Movement disorders and neurodegenerative diseases, which are sometimes interlinked, are among the many conditions that cannabis and cannabinoids may be particularly well suited to treat.
CANNABIS AND MOVEMENT DISORDERS
Movement disorders and neurodegenerative diseases, which are sometimes interlinked, are among the many conditions that cannabis and cannabinoids may be particularly well suited to treat.
The therapeutic use of cannabis for treating muscle problems and movement disorders has been known to western medicine for nearly two centuries. In reference to the plant's muscle relaxant and anti-convulsant properties, in 1839 Dr. William B. O'Shaughnessy wrote that doctors had "gained an anti-convulsive remedy of the greatest value."27 In 1890 Dr. J. Russell Reynolds, physician to Queen Victoria, noted in an article in The Lancet that for "organic disease of a gross character in the nervous centers . . . India hemp (cannabis) is the most useful agent with which I am acquainted."28
Muscular spasticity is a common condition, affecting millions of people in the United States. It afflicts individuals who have suffered strokes, as well as those with multiple sclerosis, cerebral palsy, paraplegia, quadriplegia, and spinal cord injuries. Conventional medical therapy offers little to address spasticity problems. Phenobarbital and diazepam (Valium) are commonly prescribed, but they rarely provide complete relief, and many patients develop a tolerance, become addicted, or complain of heavy sedation. These drugs also cause weakness, drowsiness, and other side effects that patients often find intolerable.
Extensive modern studies in both animals and humans have shown that cannabis can treat many movement disorders affecting older patients, such as tremors and spasticity, because cannabinoids have antispasticity, analgesic, antitremor, and antiataxia properties.29-40
In the federal court brief filed in support of physicians' right to recommend cannabis, the American Public Health Association states that "marijuana is effective in treating muscle spasticity." They point out that the government's own Institutes of Medicine report on medical use of cannabis found that "current treatments for painful muscle spasms . . . have only limited effectiveness and their use is complicated by various adverse side effects."
They go on to note that "a survey of British and American MS patients reports that after ingesting marijuana a significant majority experienced substantial improvements in controlling muscle spasticity and pain. An extensive neurological study found that herbal cannabis provided relief from both muscle spasms and ataxia (loss of coordination), a multiple benefit not achieved by any currently available medications" (amicus brief in Conant v. McCaffrey, 2001 filing).
Cannabis also has enormous potential for protecting the brain and central nervous system from the damage that leads to various movement disorders. Researchers have also found that cannabinoids can alleviate the damage caused by strokes, as well as brain trauma, spinal cord injury, and multiple sclerosis. More than 100 research articles have been published on how cannabinoids act as neuroprotective agents to slow the progression of such neurodegenerative diseases as Huntington's, Alzheimer's and particularly Parkinson's, which affects more than 52% of people over the age of 85.
An understanding of the actions of cannabis was spurred by the discovery of an endogenous cannabinoid system in the human body. This system appears to be intricately involved in normal physiology, specifically in the control of movement.41-45 Central cannabinoid receptors are densely located in the basal ganglia, the area of the brain that regulates body movement.
Endogenous cannabinoids (which are those cannabinoids produced by our bodies) also appear to play a role in the manipulation of other transmitter systems within the basal ganglia - increasing transmission of certain chemicals, inhibiting the release of others, and affecting how others are absorbed. Research suggests that endogenous cannabinoids play a part in the body's control of movements.46-50
Endocannabinoids have paradoxical effects on the mammalian nervous system: sometimes they block neuronal excitability and other times they augment it. As scientists are developing a better understanding of the physiological role of the endocannabinoids, it is becoming clear that these chemicals may be involved in the pathology of several neurological diseases. Researchers are identifying an array of potential therapeutic targets within the human nervous system.
Movement disorders can be chronic disorders which arise from the loss or destruction of neurons and other structures in the brain. nterestingly, the activation of cannabinoid receptors was shown to trigger neuronal growth, suggesting that a role in neuronal regeneration.36 Various cannabinoids found in the cannabis plant can modulate the synthesis, uptake or metabolism of the endocannabinoids that are involved in the progression of Huntington's disease, Parkinson's disease, multiple sclerosis, and Alzheimer's disease.51-53
Parkinson's disease has been linked to dysfunction in the body's dopamine system, specifically the production of too much of the neurotransmitter glutamate and oxidative damage to dopaminergic neurons. Studies have found a tight association between cannabinoids and dopamine, and recent research has produced anatomical, biochemical and pharmacological evidence supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Furthermore, the CB1 receptor appears to be deregulated in the basal ganglia of mice with this disease. Specifically, the down regulation of the CB1 receptor may be an early event in the beginning of Parkinson's disease.54-456 A profound up regulation of the CB1 receptor may occur after Parkinson's symptoms appear.
Oxidative stress in the brain is a major hallmark of motor and neurological diseases such as Parkinson's and Alzheimer's disease. Cannabinoids are able to protect neurons from oxidative damage.57 The neuroprotective action of cannabinoids appears to result from their ability to inhibit reactive oxygen species, glutamate, and tumour necrosis factor. THC, CBD, and synthetic AM404 all contain phenolic groups in their chemical structure and are thus able to reduce radical oxygen species. Notably CBD has extraordinary antioxidant properties and can effect Calcium homeostasis, both of which lead to positive effects against a wide range of neurodegenerative diseases.58
Few clinical trials have looked at Cannabinoids and Parkinson's disease. However, research has shown that 25% of Parkinson's patients smoke cannabis and 46% of these patients report improvement resulting from side effects of long term levodopa treatment.44 A randomized placebo controlled study using extracts of cannabis produced significant improvements in patients' cognition. The authors note that they did not see improvements in pain or sleep disorders. They speculate that the oral route (versus inhaled) of cannabis ingestion leads to too much variability of cannabinoids in blood.59
Plant cannabinoids, such as CBD have been effective in experimental models of Alzheimer's, Parkinson's, and Huntington's disease. Hence, cannabinods represent an emerging therapeutic option that could be available in the near future. However, cannabinoids are still in an early phase of development but research suggest that they can be useful drugs for the treatment of many disease processes of the brain and central nervous system.
Spasticity and Movement Disorder Medications
Benzodiazepines, levedopa, baclofen, dantrolene sodium, and tizanidine are the most widely used agents for reduction of spasticity. At high dosages, oral medications can cause unwanted side effects that include sedation, as well as changes in mood and cognition.
Benzodiazepines, which include Diazepam (Valium) and Clonazepam (Klonopin, Rivotril), are centrally acting agents that increase the affinity of GABA to its receptor. Diazepam is the oldest and most frequently used oral agent for managing spasticity. Benzodiazepine side effects include sedation, weakness, hypotension, GI symptoms, memory impairment, incoordination, confusion, depression, and ataxia are possible side effects of. Tolerance and dependency may occur and withdrawal on cessation. Tolerance may also lead to unacceptable dosage escalation.
Levedopa is common long-term treatment option for Parkinson's disease. Long-term use can result in diskynesia and is often a reason for not taking the drug. Diskynesia can lead to less control of voluntary movements and can result in tics or chorea. Dikynesia can result in excessive tongue rolling and after years of use it can manifest as "jerky" movements of the head and arms.
Baclofen (Lioresal) has been widely used for spasticity since 1967. It is a GABA agonist. Tolerance to the medication may develop. Baclofen must be slowly weaned to prevent withdrawal effects such as seizures, hallucinations and increased spasticity. It must be used with care in patients with renal insufficiency as its clearance is primarily renal. Side effects are predominantly from central depressant properties including sedation, ataxia, weakness and fatigue. May cause depression when combined with tizanidine or benzodiazepines.
Dantrolene Sodium (Dantrium) acts peripherally at the level of the muscle fiber and works best for cerebral palsy and traumatic brain injury. Because the action of dantrolene sodium is not selective for spastic muscles, it may cause generalized weakness, including weakness of the respiratory muscles. Side effects include drowsiness, dizziness, weakness, fatigue and diarrhea. In addition, hepatotoxicity (liver damage) occurs in < 1% of patients who take dantrolene sodium.
Tizanidine (Zanaflex) facilitates short-term vibratory inhibition of the H-reflex. Tizanidine in conjunction with baclofen or benzodiazepines has potential additive effects, including sedation and the possibility of liver toxicity. Dry mouth, somnolence, asthenia and dizziness are the most common side effects. Liver function problems and hallucinations may also occur.
How Cannabis Compares
By comparison, the side effects associated with cannabis are typically mild and are classified as "low risk." Euphoric mood changes are among the most frequent side effects. Cannabinoids can exacerbate schizophrenic psychosis in predisposed persons. Cannabinoids impede cognitive and psychomotor performance, resulting in temporary impairment. Chronic use can lead to the development of tolerance. Tachycardia and hypotension are frequently documented as adverse events in the cardiovascular system. A few cases of myocardial ischemia have been reported in young and previously healthy patients. Inhaling the smoke of cannabis cigarettes induces side effects on the respiratory system. Cannabinoids are contraindicated for patients with a history of cardiac ischemias. In summary, a low risk profile is evident from the literature available. Serious complications are very rare and are not usually reported during the use of cannabinoids for medical indications.
Is cannabis safe to recommend?
"The smoking of cannabis, even long term, is not harmful to health...." So began a 1995 editorial statement of Great Britain's leading medical journal, The Lancet. The long history of human use of cannabis also attests to its safety - nearly 5,000 years of documented use without a single death. In the same year as the Lancet editorial, Dr. Lester Grinspoon, a professor emeritus at Harvard Medical School who has published many influential books and articles on medical use of cannabis, had this to say in an article in the Journal of the American Medical Association (1995):
One of marihuana's greatest advantages as a medicine is its remarkable safety. It has little effect on major physiological functions. There is no known case of a lethal overdose; on the basis of animal models, the ratio of lethal to effective dose is estimated as 40,000 to 1. By comparison, the ratio is between 3 and 50 to 1 for secobarbital and between 4 and 10 to 1 for ethanol. Marihuana is also far less addictive and far less subject to abuse than many drugs now used as muscle relaxants, hypnotics, and analgesics. The chief legitimate concern is the effect of smoking on the lungs. Cannabis smoke carries even more tars and other particulate matter than tobacco smoke. But the amount smoked is much less, especially in medical use, and once marihuana is an openly recognized medicine, solutions may be found; ultimately a technology for the inhalation of cannabinoid vapors could be developed.
The technology Dr. Grinspoon imagined in 1995 now exists in the form of "vaporizers," (which are widely available through stores and by mail-order) and recent research attests to their efficacy and safety. Additionally, pharmaceutical companies have developed sublingual sprays and tablet forms of the drug. Patients and doctors have found other ways to avoid the potential problems associated with smoking, though long-term studies of even the heaviest users in Jamaica, Turkey and the U.S. have not found increased incidence of lung disease or other respiratory problems. A decade-long study of 65,000 Kaiser-Permanente patients comparing cancer rates among non-smokers, tobacco smokers, and cannabis smokers found that those who used only cannabis had a slightly lower risk of lung and other cancers as compared to non-smokers. Similarly, a study comparing 1,200 patients with lung, head and neck cancers to a matched group with no cancer found that even those cannabis smokers who had consumed in excess of 20,000 joints had no increased risk of cancer.
As Dr. Grinspoon notes, "the greatest danger in medical use of marihuana is its illegality, which imposes much anxiety and expense on suffering people, forces them to bargain with illicit drug dealers, and exposes them to the threat of criminal prosecution." This was the conclusion reached by the House of Lords, which recommended rescheduling and decriminalization.
In January 2013, the American Herbal Products Association (AHPA), which has a 30-year history of developing standards for the herbal products industry, issued recommendations for effectively regulating all aspects of cannabis distribution for patients. The regulatory recommendations, developed over two years by the AHPA Cannabis Committee address guidelines for cultivation, quality-assurance, analytics, cannabis product manufacture and labeling, storefront and delivery services, and personnel training.
In December 2013, the American Herbal Pharmacopeia released a monograph identifying cannabis as a botanical medicine. Written and reviewed by the world’s leading experts on cannabis, the monograph provides a full scientific understanding of the plant, its constituent components, and its biologic effects. It also establishes comprehensive standards for the plant's identity, purity, quality, and botanical properties.
Following the release of the monograph, ASA launched Patient Focused Certification, the first non-profit, third-party certification program based on the AHPA regulatory recommendations and the AHP standards. Patient Focused Certification (PFC) audits cultivators, distributors, manufacturers and laboratories to verify compliance with best-practice standards. PFC includes employee training, compliance inspections, ongoing monitoring, and an independent complaint process for customers, as well as comprehensive reviews of formulations and materials, independent testing, and facility inspections.
Cannabis or Marinol?
Those committed to the prohibition on cannabis frequently cite Marinol, a Schedule III drug, as the legal means to obtain the benefits of cannabis. However, Marinol, which is a synthetic form of THC, does not deliver the same therapeutic benefits as the natural herb, which contains at least another 60 cannabinoids in addition to THC. Recent research conducted by GW Pharmaceuticals in Great Britain has shown that Marinol is simply not as effective for pain management as the whole plant; a balance of cannabinoids, specifically CBC and CBD with THC, is what helps patients most. In fact, Marinol is not labeledfor pain, only appetite stimulation and nausea control. But studies have found that many severely nauseated patients experience difficulty in getting and keeping a pill down, a problem avoided by use of inhaled cannabis.
Clinical research on Marinol vs. cannabis has been limited by federal restrictions, but a 2001 review of clinical trials conducted in the 70's and 80's reports that ". . . the inhalation of THC appears to be more effective than the oral route."49 Additionally, patients frequently have difficulty getting the right dose with Marinol, while inhaled cannabis allows for easier titration and avoids the negative side effects many report with Marinol. As the House of Lords oberves, "Some users of both find cannabis itself more effective."
THE EXPERIENCE OF PATIENTS
Vollie Rutledge, Jr.
In July of 1990 I was driving home from work and as I came around a corner doing 55 MPH I came into a herd of deer. I tried to miss them but one of them fell down and my right front tire went up on the deer's hip like a ramp. My car flipped over and went down an embankment. It landed on the roof smashing the driver's compartment down to the level of the top of the seat. I didn't have a seat-belt on so I was able to dive into the passenger's floorboard but even that didn't save me.
I woke up in the hospital a couple of days later with a broken vertebra. Medically it was called "an unstable fracture of the second vertebra" or C-2 fracture. Somehow it didn't kill me, but it did paralyze my left side for a couple of weeks. When the feeling came back all of the nerves reacted spastically. If I reached for something I couldn't control where my hand was going. If I sneezed my hand would fly uncontrollably.
Several times I bloodied my nose with my left hand just sneezing. I finally learned to grab my left arm when I sneezed. I couldn't walk without a cane because I couldn't trust my left leg to go where I wanted it to. It was an extremely difficult time in my life. About two months after the accident my friends had come over to visit and as it happened, I sneezed. My arm came up and hit me in the face and bloodied my nose once again. I was embarrassed to say the least.
One of my friends rolled a joint and something happened... The muscles in my neck relaxed and when I reached for my coffee my arm went where it was supposed to. As long as I moved very slowly, I could move correctly. Within a week I was using my hand to shuffle a deck of cards. I can't explain how dramatic the difference was. I went from not being able to eat with a fork (previously too spastic to grab and hold a fork) to shuffling a deck of cards and dealing them in just one week. Within three weeks I could walk without a cane. Once again I could trust my legs to go where I wanted them. Marijuana is the only drug that any doctor has found, in eight years of trying different drugs, that works.
I work and lead a normal and productive life. I consume very little alcohol, I exercise and eat right. I do not smoke cigarettes. I am involved with my family, the community and participate in fund-raising events to benefit folks internationally. I have a happy, modest family. We gather weekly for activities, food and company. I have a college degree and several certifications in my field. I am a white collar professional. I am an executive for a large financial corporation and I use and grow medical marijuana for the relief of chronic neuro-muscular pain and spasms.
This plant reduces and even stops my chronic muscle spasms as a result of severe neuro-muscular damage from an industrial accident I suffered 12 years ago. In short, I nearly lost my right hand and upper arm in a terrible accident. Surgically my parts were re-attached, however my nerves are to this day temperamental and spastic. There are days my hand is locked in a fist and I am unable to release it. The pain from this literally brings me to my knees.
So called "legal" prescription drugs not only did not work for my condition, they made me very ill, prevented me from being able to do simple things in life like; work, drive, talk, cook, read and even wipe myself. My so called "legal prescriptions" all went into the garbage can where they belong. I no longer care what the propaganda machine says about marijuana anymore. This drug works without all of the undesired side effects.
For years I have suffered with chronic pain and severe muscle spasms due to a hunting accident and surgery on my back. I have taken more medicine than I can remember - over 50 different medicines that I know of - with still no relief for the pain. The only medicine that even came close to helping the muscle spasms was Valium, but my doctor took me off it for fear I would get hooked. I have been smoking marijuana for many years, and it is the only other drug that has helped me with the spasms.
When a violent spasm in my leg starts coming on, my wife will roll me a joint and within minutes of smoking half of it, the spasms start to dissipate. Before, it could spasm for hours without relief. My question is, why will this drug do this when all of the prescription medicines I have taken will not? Also, I have a medicine pump in my stomach, which was put in this February by a pain clinic doctor. I receive a half a milligram of Dilaudid every fifteen minutes from this pump. The doctor started me out on low doses and is gradually building up, but it still does not in any way compare to the effect from smoking a joint.
The Experience of Doctors
Denis Petro, M.D.
As a practicing neurologist, I saw many patients for whom uncontrollable spasticity was a major problem. Unfortunately, there are very few drugs specifically designed to treat spasticity. Moreover, these drugs often cause very serious side effects. . . Dantrium or dantrolene sodium carries a boxed warning in the Physician's Desk Reference because of its very high toxicity. . . The adverse effects associated with Lioresal Baclofen are somewhat less severe, but include possibly lethal consequences, even when the drug is properly prescribed and taken as directed. . . Unfortunately, neither Dantrium or Lioresal are very effective spasm control drugs. Their marignal medical utility, high toxicity, and potential for serious adverse effects, make these drugs difficult to use in spasticity therapy.
[Dr. Petro discussed a patient who was smoking cannabis for his symptoms. Dr. Petro asked him to refrain from smoking for six weeks.]
After six weeks he returned for another examination. At this time, he reported an increase in his symptoms to the point where he had leg pains, increased clonic activity, and uncontrolled leg spasms every night. More disturbing to him was urinary incontinence, which occurred on two occasions during leg spasms. On objective examination. . .in layman's terms, this patient's spasticity had increased dramatically in six weeks. This spasticity made his legs extremely rigid, he was finding it increasingly difficult to walk or sleep, and he was losing bladder control.
Following our examination, and at the patient's request, he left the clinic then returned one hour later to be examined for a second time. This second examination was remarkable. The earlier findings of moderate to severe spasticity could not be elicited. Deep tendon reflexes were brisk, but without spread, ankle clonus was absent, and the plantar response was flexor on the left and equivocal on the right. In short, this patient had undergone a stunning transformation. Moreover, this unmistakable improvement had occurred in an incredibly brief period of time-less than an hour separated the two examinations. On questioning, the patient informed us he had smoked part of one marijuana cigarette in the interval between examinations.
Denis Petro, M.D., Former FDA Review Officer and principal investigator on spasticity and cannabis studies, in testimony submitted before the DEA.
Leo E. Hollister, M.D.
Patients with spinal cord injuries often self-treat their muscle spasticity by smoking cannabis. Cannabis seems to help relieve the involuntary muscle spasms that can be so painful and disabling in this condition. A muscle relaxant or antispastic action of THC was confirmed by an experiment in which p.o. doses of 5 or 10 of THC were compared with placebo in patients with multiple sclerosis. The 10 mg of THC reduced spasticity by clinical measurment. Such single small studies can only point to the need for more study of the potential use of THC or possibly some of its homologs. Diazepam, cyclobenzaprine, baclofen, and dantrolene, which are used as muscle relaxants, all have major limitations. A new skeletal muscle relaxant would be most welcome.
Leo E. Hollister, Veterans Administration Medical Center and Stanford University School of Medicine, Palo Alto, California
Lester Grinspoon, M.D.
There are many case reports of marihuana smokers using the drug to reduce pain: post-surgery pain, headache, migraine, menstrual cramps, and so on. Ironically, the best alternative analgesics are the potentially addictive and lethal opioids. In particular, marihuana is becoming increasingly recognized as a drug of choice for the pain that accompanies muscle spasm, which is often chronic and debilitating, especially in paraplegics, quadriplegics, other victims of traumatic nerve injury, and people suffering from multiple sclerosis or cerebral palsy. Many of them have discovered that cannabis not only allows them to avoid the risks of other drugs, but also reduces muscle spasms and tremors; sometimes they can even leave their wheelchairs.
The years of effort devoted to showing that marihuana is exceedingly dangerous have proved the opposite. It is safer, with fewer serious side effects, than most prescription medicines, and far less addictive or subject to abuse than many drugs now used as muscle relaxants, hypnotics, and analgesics.
Thus cannabis should be made available even if only a few patients could get relief from it, because the risks would be so small. For example, as I mentioned, many patients with multiple sclerosis find that cannabis reduces their muscle spasms and pain. A physician may not be sure that such a patient will get more relief from marihuana than from the standard drugs baclofen, dantrolene, and diazepam - all of which are potentially dangerous or addictive - but it is almost certain that a serious toxic reaction to marihuana will not occur. Therefore the potential benefit is much greater than any potential risk.
Dr. Grinspoon is professor emeritus at Harvard University School of Medicine, and the author of numerous publications.
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2. See Conant v. McCaffrey, 172 F.R.D. 681 (N.D. Cal. 1997).
3. See id.; Conant v. McCaffrey, 2000 WL 1281174 (N.D. Cal. 2000); Conant v. Walters, 309 F.3d 629 (9th Cir. 2002).
4. 309 F.3d 629 (9th Cir. 2002).
5. Id. at 634-36.
6. Criminal liability for aiding and abetting requires proof that the defendant "in some sort associate[d] himself with the venture, that he participate[d] in it as something that he wishe[d] to bring about, that he [sought] by his action to make it succeed."Conant v. McCaffrey, 172 F.R.D. 681, 700 (N.D. Cal. 1997) (quotation omitted). A conspiracy to obtain cannabis requires an agreement between two or more persons to do this, with both persons knowing this illegal objective and intending to help accomplish it. Id. at 700-01.
7. 309 F.3d at 634 & 636.
8. Conant v. McCaffrey, 2000 WL 1281174, at *16 (N.D. Cal. 2000).
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