WHAT SHOULD I KNOW ABOUT MEDICAL CANNABIS?
The cannabis plant belongs to the family Cannabaceae, genus Cannabis.
Tetrahydrocannabinol (THC)
- THC is responsible for the main pharmacological effects of cannabis. It is a partial agonist of type-1 and type-2 cannabinoid receptors (CB1 and CB2, respectively). Activation of central CB1 receptors elicits cannabis-related psychoactivity.9-12
- Its synthetic version, dronabinol, has been approved by several medicine agencies for the symptomatic alleviation of chemotherapy-induced nausea and vomiting (CINV) and anorexia and wasting syndrome associated to HIV and cancer.
- Potential medical applications:10-12
- Chronic Pain (e.g. Neuropathic Pain)
- Spasticity associated to Multiple Sclerosis
- Chemotherapy-induced nausea and vomiting (CINV)
- Anorexia and wasting syndrome in HIV and cancer patients
- Sleep disorders
- Post-Traumatic Stress Disorder
- Control of tics in Gilles de la Tourette’s disease
- Anxiety and depression (only at low doses)
- Disorders of the gastrointestinal tract (e.g. peptic ulcers, IBD)
- Adverse effects such as anxiety, euphoria, paranoia, etc. have been shown to be dose-related and more common when high concentrations of THC are used. They can be avoided by starting with the lowest doses and titrating slowly until the treatment goals are achieved.13
Cannabidiol (CBD)
- Does not cause intoxication and is generally well tolerated.
- Does not activate CB1 or CB2 receptors at physiologically-relevant concentration. However, it may modulate the therapeutical profile of THC, improving its tolerability and safety.14
- CBD is a rather “promiscuous” molecule as it can interact with many different biological cannabinoid targets such as:
- Weak antagonist of CB1 and CB2 at low concentrations and negative allosteric modulator (NAM) of CB1
- Antagonist of GPR55
- Inhibitor of anandamide degradation via FAAH and AEA transport
- CBD also exerts anti-inflammatory and immunosuppressive actions mediated by non-cannabinoid targets:14
- Inhibition of neutrophil chemotaxis and proliferation
- Inhibition of the release of arachidonic acid, ↓PGE2, ↓NO
- Cytokine production: ↑IL-10, ↓IL-12, ↓IL-1, ↓IL-6 and IFNγ
- Activation of adenosine receptors A1A and A2A
- Activation of strychnine-sensitive α1 and α1β glycine receptors
- Inhibition of the equilibrative nucleoside transporter
- Agonist of serotonin 5HT1A receptors
- Potential medical applications:10-12
- Refractory Epilepsy (Lennox Gastaut Syndrome, Dravet Syndrome).
- Anxiety (e.g. Social Anxiety Disorder).
- Parkinson's Disease (Non-Motor Symptoms).
- Chronic pain (Because of its anti-inflammatory effect. Consider in patients with concomitant anxiety).
- Direct antioxidant effects.
Other minor cannabinoids on interest are:
- Cannabigerol (CBG): Molecular precursor of both THC and CBD, its clinical effects are not well described.17 Preliminary pharmacological characterization suggest that it may act as an antagonist to TRPM8 and have protective effects over neurologic and intestinal pro-inflammatory insults.15
- Cannabinol (CBN): results from the oxidation of THC. Pre-clinical studies suggest that it can produce mildly-sedative, psychoactive and analgesic effects.16
- Δ9-Tetrahydrocannabivarin (THCV): is a chemical analogue of THC with a shorter acyl chain (3 carbons instead of 5). Preliminary pharmacological characterization suggest that it may act as a partial antagonist to CB1 receptors.16
- Cannabidivarin (CBDV): is a chemical analogue of THC with a shorter acyl chain (3 carbons instead of 5). Preliminary pharmacological characterization suggest that it may present anti-inflammatory, neuroprotective, and anti-epileptic potential.16
Terpene
- Terpenes are highly volatile, aromatic compounds responsible for the characteristic smell of cannabis.17
- Terpenes originate by enzymatic polymerization of two or more isoprene units, in multiples of 5 carbons and constitute the largest group of plant chemicals and have a wide spectrum of biological actions (e.g. insect repellent).17
- They are not exclusive to Cannabis sativa L. and have a wide spectrum of biological actions (e.g. insect repellent).18
- Terpene profiles may largely vary among Cannabis sativa L. cultivars. Most prominent terpenes in cannabis include: β-caryophyllene, limonene, α-pinene, myrcene, humulene, ocimene or terpineol.17
Chemotypes
Cannabis cultivars can be classified in different chemotypes, generally depending on the relative amounts of THC and CBD (as percentage of weight) contained in the dried flowers.9 Cannabis chemotypes are:
THC-rich cannabis cultivars with little amounts of CBD (e.g. THC:CBD ratio 20:1)
Chemotype 2: cannabis cultivars containing a similar ratio of THC and CBD (ratio THC:CBD 1:1)
cannabis cultivars rich in CBD and small amounts of THC (e.g. ratio of THC:CBD 1:20)
The endocannabinoid
The endocannabinoid system (ECS) is a lipid signaling system that serves important regulatory functions in the whole organism favoring homeostasis.10, 21 This system modulates many physiological processes including the regulation of neurotransmission, as well as endocrine and paracrine actions (see figure below):
Sleep-wake cycle
Psychomotor behavior
Bone development and density
Pain perception
Emotional state
Skin
Cardiovascular system
Brain system
Digestive system
Immune system
The main components of this cellular communication system are:
1. Cannabinoid receptors
2. Endocannabinoids
(endogenous ligands of cannabinoid receptors, derived from arachidonic acid)
AEA
N-archidonoylethanolamide, or “anandamide” (AEA), named after the Sanskrit term “Ananda”, which
means “internal bliss”.
2-AG
2-Archidonoylglycerol (2-AG).
3. Enzymes responsible for endocannabinoid synthesis
NAPE
Phospholipase D (NAPE-PLD) which produces anandamide and other fatty acid amides
such as OEA or PEA.
DAGL
Diacylglycerol lipase (DAGL) which synthesizes
2-AG
4. Enzymes responsible for endocannabinoid deactivation
FAAH
Fatty acid amido-hydrolase (FAAH) which hydrolyzes AEA and related fatty-acid ethanolamides (OEA and PEA)
MAGL
Monoacylglycerol lipase (MAGL), which degrades
2-AG.
Process of production, release, and action of endocannabinoids:
- Step 1 - Synthesis of endocannabinoids: 2-AG and AEA are synthesized and released "on demand" by DAGL and NAPE-PLD from the postsynaptic terminal.
- Step 2 - Bonding to the CB1 receptor: 2-AG/AEA crosses the synaptic cleft to bind to CB1 receptors in the presynapsis.
- Step 3 - Opening of potassium channels and closure of calcium channels: Activation of CB1 receptors causes the inflow of K+ and the closure of Ca+ channels.
- Step 4 - Hyperpolarization of the presynaptic terminal and inhibition of the release of excitatory and inhibitory neurotransmitters
- Step 5 - Entry of endocannabinoids into the neuron and enzymatic degradation: 2-AG and AEA are degraded by MAGL and FAAH, respectively, inside the cell.
