Pharmacology of Cannabis
Before one can understand the science-based medicinal properties of cannabis, including the pharmacology of the compounds found in the cannabis plant, a basic understanding of the Endocannabinoid System (ECS) and its role in the body is necessary.
“Numerous physiological functions, as mood, cognition, feeding b
ehavior and pain perception, are modulated by the ECS.” 
Endocannabinoid System Basics:
The endocannabinoid system (ECS) consists of:
endocannabinoids (eCBs) – our body produces AEA & 2-AG. Endo = from within
cannabinoid receptors (CBRs) – CB1 & CB2
biosynthesizing and degrading enzymes – FAAH (metabolizes AEA), MAGL (metabolizes 2-AG)
This process takes place to maintain balance – Homeostasis.
The ECS is our most important physiological system that regulates all of our other major organ systems and it’s responsible for homeostasis in our body. Homeostasis = perfect balance. The ECS relates messages that affect how we relax, sleep, eat, forget and protect. [1, 2]
Protect – what does that mean, exactly?
Ability to forget - It is important to have the ability to protect ourselves, by forgetting traumatic events in our life, over time. PTSD is an example of remembering too much – not being able to let go of traumatic memories. This is one of the many reasons why cannabis has become so important to our veterans.
Protects on cellular level - Epidemiologic studies have shown that if you ingest THC before a serious accident, you will be more likely to have a better outcome, especially with traumatic brain injuries, including brain trauma from severe strokes. Taking THC immediately after a severe stroke or traumatic brain injury will also help with recovery, but having it in your system before injury is even better.
If you are new to cannabis education and want to learn more about the Endocannabinoid System, please don’t hesitate to schedule a one-on-one consultation.
Pharmacology of Cannabis: 
Pharmacokinetics (PK) – “The relationship between the dose of a drug and how it’s given, and the drug concentrations in your body.”
4 Important Factors for PK:
1. Absorption – how fast or completely does it absorb? (bioavailability)
2. Distribution – where in body does it go? Does it cross blood/brain barrier?
3. Metabolized – are there any active metabolites?
4. Excretion – how does the body get rid of drug?
Pharmacodynamics (PD) – “The relationship between the drug concentration and the effects – what is the drug doing to your body?”
All drugs have to have a “drug target,” like a receptor, enzyme or ion channel.
1. This leads to cell change – cell signaling…
2. …which leads to therapeutic effect and potential side effect.
This is true for all drugs, whether pharmaceutical, synthetic, or plant-based.
Pharmacology of cannabis is complicated because, “Cannabis has multiple pharmacologically active constituents, i.e., cannabidiol, acts on more than one receptor.” Cannabis is used for many types of conditions and it has different routes of administration, all of which affect dosing amounts and efficacy. The three main routes of administration are orally, inhaled & transdermally. 
“The therapeutic index of a drug determines how easy a drug can be dosed to achieve efficacy while avoiding side effects.” With regard to side effects, cannabis is considered to have a wide therapeutic index, because they are typically referring to toxic doses, when determining the therapeutic index of a drug. Cannabis is nearly impossible to overdose in a toxic or fatal way.
Therapeutically, for symptom relief, cannabis actually has a very narrow therapeutic index and a new cannabis user should always start low and slow and titrate up as needed.
Cannabis is also a biphasic drug, which means the therapeutic effects are on a bell-curve - once the therapeutic dose is determined, anything beyond that dose will give diminishing returns and can actually cause the opposite, unwanted side effects, such as dizziness, anxiety, paranoia and cognitive impairments.
Everyone’s perfect therapeutic dose is different and may change as the body heals. It is very much a trial and error type of therapy and the patient controls their dose levels. This is why many doctors shy away from cannabis as medicine – there are so many variables, but there are also so many possibilities for healing different conditions.
Pharmacodynamics of THC 
THC activates two main cannabinoid receptors, CB1 & CB2. THC is a partial agonist, which is important, especially to the CB1 receptor. Synthetic drugs like K2 and Spice are full agonist on the CB1 receptor, which is why the effects are not well tolerated. THC does not fully activate the CB1 receptor, making it much more tolerated in higher doses.
Cannabinoid receptors, CB1 & CB2 are inhibitory, which means they are linked to signaling mechanisms within cells that tend to inhibit cell activation.
For example, the CB1 receptor inhibits the release of glutamate neurons. Too much glutamate can cause seizures. This is one way THC helps to stop seizures.
CB1 receptors are found in all major areas of the brain, except the brain stem. The brain stem is responsible for basic body functions, such as breathing, swallowing, heart rate and blood pressure. Opioid drugs bind to the delta-opioid receptor in the brain stem, making them very dangerous, causing thousands of overdose deaths a year.
The absence of CB1 receptors in the brain stem is why cannabis is very safe at high doses – a toxic dose is almost impossible. In the 10,000 years cannabis has been used, there is not one death on record from overdosing cannabis.
Most conditions studied with medicinal cannabis therapies have been studied with regard to the effects of THC, because the CB1 receptors affect most of the conditions studied – Muscle Spasticity (MS), Insomnia, Nausea, Anorexia, Pain & Inflammation – they are all affected by the CB1 receptor, because CB1 receptors are found all over the body. 
THC Pharmacodynamics with regard to Pain.
“In any part of the body that produces, transmits or interprets a pain signal, there are CB1 & CB2 receptors in all of them.” 
Brain – CB1 receptors are in parts of the brain that receives pain signals and also give it emotional meaning. When THC binds to these receptors, it reduces the link between pain and feeling bad. Again, cannabinoid receptors are inhibitory.
Spine – CB1 receptors in the spine suppress pain response before the pain signal reaches the brain.
Sensory Nerves – CB1 activation inhibits sensitizing effects of neuropeptides.
Immune Cells – CB1/CB2 activation inhibits release of inflammatory mediators from immune cells, which sensitize sensory nerves.
Pharmacodynamics of CBD 
“CBD is a much more pharmacologically complex molecule than THC. Diversity of conditions it may treat is due to complex pharmacology” 
These are the most common conditions that have been studied, or are currently being studied, and have shown some level of efficacy to treat the symptoms of these conditions. 
CBD has a therapeutic effect on so many different, unrelated, types of conditions because it interacts with a very long list of receptors, not only the cannabinoid receptors, like THC, which primarily only interacts with one of the CB receptors, CB1. Following is a partial list of the different receptors, which are important for many different types of conditions, with which CBD interacts: 
CB1/CB2 – Cannabinoid Receptors
Fatty Acid Binding Proteins
Serotonin – 5-HT1A
Dopamine – D2high
Sigma 1 Receptor
CBD is mostly known to interact with the CB2 receptors, but fairly recent studies have shown that CBD actually interacts both directly and indirectly with the CB1 receptor.
Directly – CBD actually binds to the CB1 receptor, but it doesn’t activate it. It binds to a different site location on the CB1 receptor, than where THC binds. When CBD binds to the CB! Receptor, it changes the shape of the cell, making it harder for THC to bind or activate as strongly, therefore reducing the psychoactive effects of the THC. Some describe it as “turning down the volume of the CB1 receptor.”
Indirectly – CBD boosts the levels of AEA (made from the body) which then go out and bind to the CB1 receptors. The way CBD boosts AEA is fairly complex, but this is the simplified version:
1. The enzyme FAAH metabolizes and breaks down AEA
2. FAAH needs Fatty Acid Binding Proteins FABP to shuttle the enzyme into the cell to get to the AEA to metabolize it.
3. CBD also binds to FABP, inhibiting FAAH from binding to it and therefore can’t make it into the cell, to metabolize and break down the AEA.
4. This, indirectly, boosts the levels of AEA. 
CBD Pharmacodynamics with regard to Pain. 
Many animal studies show CBD to be very beneficial for pain. Following are some discoveries that have been made:
Studies found THC works faster and chronic dosing of CBD is needed to achieve the maximum relief.
2018 survey (not study, but good human anecdotal information) people taking CBD alone reported moderate to significant reduction in pain.
CBD works on all three receptors that are important for sensitization
1. Seratonin 5-HT1A – agonist – reduces central sensitization
2. Glycine Receptors – found in spinal cord – increases inhibitory glycine in currents in the spinal cord.
3. TRPV 1 receptor – agonist – reduces sensitization
CBD and inflammation 
CBD has shown to treat different types of inflammation through various types of receptors, both directly and indirectly:
1. One main effect on inflammation is through the PPARy receptor – CBD is a potent PPARy agonist. PPARy has great anti-inflammatory and neuroprotective properties.
2. CBD raises adenosine levels – Adenosine can activate the Adenosine A2A Receptor, which can have anti-inflammatory effects – Indirect effect.
3. CBD is an indirect activator of CB2 receptors, which are important for immune cell activity and inflammation. CBD indirectly activates the CB2 receptors through raising endocannabinoids that bind to CB2 receptors.
4. CBD is also a 5-HT1A agonist, which reduces central sensitization.
5. CBD is TRPV 1 agonist – TRPV 1 is expressed in the brain and periphery – it is important for neurogenic inflammation. CBD reduces this type of inflammation by activating the TRPV 1 receptor.
CannaMedU Patient Handbook
(in partnership) w Janna Champagne, RN)
1. Di Iorio G, Lupi M, Sarchione F, et al. The endocannabinoid system: a putative role in neurodegenerative diseases. Int J High Risk Behav Addict. 2013;2(3):100–106. doi:10.5812/ijhrba.9222
3.Dr. Michael Tagen, PhD of Pharmacology, Green Flower Academy, Medical Applications of Cannabis.