disease.
- THC also possesses anxiolytic (anti-anxiety) and anti-psychotic properties. (1)
- Marinol (dronabinol, ∆9-THC) is approved for medical use in refractory nausea and vomiting caused by cancer drugs and for appetite loss in anorexia and HIV/AIDS patients.
- Cesamet (nabilone) is also used to treat nausea and vomiting associated with cancer chemotherapy.
There is also increasing evidence for therapeutic effects of THC and cannabis extracts in:
- Spasticity due to multiple sclerosis and spinal cord injury
- Chronic pain
- Tourette‘s syndrome
- Dystonia (abnormal muscle contractions) and abnormal, uncontrolled, involuntary movements that result in the treatment of Parkinson’s disease
There are also some conditions where the evidence suggests that endocannabinoids are helpful, but the evidence is not yet conclusive:
- Inflammation from arthritis
- Bipolar disorders and anxiety disorders
- Dependency to opiates and alcohol and treatment of withdrawal symptoms
- Agitation in Alzheimer‘s disease.
So here is where it starts to get really interesting. Although cannabinoids may be effective in treating many disorders, these drugs are complicated. For example, anandamide, which you may recall is one of the most important naturally occurring cannabinoids, not only binds to cannabinoid receptors but also stimulates vanilloid receptors. Vanilloid receptors are associated with ‘hyperalgesia’ or an abnormally heightened sensitivity to pain.
Also, some antagonists (drugs that block the action of a receptor) may behave as inverse agonists. This means that they not only block the effects of naturally occurring cannabinoids but they actually produce effects that are opposite from those produced by cannabinoid receptor stimulation. Translation – if you take a synthetic cannabinoid type drug that should reduce pain, it may actually cause increased pain.
Another potential problem with using synthetic cannabinoids is finding the correct dose for each person. In studies with mice, low doses of anandamide stimulated immune function while high doses decreased immune functions.
The median lethal dose of oral THC in rats was 800–1900 mg/kg. There were no cases of death due to toxicity following the maximum oral THC dose in dogs (up to 3000 mg/ kg THC) and monkeys (up to 9000 mg/kg THC.
Acute fatal cases in humans have not been substantiated. However, myocardial infarction may be triggered by THC due to effects on circulation. Marijuana can induce a schizophrenic psychosis in vulnerable persons and there is increasing evidence that there is a distinct cannabis psychosis. (1)
Between 2009 and 2015, Colorado’s Regional Poison Control Center studied the effects of legalized cannabis and while the number of accidental poisonings in children increased five-fold, there was only one reported death in an 11-month-old. The patient presented to the hospital unresponsive and in a wide complex tachycardia with a severe metabolic acidosis (pH of 6.7). The patient underwent cardiopulmonary resuscitation for 20 minutes without return of spontaneous circulation. Urine drug screen results were positive for THC and confirmed on post-mortem analysis. The cause of death after autopsy was myocarditis. (2)
Results from a study on admissions to the Colorado Children’s Hospital revealed the following useful facts:
- The median age of patients was 2.4 years
- Between 2009 and 2015, 21 of 62 exposures (34%) were from medical marijuana
- Known marijuana products involved in the exposure included infused edible products (48%)
- Of those 17 where baked goods (cookies, brownies, and cake),10 where candies, and 2 popcorn products.
- Forty patients (65%) were observed in the ED, and 13 patients (21%) were admitted to an inpatient ward unit.
- An additional 9 patients (15%) were admitted to the intensive care unit.
- Two of these required respiratory supports, a 3-year-old who was intubated for apnea and an 8-month-old who received continuous positive pressure for respiratory insufficiency. (2)
Interactions with other drugs
Other medicines may enhance or reduce certain actions of THC. And certain actions of these medicines may be enhanced or depressed by THC.
The most important interactions may be between cannabinoids and sedatives like alcohol and benzodiazepines. This is because cannabinoids can increase sedation and cause a further decrease in impairment and the level of consciousness.
Other dangerous interactions are between cannabinoids and substances that act on the cardiovascular system. Drugs found on the following list can be seriously influenced by THC:
- Tricyclic antidepressants
Most of the cardiovascular effects of cannabinoids are caused by activation of the sympathetic nervous system and inhibition of the parasympathetic nervous system. Smoking cannabis results in an immediate increase in heart rate that may last more than 1 h after exposure. This is followed by a substantial rise in serum norepinephrine level at 30 minutes. Acute exposure to cannabis may also result in elevation of supine systolic blood pressure and may induce atrial fibrillation. Despite the overwhelming public perception of the safety of these substances, an increasing number of serious cardiovascular adverse events have been reported in relation to recreational cannabis use. These have included sudden cardiac death; coronary, cerebral and peripheral vascular events; arrhythmias and stress cardiomyopathy among others. Under controlled experimental conditions, cannabis is believed to cause an acute vasodilatory response. However, this arteriolar vasodilation is not universal to all vascular beds as vasoconstriction has been seen in the coronary, cerebral and peripheral arterial systems and has been directly responsible for many instances of acute myocardial infarction (AMI), stroke and peripheral artery issues. (3)
In patients with ischaemic heart disease, cannabis increases the frequency of anginal symptoms at low levels of exercise, owing to an increase in heart rate and myocardial contractility, and a reduction in the oxygen carrying capacity of blood due to the formation of carboxyhaemoglobin. These adverse haemodynamic changes may trigger plaque rupture in vulnerable individuals culminating in myocardial infarction. Myocardial infarction has also been reported in the presence of normal coronary arteries, suggesting coronary vasospasm. Other reported cardiovascular effects associated with cannabis consumption include transient ischaemic attacks and strokes. (3)
But there are also a number of positive interactions, where cannaboid consumption may beneficially increase the desired effect of the drug. These include:
- The enhancement of muscle relaxants, bronchodilators and anti-glaucoma medication
- The increased analgesia by opiates
- The antiemetic effect of phenothiazines (medications used to treat schizophrenia and manifestations of psychotic disorders)
- The antiepileptic action of benzodiazepines
The cyclooxygenase inhibitors indomethacin, acetylsalicylic acid, and other non steroidal anti-inflammatory drugs antagonize or block THC effects. Indomethacin significantly reduced the subjective “high” and tachycardia in the heart. (1)
So, there you have it. Cannabis is complex, and we are just beginning to understand how it affects us. And there are clearly things that we need to understand as paramedics to provide optimal care.
We are all on a long and strange trip. Where it leads is debatable. But it seems certain that very soon, research will lead to a greater understanding of the endocannabinoid system. Hopefully, there will be frequent updates.
- Pharmacology of Cannabinoids, Franjo Grotenhermen, in Neuro endocrinology letters 25(1-2):14-23 · February 2004. Available from https://www.researchgate.net/publication/8546102_Pharmacology_of_cannabinoids
- Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015; George Sam Wang, MD1,2; Marie-Claire Le Lait, MS2; Sara J. Deakyne, MPH3; et al. JAMA Pediatrics. 2016;170(9):e160971. doi:10.1001/jamapediatrics.2016.0971
- Cardiovascular Complications of Marijuana and Related Substances: A Review; Amitoj Singh, et all. Cardiology Therapy 2018 Jun; 7(1): 45–59.Availabe from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986667/