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Tourette's Syndrome

Medical cannabis in Tourette’s syndrome: case reports and a small randomized controlled clinical trial

Virginia Thornley, M.D., Neurologist, Epileptologist
June 11, 2018

@VThornleyMD

Introduction
When one hears Tourette’s syndrome the glorified Hollywood impression young person who shouts obscenities comes to mind. It is composed of complex motor or vocal tics generally preceded by a premonitory urge. Vocal tics may consist of coprolalia and echolalia. Motor tics may involve complex actions including copropraxia or simple motor tics. Obsessive compulsive disorder and other neuropsychiatric conditions are often associated with it.

The underlying problem is thought to be related to an imbalance of the neurotransmitters necessary to maintain the fine coordination necessary to avoid excessive motor activity. When that balance is impaired there is less inhibition of motor loop control resulting in reverberating loops and excess movements involving motor groups including muscles controlling speech and body movements. Because the pathophysiology is not entirely clear, these may be some of the most challenging neurological disorders in terms of treatments from a neurological standpoint.

Background on Cannabinoid Mechanisms
With the advent of medical cannabis used in neurological conditions, new indications are discovered. The mechanism is at the level of the endocannabinoid system already inherent within the system. There are 2 receptors, CB1 and CB2. The CB1 receptor is found mostly within the nervous system. The CB2 receptor is mostly in the immune system but is found in other organ systems to a lesser extent. Tetrahydrocannabinol (THC) is a mimetic of Anandamide which works within the endocannabinoid system and has medical properties. THC interacts with the CB1 receptor which is responsible for psychoactive properties most people are familiar with. It is likely at the CB1 receptor where other neurological symptoms are alleviated since this most abundantly found in the nervous system and many neurological symptoms are ameliorated with medical cannabis. Cannabidiol (CBD), which is non-psychoactive, is a pharmacomimetic of 2-AG or diarachidonylglycerol. It is an non-competitive allosteric modulator of the CB1 receptor which alleviates any side effects from THC when they are combined together (1).

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Clinical Reports
There is one report of a patient treated with nabiximol where there was improvement of tics. There was overall improvement in quality of life and global improvement. There was lessening of premonitory urges. Patients feel the premonitory symptoms are more bothersome. In one study anti-psychotics helped ameliorate the motor tics but did not improve the premonitory symptoms (2). Nabiximol was used in this study where 1 puff contained 2.7mg of THC and 2.5mg of CBD. Assessments included the Yale Global Tic Severity Scale (YGTSS), Tourette’s Syndrome Symptom LIst (TSSL), Modified Rush Video Tic Scale, Premonitory Urge for Tic Scale, Global Clinical Impairment, Visual Analogue Scale for satisfaction for the GTS-Quality of Life. The study showed the best results in the quality of life in terms of alleviating premonitory urges. Larger clinical trials are needed to further this study (2).

In a recent case report, THC (trademark Sativex) was used with success to treat a patient using 10.8mg THC and 10mg CBD daily. Yale Global Tic Severity Scale (YGTSS) and the Original Rush Video Tic Scale were used as measures of evaluation. The results demonstrated effective use of THC in combination with THC for treatment in medically refractory patients (5).

In one single dose, cross over study in 12 patients and a randomized trial in 24 patients spanning 6 weeks was performed (3). The study demonstrated that THC reduces tics without any disruption in cognitive function. Neuropsychological impairment was not seen (3).

In the randomized double blinded placebo-controlled clinical trial of 24 patients, THC of up to 10mg was used in the treated cohort over 6 weeks. Measures used included the Tourette’s Syndrome Clinical Global Impression Scale (TS-CGI), Shapiro Tourette Syndrome Severity Scale (STSS), the Yale Global Tic Severity Scale (YGTSS), Tourette Syndrome Symptom List (TSSL) and the videotape based rating scale. Patients were rated at visits 1 for baseline, visits 3-4 during treatment and visits 5-6 after withdrawal. There was a significant difference between both groups. There was a significant reduction in motor tics, vocal tics and obsessive compulsive disorder. No significant adverse cognitive effects were noted (4).

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More randomized controlled clinical studies are necessary
While there may be a paucity of large clinical trials of the use of medical cannabis in Tourette’s syndrome, tetrahydrocannabinol is a potential therapeutic agent in a neurological disorder where treatment options are very limited and often times unsuccessful. Adverse side effects can preclude treatment using conventional pharmaceutic agents.

While large randomized controlled clinical trials are necessary in providing standard of care, tetrahydrocannabinol has emerged as a potential treatment option used by clinicians who are on the frontlines of treating this debilitating disorder.

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Reference
1. Laprairie, et al, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” Br. J. Pharmacology, 2015, Oct., 172(20):4790-4805
2. Kanaan, et al, “Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximol,: Brain Science, 2017, Apr., 7 (5):47
3. Muller-Vahl,”Cannabinoids reduce symptoms of Tourette’s syndrome,” Expert Opin Pharmacother., 2003, Oct., 4(10):17-1725
4. Muller-Vahl, “Delta-9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6 week randomized trial,” J. Clin Psychiatry, 2003, Apr., 64 (4):459-65
5. Trainor, “Severe motor and vocal tics controlled with Sativex®,” Australas Psychiatry, 2016, Dec, 24 (6):541-544

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schizophrenia

Cannabidiol may treat psychosis while tetrahydrocannabinol can induce schizophrenia in those susceptible  

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

There is a well-known correlation of use of cannabis whether it is medical or recreational to the onset of schizophrenia. It unclear if this could be to a direct correlation and disinhibition of the genetic component or the behavior of using it is a prodrome leading up to schizophrenia. This review seeks to elucidate the mechanisms in the correlation of the use of cannabis and onset of schizophrenia.

Mechanisms related to the underlying genetic composition

Schizophrenia may be linked when some of the normal pathways become disrupted with an introduction of THC.  There are 4 genes that were described after a lifetime use of cannabis including KCNT2 which were THC responsive, NCAM1 and CADM2 are significant in functioning in post-synapse. With THC in the system, there are more post-synaptic density genes (1).

Mechanisms related to other neurotransmitter pathways influenced by cannabinoids

In one study, because of the alarming rate of potent synthetic cannabis used recreationally which was found to leave long-lasting schizophrenia disorder in recreational users, this has accelerated research into the pathophysiology. Because cannabinoids work on the CB1 receptor, it is likely that it plays a modulatory role on the other neurotransmitters that can give rise to schizophrenia including dopaminergic, glutamatergic and serotonergic pathways. These pathways are well-established as playing a role in a pro-psychotic state. High efficacy synthetic cannabinoids which are manufactured for recreational purposes are highly more potent compared to natural organic cannabinoids and there is an alarming increase in the correlation of schizophrenia in these users (2).

In one study it is thought to be due to the hypofunctioning of the glutamate system which is directly affected by THC. Exposure to tetrahydrocannabinol appears to reduce the activity at the level of the glutamate receptor as well as deregulate genes for synaptic function(1).

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Susceptibility is related to the development of schizophrenia

In one animal model, the set-up tried to mimic a more real state seen where not all adolescents exposed to synthetic cannabinoids react by developing schizophrenia, there are some studies where all animals develop schizophrenia with exposure. In this animal model, they provided a model that resembles the human model more closely and found that exposure to synthetic cannabinoids in schizophrenia-prone animals caused hyperfunctioning of dopaminergic pathways compared to the control group who were not susceptible at the same dosages. There may be underlying genetic or environmental factors that cause certain individuals to become more prone (2).

THC can cause anxiety and behavioral disorders but can be prevented with CBD

In one animal study, it was found in a rat study that THC can induce anxiety and behavioral disorders. With THC  administration object recognition was impaired in adolescent rates. The studies support effect on the developing brain in relation to cognitive impairment in the animal model. In addition, when rats were exposed to THC there was increased marble burying behavior which in scientific research is thought to signify anxiety or obsessive-compulsive type behavior usually ameliorated with serotonin reuptake inhibitors or benzodiazepines(4).

It was found, however, that a combination of CBD and THC or cannabidiol alone was administered, these behaviors were not produced or produced only minimally. The thought is that CBD is an allosteric competitive inhibitor at the CB1 receptor so that one sees less of the toxic undesirable effects of THC if administered alone (4).

Cannabinoids have a similar profile to atypical anti-psychotics and may be a possible adjunctive treatment in the treatment of psychotic events (5).

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In summary

There is historical evidence that exposure to THC can give rise to schizophrenia in those individuals that are susceptible accounting for the fact that it does not happen to everybody exposed to it. This is related to its influence on serotonergic, dopaminergic and glutamate pathways. THC can induce anxiety, repetitive behaviors which are ameliorated by CBD. CBD may be a useful adjunctive treatment for psychotic disorders. However, the elucidated mechanisms are based on scientific research based on animal models which may not translate into humans.

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References

  1. Guennewig, et al, “THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorder,” Transl. Psychiatry, 2018, Apr., 8(1):89.
  2. Fantegrossi, et al, “Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems, Drug Metab. Review, 2018, Jan, 50(1)
  3. Aguilar, et al, “Adolescent synthetic cannabinoid exposure produces enduring changes in dopamine neuron activity in the rodent model of schizophrenia,” Int. J. Neurpsychopharmacol., 2018, Apr., 31 (4):393-403.
  4. Murphy, et al, “Chronic adolescent delta9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive behavioral dysfunction which is prevented by concurrent cannabidiol treatment,” Cannabis Cannabinoid Res., 2017, 2(1):235-246.
  5. Deiana, et al, “Medical use of cannabis: a new light for schizophrenia?” Drug Test Analysis, 2013, Jan., (5)1:46-51
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Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D. Neurologist, Epileptologist

Introduction

The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010.  Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.

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How it works–the nitty gritty

Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly.  Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated.  CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.

Current legal state of affairs

Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law.  In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store.  Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.

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In conclusion

In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.

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