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The Ultimate Guide to Medical Cannabis [And How Cannabis Works With Your Body]

The science behind medical cannabis is complicated. There are 5 very good reasons as to why this is:

  1. The cannabis plant contains up to 150 cannabinoids, 220 terpenes/terpenoids and 20 flavonoids, all of which have different effects when used on their own or combined with each other. This makes cannabis a very versatile medication, but also difficult to figure out.
  2. Cannabinoids are biphasic, meaning they can have different effects at different dosages. For example, where low doses of THC can beat stress & anxiety, high doses can promote it.
  3. Study on the endocannabinoid system (ECS) is still in its early stages. We’re still trying to figure out more about how the ECS works and how cannabis interacts with it.
  4. Depending on the condition, much of the evidence behind the therapeutic effects of cannabis is anecdotal. There are many studies on medical cannabis, but not all of them fit the gold standard of placebo-controlled, clinical trials. This means that making any definitive claims is very difficult.
  5. The legal status of cannabis makes it even more difficult to research medical marijuana properly.

However, there is more-and-more research coming out showing that cannabis is indeed useful for a number of different conditions. Here’s more on how and why, with links to more articles for a more in-depth look into the science behind medical marijuana.

Table of Contents
  1. What is the Endocannabinoid System (ECS)? What Makes Marijuana Medicine?
  2. What Are Cannabinoid Receptors?
  3. What Are Endocannabinoids?
  4. What Are Phytocannabinoids?
  5. What Are the Acidic Cannabinoids? A Closer Look at THCA, CBDA etc.
  6. What Are Terpenes and Terpenoids?
  7. What Are Flavonoids?
  8. A Closer Look at Our Naturally-Occurring Cannabinoids
  9. Some Advice on Dosing Medical Marijuana
  10. Does Medical Marijuana Interact With Other Medications?
  11. What Health Problems and Conditions Can Medical Cannabis Help With?

What is the Endocannabinoid System (ECS)? What Makes Marijuana Medicine?

The body produces its own natural versions of tetrahydrocannabinol (THC) and cannabidiol (CBD), called endocannabinoids. When the body does not produce enough cannabinoids (clinical endocannabinoid deficiency), or if their production is dysregulated in some other way, inflammation can go haywire, leading to health problems. THC, CBD and other cannabinoids in the cannabis plant help replace these lost cannabinoids, and also have anti-inflammatory effects. This is what makes marijuana medicine. We’ve written a whole blog on the Endocannabinoid System here.

Download Our Introductory Guide To the ECS

The ECS plays a role in homeostasis, which is defined as “the tendency towards a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes.” This makes the ECS a hugely important receptor system.

The ECS plays a hugely important role in the fundamental processes of life, including:

  • Autophagy – which means “self-devouring” – is controlled by the ECS. Autophagy is when a cell isolates a part of its contents for self-digestion and recycling. Autophagy plays a huge role in the immune system.
  • Communication between different types of receptors – Cannabinoids are found at the intersections of the body’s systems, allowing for coordination and communication between different cell types. The ECS behaves as a “mainframe” or even a “supercomputer” for the body.
  • Cannabinoids can be found at the site of an injury, stabilizing nerve cells to prevent excessive firing and decreasing the release of activators and sensitizers from the injured tissue.
  • Cannabinoids can calm down nearby immune cells to prevent the release of substances that can cause inflammation (e.g. cytokines like IL-12) .

Understanding the Endocannabinoid System (ECS)

What Are Cannabinoid Receptors?

There are two main primary cannabinoid receptors:

  1. CB1 receptors, which are mostly found in the brain, central nervous system (CNS), and peripheral organs and tissues; and
  2. CB2 receptors, which are found in the immune system, peripheral nervous system (PNS), brain and gastrointestinal system.

Both are G protein-coupled receptors. There are some similarities between the two receptors, but they have significant differences as well – the two receptors are about 44% similar. G-coupled protein receptors are a protein family of receptors that detect molecules outside of the cell, activating signal transduction pathways and cellular responses

There are actually several other cannabinoid receptor types. For example, GPR55, PPARs and vanilloid TRPV1, which are respectively involved in the development of anxiety, glucose metabolization and the regulation of internal temperature. Some people consider these receptor types as cannabinoid receptors, and GPR55 has been described as a CB3 receptor.

The Endocannabinoid System (ECS). How THC moves along the ECS. Synaptic signaling.
The Endocannabinoid System (ECS). Synaptic signaling of THC across the presynapse and postsynapse.

 

What Are Endocannabinoids?

There are two main endocannabinoids (cannabinoids the human body produces naturally):

  1. Anandamide (AEA)
  2. 2-Arachidonoylglycerol (2-AG)

The endocannabinoid anandamide targets CB1 receptors. THC is anandamide’s mimetic phytocannabinoid, meaning the two compounds have similar properties and behaviors. CB1 receptors were first cloned in 1990.

THC was first identified and synthesized by Professors Raphael Mechoulam and Y. Gaoni. Professor Raphael Machoulam and S. Ben-Shabat also coined the term “entourage effect” to describe the unique medical properties and interactions that cannabinoids, flavonoids and terpenoids have together.

THC is a partial agonist of the CB1 receptor, so it is not perfectly analogous to anandamide. Anandamide is so-called because it is derived from the Sanskrit word ananda, meaning “joy” or “bliss”, and it is one of the main “pleasurable” neurotransmitters released during exercise. Professors Lumír Ondřej Hanuš and William Anthony Devane first described the structure of anandamide.

The endocannabinoid 2-Arachidonoylglycerol (2-AG) is active on both CB1 and CB2 receptors. CB2 receptors were first cloned in 1993. There is some suggestion that, where THC is semi-analogous to anandamide, CBD is semi-analogous to 2-AG. Levels of 2-AG found in the human body increase when CBD is used.

However, CBD does not have an affinity for CB1 and CB2 receptors, and can act as an antagonist of these receptors. This is why CBD is not completely comparable to 2-AG.

The enzyme that breaks down anandamide and THC is called fatty acid amide hydrolase (FAAH). Regular cannabis users who use THC-rich varieties actually have lower levels of FAAH, meaning more anandamide is available in the body, leading to pleasurable effects.

CBD is broken down by the enzyme Monoacylglycerol lipase (MAGL), as is 2-AG. These enzymes are also a part of the ECS, and they break down THC and CBD so quickly that consuming even extremely large amounts do not lead to a deadly overdose.

We will look at endocannabinoids in more detail later in this article.

Chemical formula for anandamide. Skeletal formula.
Anandamide skeletal structure. C22H37NO2. Picture from: https://commons.wikimedia.org/wiki/File:Anandamide_skeletal.svg.

 

What Are Phytocannabinoids?

Phytocannabinoids are cannabinoids derived from the cannabis plant. There are 6 main or “big” cannabinoids, including:

  1. THC – tetrahydrocannabinol
  2. CBD – cannabidiol
  3. THCV – tetrahydrocannabivarin
  4. CBG – cannabigerol
  5. CBN – cannabinol
  6. CBC – cannabichromene

Sometimes, all other cannabinoids beyond CBD and THC are referred to as “minor cannabinoids”, as they are not as commonly found in the cannabis plant, and when they are they are usually in low concentrations.

Chemical structures of THC, THCV, CBG, CBDV and CBGV
By Serena Deiana. July 2011 Psychopharmacology 219(3):859-73
DOI: 10.1007/s00213-011-2415-0
Source: PubMed

 

What is THC (Tetrahydrocannabinol)?

 

THC is the main psychoactive compound found in the cannabis plant, and directly attaches itself to receptors (CB1 receptors) in the brain. THC is often the cannabinoid found in the highest concentrations in the cannabis plant. We’ve written a whole blog called ‘What is THC’? which you can read here.

Download Free Guide to THC

THC is the main psychoactive component of the cannabis plant, and is a partial agonist of both the CB1 and CB2 receptors. This means that THC can partially turn on CB1 receptors in the brain (hence the psychoactivity) and the CB2 receptors in the immune system (hence the anti-inflammatory effects).

THC is an effective painkiller, and could also be useful as an anti-inflammatory, spasticity, antiemetic (nausea/vomiting prevention), appetite stimulant, and a treatment for an overactive bladder. THC could be useful for the treatment of chronic pain, neuropathic (nerve) pain, the side-effects of chemotherapy, insomnia, nausea/vomiting, anxiety, tremors and tics. THC could be very useful for the treatment of chronic pain, autoimmune disorders, cancer, nausea, multiple sclerosis, Parkinson’s Disease, Alzheimer’s Disease, and insomnia.

The acidic form of THC is tetrahydrocannabinolic acid (THCA). Acidic cannabinoids are converted into their non-acidic form when they age and are exposed to heat. THCA converts into THC when it loses a carbon dioxide molecule from its chemical structure. This is called decarboxylation, which activates the cannabinoid.

What is CBD (Cannabidiol)?

CBD is the second most prevalent cannabinoid in the cannabis plant, after THC. We’ve written a whole blog called ‘What is CBD’? which you can read here. It accounts for up to 40% of the plant’s extract.

CBD has a physiological effect on the body and can be used as a mood enhancer. While it is not psychoactive in the same way as THC, CBD does have a non-typical form of psychoactivity.

Download Free Guide to CBD

Some say that CBD gives them a broadly relaxed feeling. Less “on-edge” and more emotionally “even”. This relaxing feeling, combined with CBD’s anti-inflammatory effects, could help it treat pain and insomnia.

However, for some people, higher doses of CBD may actually make people feel more awake. This makes sense, as CBD is a CB1 receptor antagonist (blocks or “turns off” the CB1 receptor) to some extent, so will likely not have the same sleepy effects that THC has.

CBD also calms down inflammation in the brain and nervous system, especially when combined with THC. This can make CBD useful for conditions like epilepsy, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis (MS) and neuropathic (nerve) pain.

CBD affects the following receptors and enzymes in the brain and body:

  • Serotonin receptors – CBD is a partial agonist of serotonin receptors, meaning CBD binds and activates serotonin receptors, treating anxiety, depression, PTSD and nausea.
  • Vanilloid receptor (TRPV1) – this is a receptor in the body that acts as an internal thermometer. CBD desensitizes this receptor, which is also involved in the transmission of pain signals.
  • Mu- and delta – opioid receptors – changing the way they process pain signals.
  • COX-2 enzyme – CBD desensitizes this enzyme, making it a potent anti-inflammatory. Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen work in a similar manner.
  • Cytochrome P450 (CYP450) enzyme – found in the liver, CBD desensitizes this enzyme. CYP450 also processes many other drugs, such as anti-epileptic drugs (AEDs), meaning anyone using medications in the benzodiazepine class will need to taper their use when using CBD.

The acidic form of CBD is cannabidiolic acid (CBDA).

What is THCV (Tetrahydrocannabivarin)?

In low doses, THCV is not psychoactive, has an appetite-suppressing, energizing effect, and blocks THC. In high doses, THCV is psychoactive and combines with THC for even greater psychoactive effects. We’ve written a whole blog about THCV and its uses here.

Download Free Guide to THCV

THCV can therefore have the following effects:

  • Reducing appetite and reversing insulin resistance – low doses – useful for obesity and diabetes
  • Energizing – low doses – useful for depression
  • Antipsychotic – low doses
  • Psychoactive – high doses – a more “clear-headed” and less sedative effect compared to THC, but still somewhat sedative in high doses
  • Anti-inflammatory

What is CBG (Cannabigerol)?

CBG is sometimes referred to as the “parent cannabinoid”, as the plant converts cannabigerolic acid (CBGA, which is what CBG is before it is exposed to UV light and/or heat) into tetrahydrocannabinolic acid. We’ve written a whole blog about CBG here.

Download Free Guide to CBG

CBG is an indirect antagonist of CB1 and CB2 receptors, but with a low affinity for them. The mechanism of action of CBD and CBG differ to some degree, they are similar in that both have little psychoactive effect.

CBG does not make you feel “high” or “stoned.” In fact, CBG may counteract the psychoactive effects of THC. However, CBG does still have a physiological effect. It could be said that CBG is more of a “non-intoxicating” cannabinoid than a non-psychoactive one.

As CBG has the ability to boost anandamide without psychoactive effects, it could be a great alternative or addition to THC. CBG may be very useful in the treatment of chronic pain, cancer and superbugs like MRSA.

Low doses of CBG can beat nausea. However, regular consumption of high doses of CBG can prompt nausea in some, and may interfere with CBD and its antiemetic (nausea & vomiting-beating).

What is CBN (Cannabinol)?

Unlike many other cannabinoids, cannabinol (CBN) does not stem from cannabigerol (CBG). CBN is a metabolite of THC that is formed as cannabis ages. THC degrades into CBN over time and exposure to ultraviolet (UV) light. We’ve written a whole blog about CBN, the sleepy cannabinoid here.

Download Free Guide to CBN

CBN could be useful for the following:

  • Chronic Pain – CBN is a mild painkiller and anti-inflammatory.
  • Anti-epileptic – CBN’s slight sedative effects could be useful for the treatment of seizures and convulsions.
  • Appetite stimulant CBN’s slight affinity for CB1 receptors could help stimulate the appetite.
  • Antibacterial – CBN could slow bacterial growth, which could make it useful for the treatment of superbugs like MRSA.
  • Insomnia – CBN has sedative effects.

CBN acts as a partial agonist of both the CB1 and CB2 receptors, but has a lower affinity for them compared to THC. CBN could be very useful for those looking to use cannabis for its sedative effects, but find moderate or high doses of THC to be intolerable.

What is CBC (Cannabichromene)?

Cannabichromene (CBC) is the third most prominent cannabinoid found in the cannabis plant. The precursor to CBC is cannabichrome carboxylic acid (CBCA), cannabichromenic acid. We’ve written a whole blog about CBC which you can read here.

Download Free Guide to CBC

CBC is not active at CB1 or CB2 receptor sites, and so does not produce a euphoric high like that caused by THC. CBC does, however, bind with other receptors in the body. This includes the vanilloid receptor 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), both of which are linked to pain perception.

Activation of the TRP receptors can inhibit anandamide uptake (similar to how CBD works, which is also a CB1 receptor antagonist), increasing the amount of anandamide available in the body.

CBC is actually thought to be up to 10 times more potent than CBD for the treatment of stress and anxiety, and also has significant anti-inflammatory, pain-reducing, antiviral, anti-tumor and bone-growth-stimulating properties.

THC to CBN Biosynthesis
THC to CBN. From https://www.marijuana.com/news/2014/07/biosynthesis-and-degradation-of-cannabinoids-part-2-thcv-%CE%B48-thc-and-cbn/

 

What Are the Acidic Cannabinoids? A Closer Look at THCA, CBDA etc.

THCA stands for tetrahydrocannabinolic acid, and has a chemical formula of C22H30O4. CBDA stands for cannabidiolic acid, and has the chemical formula C21H30O4. They are known as the acidic cannabinoids, and are precursors to CBD and THC. Basically, when CBDA or THCA are heated, they release carbon dioxide (CO2) and become activated and turn into neutral cannabinoids, CBD or THC.

CBG, CBC and THCV also have their acidic precursors: cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), and tetrahydrocannabivarinic acid (THCVA). Cannabinol (CBN) does not have an acidic precursor as it comes from the degradation of THC. Here are some potential benefits of THCA, CBDA, CBGA, CBCA and THCVA.

THCA – tetrahydrocannabinolic acid

  • Anti-inflammatory – chronic pain
  • Appetite stimulant – eating disorders; chemotherapy treatment
  • Treating sleeplessness – insomnia
  • Anti-tumor – cancer
  • Antispasmodic and neurological illnesses multiple sclerosis (MS) and epilepsy

CBDA – cannabidiolic acid

  • Anti-inflammatory – CBDA is a COX-2 enzyme inhibitor, which is how NSAIDs like ibuprofen work to beat inflammation.
  • Anti-tumor CBDA could help treat cancer.
  • Mood enhancer & antiemetic – CBDA works on the serotonin receptors, making it potentially very useful for beating anxiety and nausea.

CBGA – cannabigerolic acid

  • Cardiovascular diseasesPotentially very useful for treating cardiovascular diseases by acting as an antioxidant and reducing oxidative stress.
  • Diabetes The treatment of metabolic disorders like diabetes.
  • IBDs Treatment of inflammatory bowel disorders.

CBCA – cannabichromenic acid

THCVA – tetrahydrocannabivarinic acid

What Are Terpenes and Terpenoids?

Terpenes are a class of hydrocarbon-based compounds that give cannabis its unique smell. You will also see the term terpenoids used. Terpenoids are a class of terpenes, but are modified chemically in some way to act differently when ingested.

Cannabinoids and terpenes share the same chemical precursor, geranyl phosphate. This means that terpenes and cannabinoids are linked. Terpenes can control the amount of THC that crosses the blood-brain barrier (BBB), and can influence the way cannabinoids behave in other ways as well.

The terpenes found in CBD and cannabis oil, and what they do.
The terpenes found in cannabis and full-spectrum CBD (cannabidiol) oil.

 

Alpha and Beta Pinene

Pinene is also found in pine needles, dill, parsley, rosemary, and basil, and is the main terpene that contributes to cannabis’ pine-like smell. Pinene’s effects include alertness, memory retention, and counteracting some of the negative effects of THC.

Pinene is useful for asthmatics due to pinene’s bronchodilator effects. Pinene also has antibacterial and antiseptic properties and could be used for superbug treatment and antibiotic resistance.

Myrcene

Myrcene is an antioxidant, anticarcinogenic, anti-inflammatory and antidepressant, and can have sleepy effects. Myrcene is found in hops, mango, lemongrass, and thyme. Myrcene may combine with THC and CBN to increase this sleepy effect. Myrcene also targets TRPV1 (vanilloid) receptors, which contributes to cannabis’s anti-inflammatory effects.

Limonene

Limonene is responsible for that “citrus” or “lemony” aroma and taste found in some strains. Limonene is found in fruit rinds, juniper berries, peppermint, and rosemary. Limonene can elevate the mood and provide stress relief.

When combined with other of the “sleepier” terpenes, limonene can actually help aid sleep. In higher doses and mixed with pinene, beta-caryophyllene, THC, and THCV, the effect becomes more energetic.

Terpenes and terpenoids can have biphasic effects, just like cannabinoids, i.e. the same compound can have different effects at different dosages.

Linalool

Linalool is found in lavender and jasmine, giving some varieties of cannabis a flower-like, air-freshener smell. Linalool is useful for anxiety relief and sedation, and also has anticonvulsant, antidepressant, and anti-acne properties. Combined with THC, some CBD, CBN, and myrcene, and you have something that can be very useful for chronic pain and insomnia!

Linalool could be a positive allosteric modulator of the GABAA receptor, which could be why it has sedative effects (i.e. it turns up the GABA receptor’s volume, allowing GABA to have even greater effects).

Beta-Caryophyllene

Beta-caryophyllene, sometimes just called caryophyllene, has antinociceptive (pain-blocking), neuroprotective, anxiolytic, and antidepressant effects. Beta-caryophyllene is a selective agonist of the CB2 receptor, making it a cannabinoid as well as a terpenoid.

Beta-caryophyllene can be used for the treatment of pain, cancer, inflammation, addiction (particularly alcohol and opiate/opioid addiction), anxiety, depression, epilepsy, and fungal and bacterial infections.

Humulene

Earthy, woody, spicy aromas and flavors are usually associated with humulene and occur naturally in clove, basil, and hops. Due to its smell and similarities to beta-caryophyllene, humulene is sometimes also referred to as alpha-caryophyllene.

Humulene has antibacterial, antitumor, analgesic, and anti-inflammatory properties. Humulene may also combine with THCV and have appetite-suppressant effects.

The above terpenes are just a small selection of the terpenes found in the cannabis plant, which can contain up to approximately 220 terpenes. It is important to look at a plant’s terpene content as well as cannabinoid content if you want to get an idea of what it feels like before you use it.

What Are Flavonoids?

Flavonoids are compounds in the cannabis plant that contribute to its flavor. The cannabis plant contains up to 20 flavonoids.

List of flavonoids - the chemical compounds that give fruit, vegetables and cannabis their unique flavors.
Mind map of flavonoids. Author: Nevit Dilmen. From https://commons.wikimedia.org/wiki/File:Flavonoids.svg. CC BY 3.0.

 

Cannflavins A, B and C

Cannflavins are produced exclusively by the cannabis plant. Cannaflavins are:

  • Neuroprotective
  • Antioxidants
  • Have anticancer properties in several animal models.
  • Cannflavin A is of particular interest and has been the most studied of the cannaflavins. Cannflavin A may interact with CBD and THC, and may inhibit the COX-2 enzyme and reduce inflammation.

Βeta-Sitosterol

Beta-Sitosterol is a white, waxy flavonoid with a chemical structure that is similar to cholesterol, but can actually lower cholesterol levels. This flavonoid could be used in combination with THCV for the treatment of obesity and coronary heart disease. Beta-sitosterol is often found in avocados and nuts, and some claim it has a yoghurt-like smell/taste.

Kaempferol

Kaempferol has a yellow color and can be found in kale, beans, tea, spinach and broccoli. Kaempferol has a bitter flavor, and could be useful for the treatment of cancer. Kaempferol:

  • Modulates apoptosis (cell death or suicide)
  • Angiogenesis (formation of new blood cells)
  • Inflammation
  • Metastasis (the development of secondary malignant growths at a distance from a primary site of cancer).

Kaempferol also affects the human body’s antioxidant effects against free radicals.

Quercetin

Quercetin has a bitter flavor, and is commonly used as an ingredient in foods and beverages.

Quercetin is a flavonoid found in almost all vascular plants (particularly capers, kale, apples and red onions), providing anti-inflammatory, antimutagenic (i.e. they can prevent changes in DNA sequences), antiviral, antifungal and antioxidant effects. Quercetin may also improve mental and physical performance.

Orientin

Orientin is a potent antioxidant with antibiotic, anti-inflammatory and anti-cancer properties. It is common in both cannabis and tea plants such as rooibos. Orientin has been described as having a sharp or bitter taste.

The Effect of Cannabis Beyond Endocannabinoid Receptors

Beyond the cannabinoid receptors CB1 and CB2, cannabis also affects the following receptor types:

  • G Protein-Coupled Receptors (GPR or GPCR)
  • Serotonin Receptors (5HT)
  • Dopamine Receptors
  • Opioid Receptors
  • Norepinephrine (Noradrenaline) Receptors
  • Epinephrine (Adrenaline) Receptors
  • Peroxisome Proliferator-Activated Receptor (PPAR)
  • Glycine Receptor (GlyR)
  • Transient Receptor Potential (TRP) Channels

Cannabinoids’ ability to affect how these receptors behave is one of the reasons why cannabis can be used to reduce or replace so many other medications.

A Closer Look at Our Naturally-Occurring Cannabinoids

Fatty acid amide hydrolase aka FAAH

FAAH is a member of the serine hydrolase family of enzymes, meaning that they contain nucleophilic serine (an amino acid) in their active sites, and are hugely important for the hydrolysis of substrates such as fatty acids. FAAH hydrolyses anandamide, N-acylethanolamines, oleamide and N-acyltaurines, which are TRP agonists. FAAH may be a target for pain relief and a treatment for anxiety disorders.

Alongside anandamide and 2-AG, FAAH is one of the first parts of the ECS people usually come across. This is because THC inhibits the FAAH, which increases the amount of anandamide available in the body. This works alongside CBD, which also increases the amount of anandamide available in the bloodstream via inhibition of TRP channels.

Although CBD acts as a selective antagonist of CB1 receptors, buffering some of THC’s psychoactive side-effects, this action by CBD can also increase the amount of time THC stays in the bloodstream.

Anandamide, aka N-arachidonoylethanolamine, AEA (C22H37NO2)

A fatty acid neurotransmitter. Anandamide is degraded by the enzyme, fatty acid amide hydrolase (FAAH), converting anandamide into ethanolamine and arachidonic acid (AA). FAAH inhibitors like THC lead to elevated anandamide levels. Anandamide’s effects can occur in either the central nervous system (CNS) or the peripheral nervous system (PNS). Anandamide is said to be analogous to THC.

Anandamide plays a role in memory, the regulation of feeding behavior, reward, motivation and implantation of the early stage embryo in its blastocyst form into the uterus. Modulating anandamide also may inhibit the growth of breast cancer cells. Anandamide can also be found in dark chocolate.

2-Arachidonoylglycerol, aka 2-AG (C23H38O4)

2-AG was discovered by Raphael Mechoulam and Shimon Ben-Shabat. Although not a perfect analogy, CBD is thought to partially mimic 2-AG’s effects.

2-AG is the most abundant endocannabinoid in the human body. 2-AG may also play a role in inhibiting cancer cell growth. 2-AG potentiates GABAA receptors at low concentrations of GABA. Using CBD may boost the body’s levels of 2-AG.

2-AG is an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the receptor. Like other cannabinoid receptors, 2-AG has more than one endogenous ligand. 2-AG is an ester formed from glycerol and the omega-6 fatty acid, arachidonic acid.

Unlike anandamide, 2-AG is found in relatively high concentrations in the CNS. Formation of 2-AG is dependent on calcium and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) – both key enzymes in the biosynthesis of 2-AG.

2-AG is degraded by monoacylglycerol lipase (MAGL), FAAH and some other enzymes that haven’t been properly characterized as of yet. 2-AG is formed in a similar way to anandamide, except it requires glycerol rather than a free amine. 2-AG can be found in maternal human and bovine milk. 2-AG plays a role in immune response, appetite regulation, inflammation and pain.

2-Arachidonoylglycerol, 2-AG. Chemical formula of 2-AG in skeletal format. C23H38O4
2-Arachidonoylglycerol (2-AG) chemical formula. C23H38O4.

 

Arachidonic Acid, aka AA (C20H32O2)

AA is a polyunsaturated omega-6 fatty acid, and is related to the saturated arachidic acid, found in cupuassu butter. AA is a carboxylic acid with a 20-carbon chain and four cis-double bonds. AA is present in the phospholipids of the membranes of the body’s cells. AA is found in particularly high concentrations in the brain, muscles and liver.

Skeletal muscle is an especially active site for AA retention, and AA is very important in promoting the growth and repair of skeletal muscle tissue. This makes AA of great interest to those suffering from various kinds of muscle and bone injuries, and athletes may also potentially use AA to build and rebuild muscle.

AA concentration in the body may also be associated with the onset of Alzheimer’s disease – cannabinoids may be able to control the amount of AA the body produces and mitigate inflammation.

N-Arachidonoyl Dopamine, aka NADA (C28H41NO3)

NADA plays a regulatory role in both the CNS and PNS, and is found in high concentrations in the hippocampus, cerebellum and striatum. NADA is a CB1 receptor and TRPV1 agonist. Although NADA has been found to possess immunomodulatory activity in humans, most of its effects have been studied in rodents.

NADA may also be involved in smooth muscle contraction, vasorelaxation in blood vessels, immune response and inflammation, and may have antioxidant and neuroprotective properties. NADA and anandamide may have some opposing effects.

Arachidonoyl Serotonin, aka AA-5-HT (C30H42N2O2)

AA-5-HT is present in the ileum and jejunum of the gastrointestinal tract. AA-5-HT is an inhibitor of FAAH, and is an antagonist of the TRPV1 receptor.

AA-5-HT may have analgesic properties, and could be effective against both acute and chronic peripheral pain.

2-Arachidonyl glyceryl ether aka 2-AGE, Noladin Ether (C23H40O3)

CB1 and CB2 agonist. Partial agonist for the heat-detecting protein, transient receptor potential V1 (TRPV1). Regulates calcium uptake and gamma-aminobutyric acid (GABA), which regulates neuronal excitability. 2-AGE also lowers intraocular pressure. There is still some debate as to the extent 2-AGE occurs in the human body.

N-Arachidonylglycine, aka NAGyl (C22H35NO3)

NAGyl is a carboxylic analog of anandamide. NAGyl has a wide range of signalling targets in the brain and immune system. NAGyl binds to the abnormal cannabinoid receptor, GPR55, and is found in high concentrations throughout the body.

How NAGyl is biosynthesized is not fully understood, but there are two theories. 1) NAGyl could be the enzymatically regulated conjugation of arachidonic acid and glycine; or 2) NAGyl could be developed by the enzyme alcohol dehydrogenase, catalyzing the oxidation of anandamide into NAGyl. NAGyl may suppress pain, and could be especially useful for treating neuropathic pain.  NAGyl may also induce cell migration.

Both THC and NAGyl are full GPR18 agonists and induce migration in human endometrial HEC-1B cells. This means NAGyl may be useful in treating endometriosis.

Docosatetraenoylethanolamide, aka DEA (C24H41NO2)

DEA has a similar structure to anandamide (only containing docosatetraenoic acid instead of arachidonic acid), and acts on CB1 receptors. However, DEA does not seem to bind to CB1 receptors to the same extent as anandamide. DEA’s role as a neurotransmitter is not understood.

N -Acyl-Phosphatidylethanolamine, aka NAPE

NAPEs are hormones released by the small intestine into the bloodstream when it processes fat. They are formed from phosphatidylethanolamines (a group of phospholipids that plays a role in membrane fusion and curvature).

When phospholipases cleave NAPEs, they can be transformed into N-acylethanolamines, including anandamide. NAPEs affect the hypothalamus in the brain, and can suppress appetite. This could be one reason why cannabinoids may be used to treat obesity. NAPEs are not endocannabinoids per se, but are important intermediaries in the biosynthesis of cannabinoids.

NAPE-specific phospholipase D aka NAPE-PLD

The enzyme that catalyzes the release of N-acylethanolamine from NAPE. This enzyme is a major part of the process that converts lipids into chemical signals like anandamide and oleoylethanolamine, and may even play a part in the detection and reduction of bile acid.

Monoacylglycerol Lipase aka MGL

A key enzyme in the hydrolysis of 2-AG by converting monoacylglycerols into fatty acid and glycerol. Works together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores. Chronic inactivation of MAGL results in massive elevations of 2-AG and downregulation of CB1 receptors in the brains of mice.

Lysophosphatidylinostol, aka LPI, L-α-lysophosphatidylinositol (C25H49O12P)

LPI is an endogenous lysophospholipid and endocannabinoid neurotransmitter has been proposed to be one of the endogenous ligands of the protein, GPR55. This suggests that cannabinoids have a role to play in obesity and a variety of other metabolic diseases.

Oleamide (C18H35NO)

Oleamide is an amide derived from oleic acid. Oleamide is biosynthesized from N-oleoylglycine. Oleamide accumulates in cerebrospinal fluid during sleep deprivation, and induces sleep in mammals.

Oleoylethanolamide, aka OEA (C20H39NO2)

OEA is the monounsaturated analog of anandamide, but acts independently of the cannabinoid pathway. OEA does bind to the cannabinoid receptor GPR119. OEA is produced by the small intestine. OEA regulates feeding and body weight in vertebrates. OEA is not a strict endocannabinoid as it lacks affinity for CB1 and CB2 receptors. OEA may be involved in neural responses to food stimuli.

Palmitoylethanolamide, aka PEA (C18H37NO2)

As with OEA above, PEA cannot be considered an endocannabinoid as it does not show an affinity for the CB1 or CB2 receptors. PEA does, however, have an affinity for the cannabinoid-like G-coupled receptors, GPR55 and GPR119. PEA enhances anandamide activity, and an imbalance in the endocannabinoid system and alterations of the levels of PEA occurs during chronic inflammation. PEA has analgesic, neuroprotective and anticonvulsant properties.

RVD-Hpa RVD-Hpa is a selective agonist for the CB1 receptor. May be involved in the integration of signals from both lipid- and peptide- derived signalling molecules.

Stearoylethanolamide (SEA)

Stearoylethanolamide is an endocannabinoid neurotransmitter that may downregulate liver enzymes. SEA may also work in combination with AEA to produce an “entourage effect”.

Virodhamine, aka O-arachidonoyl ethanolamine; O-AEA (C22H37NO2)

O-AEA is an endocannabinoid and nonclassic eicosanoid (a signalling molecule made by the oxidation of arachidonic acid or any other polyunsaturated fat. Virodhamine may regulate body temperature. O-AEA is a CB1 receptor antagonist or partial agonist and a potential CB2 receptor agonist.  O-AEA may be involved in the regulation of body temperature and the relaxing of arteries.

Dosing medical marijuana - learning about how much medical cannabis is right for you.
Learn more about dosing medical marijuana.

 

Some Advice on Dosing Medical Marijuana

  • Microdosing is usually ideal, especially when it comes to THC, where a starting dose 1 – 5 mg for beginners, going up in small increments only when necessary. You can always use more, but not less.
  • If the THC proves overwhelming, you can use CBD to reduce its psychoactivity.
  • What works for one person may not work for you. Cannabis can be a very individualized medicine, as everyone has a unique endocannabinoid system. Yes, there are some patterns according to condition and physiology, but there can still be some variations. You have to find what works best for you.
  • Take into account all the conditions you suffer from, and which symptoms you’re trying to reduce or overcome. This can help inform you about which cannabinoids and terpenes you ought to use, and which to avoid.
  • Ask yourself, “What do I hope to achieve with cannabis?” Is it sleeping 6+ hours? Is it being able to eat a proper meal? Is it to walk a mile without any pain? This can help you set goals and a target to achieve.
  • A product with a wide range of cannabinoids and terpenes is likely to be the most well-tolerated, as they all balance each other out and can mitigate some of the negative effects whilst still providing some therapeutic benefits. This is known as the entourage effect. However, some people may require a particular cannabinoid or set of cannabinoids for their condition. Utilizing multiple cannabinoids and terpenes can both increase a plant’s potency as well as reduce psychoactivity.
  • Cannabinoids are biphasic. This means that they can have two different effects at different dosages. THC, for example, can beat anxiety in low doses but cause anxiety in higher doses. The cannabinoid THCV (tetrahydrocannabivarin) can inhibit the psychoactivity of THC in low doses, but increase the psychoactivity of  THC in higher doses.
  • Figure out your favorite way to consume cannabis. Inhaling cannabis vapor or smoke has immediate effects lasting around 1 – 4 hours, but is not necessarily the healthiest method of ingestion. Edibles can have long-lasting effects (8 hours +), but can take 1 – 2 hours to kick in and can be difficult to dose properly. Oil-based tinctures taken sublingually (under the tongue) take effect within 30 minutes (occasionally 1 – 2 hours) after ingestion and last 6 – 8 hours.

Dosing Guide – Download Now

Does Medical Marijuana Interact With Other Medications?

Yes, medical marijuana does interact with other medications, although more study is needed to understand the nature and severity of the interactions more fully. Cannabis can interact with the following drug classes:

Opioids and opiates – mixing cannabis with such drugs can increase the CNS-depressant (CNS = central nervous system) effects of opioids, causing breathing to become even shallower. Those who use cannabis to overcome painkiller addiction ought to reduce opioid/opiate use over time (called tapering) in order to reduce the chances of negative interactions, withdrawal symptoms, and long-term complications. CB1 receptors and opioid receptors reside in the same areas of the brain, and cannabinoid receptors “talk” to opioid receptors. This is one of the reasons why cannabis may replace or reduce opioid intake.

Benzodiazepines, barbiturates and other sedatives – similar reasoning to opiates above. In the case of benzodiazepines, CBD desensitizes the liver enzyme that metabolizes it, called cytochrome P450 (CYP 450). This means that benzodiazepines are not processed and stay in the blood, increasing the chances of an overdose. Benzodiazepines may be prescribed for epilepsy and anxiety. Cannabinoids can be a safer, less addictive alternative to sedative-based medications.

Antidepressants – Some types of antidepressants, such as sertraline (Zoloft) and fluoxetine (Prozac), may have negative interactions with cannabis. Older antidepressants and mood disorder medications such as amitriptyline, dosulepin and monoamine oxidase inhibitors (MAOIs) such as moclobemide and phenelzine tend to have more negative effects than newer antidepressant medications.

Steroids – CBD desensitizes the action of the liver enzyme CYP3A4 (a subtype of CYP 450), meaning it can inhibit the processing of drugs like prednisone.

Alcohol – The desensitizing of the liver enzyme CYP2E1 also makes a cannabis user more sensitive to alcohol (ethanol).
Cannabinoids can affect the immune system, dampening inflammation. Cannabinoids can therefore act as an immunosuppressant.

Immunosuppressants – Combined with its liver enzyme desensitizing properties, CBD in particular can interfere with immunosuppressant drugs.
The immunosuppressant effects of cannabinoids must also be taken into account for those undergoing immunotherapy for cancer, as this can be a negative interaction.

Warfarin – there is some evidence showing that cannabis may increase the blood-thinning properties of warfarin.

You can see a full list of medications that have a negative interaction with cannabis here.

Medical Conditions MMJ Card
Medical Conditions medical marijuana certificate and MMJ Card

 

What Health Problems and Conditions Can Medical Cannabis Help With?

If you suffer from one or more of the above conditions, you may qualify for a medical marijuana card online, depending on your state’s qualifying conditions. Speak to a licensed medical cannabis physician online today, and you may get certified for medical cannabis!

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Written by
Dipak Hemraj
Dipak Hemraj - Chief Research Officer

Dipak Hemraj is a published author, grower, product maker, and Leafwell’s resident cannabis expert. From botany & horticulture to culture & economics, he wishes to help educate the public on why cannabis is medicine (or a “pharmacy in a plant”) and how it can be used to treat a plethora of health problems. Dipak wants to unlock the power of the plant, and see if there are specific cannabinoid-terpene-flavonoid profiles suitable for different conditions.

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