- Created: Sunday, 02 February 2014 19:41
- Written by Dr. Robert Townsend
The Cannabinoids and the Evolution of Cannabis as Medicine
The History of Cannabis as Medicine
Cannabis or Marijuana has been used in human medicine for thousands of years for conditions ranging from pain and cramping (documented in China in the 3rd millennium BC) to Anxiety (India 1st millennium BC) to nausea and a host of other medical conditions in the 19th Century. Cannabis has pyschoactive properties that led, in part, to its use being banned in 1937- But that is another story.
Recently with the medical marijuana movement in the United States and elsewhere, the emerging research on the cannabinoids and their use in medicine, cannabis is enjoying a resurgence as a useful medicine. This discussion is meant to provide background informatin for that discussion and the rational use and physiologic basis of cannabis as medicine.
The Discovery of Cannabanoids and related Endocannabinoids
THC, the pyschoactive chemical in cannabis sativa, was identified in 1964. It is one of 60 cannabinoids subsequently discovered over the next 25 years. Due to the fact that only certain isomers (mirror image molecules of the same chemical composition) of THC were psychoactive suggested to researchers that there was one or more specific receptors for cannabinoids in humans. These receptors were identified in the early 1990′s and called CB1 and CB2 receptors. In combination with this work, questions arose as to why there were receptors to plant cannabinoids in humans, and these efforts led to the discovery of naturally occurring ‘endo’ cannabinoids.
THC is an exogenous plant cannaboid that stimulates the CB1 receptor. The endocannaboid equivalent is ‘anandamide’. Anadamide is human thc much as endorphins are human morphine. Now we have a situation where we have receptors in humans that are responsive to external, plant derived, and internal endocannabinoids. The next phase of the investigation centered around ‘why are they here’ and ‘why do we need them’. This article attempts to, using available information, provide a layman’s level explanation of what the endocannabinoid system does, what we can use it for now, and suggest some possible uses in the future as the science of cannabis evolves.
Plants commonly develop properties that make them attractive to other species. For an interesting perspective on this, watch ‘The Botany of Desire”
The Physiologic Basis of Cannabanoids as Medicine
Both CB1 and CB2 receptors are found throughout the body. CB1 is mostly in the central nervous system, while CB2 are more peripheral. There are at least 2 other postulated but, as of yet, undiscovered receptors being investigated. The location of the receptors gives some hint as to what effects they have- for example, receptors in the spinal cord mediate pain, whereas those in the hypothalmus affect appetite. Receptors act as locks, there are specific keys that operate those locks.
An example is THC and the CB1 receptor. When a ligand (key) engages a receptor (lock) one of three things happens. Either the action of the receptor is triggered, or turned on (agonist); the action of the receptor is ‘turned off’ (antagonist), or the receptor is held neutral but occupied so no further action can take place (blocked). Ligands can bind ‘stongly’ or ‘weakly’- a strongly binding ligand can actually ‘bump off’ and replace a weakly binding one. They can also be ‘full’ or ‘partial’ agonists/antagonists.
An example of this would be the mu receptors for narcotics- methadone is a strong agonist compared to suboxone, so it is MUCH better with pain control, but suboxone binds more tightly and lasts much longer- methadone is blocked because it cannot replace the suboxone at the receptor. This is one of the physiologic foundations of suboxone therapy for narcotic addiction.
Mechanisms of Action in Specific Disease States
Diseases of Energy Metabolism:
The appetite stimulant effects of cannabis were reported in the literature as early as 1845. THC (CB1 Agonist) stimulates appetite when present in low levels. High levels interfere with the mechanical aspects of feeding due to the psychotropic and sedative effects of THC. CB1 receptors are found in the brain and central nervous system, in fat cells, and in the liver.
- The hypothalamus is the area of the brain responsible for appetite and is rich in CB1 receptors. Animal experiments confirm that activation of these receptors with anandamide trigger feeding activity, while blockade impairs appetite. The cannabinoid equivalent to anandamide is thc, which has psychotropic effects. Low levels of thc also trigger appetite, but high levels impair actual feeding activity in animals due to the psychoactive properties.
- In fat cells, CB1 receptors modulate lipid metabolism and promote fat deposition. An adverse effect in humans is obesity and metabolic syndrome, however blockade holds promise for treatment of these conditions. In situations where the patient is nutritionally compromised, as in wasting syndrome and cachexia due to diseases such as HIV and Cancer, these CB1 effects on lipids and appetite hold promise to reverse the nutritional deficiency and return the patient to a healthier body weight.
- CB1 receptors in the liver predispose the patient to ‘fatty liver’ due to the effects on lipid metabolism. Again, blockade of these receptors may be useful in the treatment of this condition (no treatments are available at this time).
- Skeletal muscle CB1 receptors play a role in promoting insulin resistance and metabolic syndrome/type 2 diabetes. This could make CB1 receptor blockers useful in the treatment of type 2 diabetes.
- The Endocannabinoid System is involved in suckling activity of newborns.
Proper nutrition is essential for a healthy immune system. Cachexia results with the energy expenditure of the body outstrips the intake of nutrition- one example known to many people is emphysema where the lungs do not properly absorb oxygen resulting in rapid breathing to increase the amount of air available for exchange- the resulting work outstrips the patient’s ability to take in nutrition and the body weight falls. Furthermore, age and hormonal related changes in appetite and absorption of nutrition (and deposition of fat), also play a part. When compounded by chronic disease, this effect becomes significant enough to require treatment.
Increasing the caloric intake and fat deposition by activation of the CB1 receptors holds promise to reverse the nutritional deficits caused by the stress of chronic disease. Selective or general blockade of CB1 receptors holds promise for the treatment of metabolic syndrome, fatty liver, and insulin resistance in type 2 diabetes. Selective blockade of hypothalamic receptors may find use as an appetite suppressant in the treatment of obesity.
Pain and Inflammation:
The treatment of pain is one of the oldest uses of cannabis. In controlled studies with acute pain, cannabinoids have been found useful against both chemical and thermal pain. It has also been studied in chronic pain of both neuropathic and inflammatory origin and found to be effective. In both situations the combination of cannabis and non-steroidal anti-inflammatory medications such as ibuprofen has been shown to be synergistic.
Cannabinoids are involved in the release of endogenous opioids which further moderate pain. The pain mediation responses of cannabis are related to the location of CB1 receptors in central nervous system and peripheral nerves. CB2 receptors are active in both acute and chronic pain, especially that of inflammatory origin.
While some studies have suggested that cannabis is no more effective than codeine in controlling pain (due to dose limitations because of psychoactive side effects), the side effect profile of cannabis vs narcotic pain control is worth considering as a factor- something not done in the initial study. Early studies used very low doses of cannabinoids and were somewhat inconclusive. Later studies used higher levels with more significant impacts on chronic pain and quality of life
Examples of studies concerning the use of cannabis as pain control include:
- In Multiple Sclerosis several studies (including one with over 600 patients) showed that Marinol (a synthetic form of THC) had modest but significant affects on pain levels. A second study with Sativex (cannabis extract) showed further reduction of neuropathic MS pain.
- Use of cannabis extract in the post operative period reduced the need for ‘rescue’ analgesic with narcotics compared to placebo.
- In a questionnaire study of over 500 HIV patients, >90% of those admitting to cannabis use reported resulting decrease in neuropathic and muscular pain.
- A clinical trial (25 patients) with neuropathic pain using ajulemic acid (a CB1 agonist derivative of THC) produced effective pain relief without psychoactive side effects. This suggests multiple subtypes of CB1 receptors (CB1a and CB1b) separating the pain and psychotropic actions of CB1 agonists.
With inflammation, there are multiple sites of action for both CB1 and CB2 agonists in the immune system. Stimulation of the immune system by bacterial toxins and other agents prompts the release of endocannabinoids and their related enzymes. They act in an anti-inflammatory capacity. Further discussion continues in the next 2 sections.
Central Nervous System Disorders:
Continuing the discussion on cannabis and inflammation started in chronic pain, we proceed to CNS disorders not commonly associated with medical cannabis. Most effects discussed are related to the CB2 anti-inflammatory effects of exogenous (external-plant) cannabinoids and endogenous (internal-human) endocannabinoids as they relate to cellular damage and the inflammatory and cytodestructive response to insult such as stroke. The high number of CB1 receptors in the areas of the brain responsible for movement, mood, memory, learning and internal ‘reward’ mechanisms led to research in these areas to investigate possible treatments for disorders involving those systems as well.
Both acute neural injury syndromes (traumatic brain injury, stroke, epilepsy) and degenerative neurologic disease such as MS, Parkinson’s, ALS, Huntington’s Disease and Alzheimer’s have demonstrated neuro-protective roles for CB1 and CB2 agonists- in many cases by modulating inflammation, reducing the release of damaging neurotransmitters while promoting the release of protective ones, anti-oxidant properties and the stabilization of cell membranes.
- Neurotoxicity and Neurotrauma- Endocannabinoids are involved in neuroprotection following both acute injury (Traumatic Brain Injury, Stroke, and Seizure) and neurodegenerative disorders (Multiple Sclerosis, Parkinson’s Disease, Huntington’s Disease, ALS and Alzheimer’s Disease). In TBI studies with the non-psychoactive cannabinoid dexanabinol reduced damage and improved both motor and cognitive function.
With CB1 agonists another study demonstrated a decrease of 70% in infarct size. A third study with dexanabinol demonstrated increased intracerebral profusion with no affect on systemic blood pressure. It was well tolerated by the study patients.
- Stroke- Some of the earliest work with the CNS effects of cannabinoids was in the field of stroke research. In experimental models of thrombotic stroke, dexanabinol (CB1 Agonist) decreased the infarct size if administered soon after the event- within 60 to 180 min.
- Multiple Sclerosis- With MS, an inflammatory mediated disease of the central and peripheral nervous system, and spinal cord disease the main symptoms are spasticity and neuropathic pain. Cannabis has been used since antiquity for the relief of pain and spasm, and now the mechanism is being elucidated and appears to be related to the neuroprotective and anti-inflammatory properties of CB1and2 agonists.
While several studies using standardized reporting of spasticity did not show significant differences between placebo and active groups, patient reports showed significant improvement in self perception of spasticity, pain, quality of sleep and overall sense of well being. Hospital admissions for complications of MS were reduced in the treatment group as well. In a 12 month follow up the cannabis group demonstrated significant improvement in tremor.
- Movement Disorders- In movement disorders related to basal ganglia dysfunction, such as Parkinson’s, Huntington’s, and Tourette’s CB1 receptors are increased in the basal ganglia, perhaps in an effort to return function in Parkinson’s in the absence of dopamine. Treatment with CB1 agonists can decrease the tremor of Parkinsons. Additionally CB1 can improve bradykenisis (shuffling walk) in PD.
Huntington’s Disease is a devastating syndrome characterized by movement disorders, dementia, and dystonia. Early in the disease, there is a decrease in CB1 receptors and ‘tone’ of the endocannabinoid system much as there is a loss of dopamine and dopaminergic ‘tone’ in Parkinson’s Disease. It is suggested that replacement therapy with CB1 agonists such as thc can be helpful symptomatically. With Tourette’s, cannabis has been found to reduce the tics and vocalizations that characterize the syndrome.
- ALS/Lou Gehrig’s Disease- A common adult onset neurologic disorder producing motor neuron degeneration, weakness, paralysis and death. The neuroprotective and other effects of cannabis have been helpful with appetite, spasticity and insomnia. In some animal models of the disease, life span was improved. Further study is needed in humans.
- Alzheimer’s Disease- Studies with anandamide demonstrated reduction in neurotoxicity due to inhibition of the release of Nitrous Oxide and other toxic metabolites. CB2 receptors are ‘over-expressed’ in the plagues found in the brains of AD patients and test animals. Studies suggest that the endocannabinoid system is triggered in AD to release cytoprotective agents to mediate the damage. In one series of 6 patients treated with Marinol (CB1 agonist) significant improvement in agitation and motor skills with 2 weeks of daily treatment.
- Epilepsy- Seizures are very much like a nuclear reactor. The pre-synaptic neurons (Uranium) release signals which are absorbed by the post-synaptic neurons, absorbed and inhibitory substances released (lead rods). If the pre-synaptic neurons release more signals than the post-synaptic neurons can control, the inhibitory substances are overwhelmed and a ‘chain reaction’ or seizure results.
Endocannabinoids are released by the post-synaptic neurons to trigger CB1 receptors on the pre-synaptic neuron- which inhibit the release of further signals from the pre-synaptic neuron. They basically put the rods a little further into the core and slow things down. Conventional epilepsy treatment is ineffective in about 30% of the patients, and cannabis has been used to treat seizures for centuries.
In Part II
- Liver and GI Disorders
- Eye Disorders
In Part III
- Myocardial Infarction, Hypertension
- Mental Disorders
- Respiratory Disease, Asthma
- Substance abuse treatment
- There are many links for further reading on each condition. Follow them to an expanded discussion, results of medical research, etc
- This will be a year long on-going project to conduct a definitive discussion of the human endocannabinoid system for laypersons and patients as possible.
- It is designed to act as medical resource, legal resource and reference document for the media, discussions with your family doctor, etc.