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Cannabinoids and Huntington’s disease

By Manuel Guzmán

Manuel Guzmán is Professor of Biochemistry and Molecular Biology at Complutense University of Madrid, member of the Spanish Royal Academy of Pharmacy, and member of the Board of Directors of the International Association for Cannabinoid Medicines. His research focuses on the study of the mechanism of action and therapeutic properties of cannabinoids, especially in the nervous system. This work has given rise to more than one hundred publications in specialized international journals, as well as to several international patents on the possible therapeutic applications of cannabinoids as anticancer and neuroprotective drugs. He routinely collaborates with scientific reviewing and funding agencies.

Huntington’s disease (HD) is a devastating neurodegenerative disease that begins with choreic movements and goes on to include serious motor, behavioural and cognitive alterations (Walker, 2007).

There is currently no known cure for HD. It leads to the death of the patient between 10 and 20 years from the onset of the symptoms. The disease has an approximate prevalence of 1 case per 10,000 and is caused primarily by the degeneration of a specific population of neurons, called “medium spiny neurons” (MSNs). These cells make up practically all (

95%) of the neurons in an area of the brain known as the “dorsal striatum” (or, more strictly, in humans the “caudate/putamen”), which monitors important neurobiological processes such as motor activity, cognitive functions and emotional control.

From a molecular point of view, it has been known for some time that HD results from the mutation of a single gene, which codes the protein known as “huntingtin” (The Huntington’s Disease Collaborative Research Group, 1993). However, the precise mechanisms by which the mutated huntingtin causes progressive degeneration of MSNs are extraordinarily complex and only partially known (Ross et al., 2014).

Cannabinoids and HD: preclinical data

The cannabinoid receptor CB1 (CB1R), the main molecular target of endocannabinoids and THC, is expressed in very high quantities in MSNs, which, as mentioned are the cells that primarily degenerate in HD. The receptor is also present in the terminals of “corticostriatal neurons”, which, as their name suggests, project from the cortex to the striatum and are responsible for fine controlling the activity of the MSNs (Fernández-Ruiz et al., 2011; Castillo et al., 2012). CB1R levels drop early and notably in MSNs in patients (e.g. Richfield y Herkenham, 1994; Glass et al., 2000; Allen et al., 2009) and animal models (e.g., Denovan-Wright y Robertson, 2000; McCaw et al., 2004; Casteels et al., 2011) of HD.

In contrast, CB1R expression is not affected in corticostriatal projections during HD (Chiodi et al., 2012; Chiarlone et al., 2014). The expression of other elements of the endocannabinoid system also changes during the development of HD (Fernández-Ruiz et al., 2011; Laprairie et al., 2015). Levels of the cannabinoid receiver CB2 (Palazuelos et al., 2009; Sagredo et al., 2009) and the FAAH enzyme (fatty acid amide hydrolase, the principal enzyme degrading anandamide; Blázquez et al., 2011) increase in the striatum of patients and animal models of HD, whereas levels of anandamide and other endocannabinoids are reduced (Bisogno et al., 2008).

Studies carried out by two independent laboratories have shown that genetic inactivation of CB1R aggravates HD in mouse models of the disease (Blázquez et al., 2011; Mievis et al., 2011). Analogously, administration of THC (2 mg/kg/day; Blázquez et al., 2011) or the synthetic cannabinoid WIN-55.212-2 (0.3 mg/kg/day; Pietropaolo et al., 2015) in mice models of HD delays the onset and attenuates the pathology and motor symptoms of the disease. Nonetheless, an additional study found no beneficial effects of THC (albeit at a very high dose, 10 mg/kg/day), the synthetic cannabinoid HU-210 (0.01 mg/kg/day) or the inhibitor of FAAH URB597 (0.3 mg/kg/day) in a mouse model of HD (Dowie et al., 2010).

For many years it was hypothesized that an early and accentuated drop in the expression of CB1R in MSNs might play a pathogenic role in HD (Maccarrone et al., 2007; Fernández-Ruiz et al., 2011). However, selective genetic inactivation (Chiarlone et al., 2014) or selective genetic overexpression (Naydenov et al., 2014; Blázquez et al., 2015) of CB1R in the MSNs of mouse models of HD does not affect the motor impairments suffered by these animals. On the contrary, selective genetic inactivation of CB1R in their corticostriatal projections markedly worsens their motor behaviour (Chiarlone et al., 2014). From a biomedical perspective, therefore, it is very likely that the therapeutic target of the neuroprotective effects of cannabinoids in animal models of HD is the CB1R population located in the corticostriatal neurons and not that located in the MSNs.

Cannabinoids and HD: clinical data

Several clinical trials have been conducted to date with cannabinoids in HD. A first 6-week double-blind, crossover, placebo-controlled trial on 15 HD patients who were administered 10 mg/kg/day of CBD orally showed that this cannabinoid was safe but did not affect the severity of the chorea and other symptoms of the disease (Consroe et al., 1991).

Two additional uncontrolled single-patient studies using the synthetic cannabinoid Nabilone gave contradictory data on HD-associated chorea: one of the patients worsened (with 1.5 mg of Nabilone per day; Muller-Vahl et al., 1999), whereas the other improved (with 1 mg of Nabilone twice a day; Curtis y Rickards, 2006). Subsequently a double-blind, crossover, placebo-controlled trial was conducted in which Nabilone (1-2 mg per day) was administered to 37 HD patients during two 5-week periods, separated by a 5-week washout period (Curtis et al., 2009). The Nabilone was safe and well tolerated, but its effects were practically identical to those of the placebo in the different motor, cognitive, behavioural and neuropsychiatric scales analysed.

Finally, a double-blind, crossover, placebo-controlled trial was performed in which Sativex was administered (approximate average dose: 20 mg of THC and 20 mg of CBD per day) to 24 HD patients for two 12-week treatment periods, separated by a 4-week washout period (Lopez-Sendon Moreno et al., 2016). The Sativex was safe and well tolerated, but no significant effects were observed either in the motor, cognitive, behavioural and functional parameters or in the biomarkers assessed.

Conclusions

Numerous preclinical studies have demonstrated the neuroprotective power of cannabinoids in different animal models of neurodegeneration. This has raised hopes on possible clinical utility, especially in very serious diseases such as HD, for which no effective treatment is known.

However despite being globally safe and well tolerated, cannabinoids have not as yet shown any neuroprotective activity in humans. This discrepancy between the basic and clinical research may be due to factors such as the substantial biological differences between the animal models and human pathology or to inadequate design of the clinical trials, which have to date been geared towards assessing safety more than effectiveness. It therefore seems logical to suggest that future clinical trials should be conducted in earlier stages of HD with longer periods of treatment with cannabinoids. It might also be useful to know the pattern of cannabis use by HD patients and to have some biomarkers related to CB1R activity during the development of HD.

In all, the safety and tolerability shown thus far by different cannabinoids in clinical trials on HD should encourage more exhaustive future trials to assess whether these compounds might be used as therapeutic agents for treating this highly aggressive disease.

Bibliography

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Bisogno T et al. (2008) Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington’s disease. Neurochem Int 52:307-313.

Blázquez C et al. (2015) The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ 22:1618-1629.

Blázquez C et al. (2011) Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134:119-136.

Casteels C et al. (2011) Metabolic and type 1 cannabinoid receptor imaging of a transgenic rat model in the early phase of Huntington disease. Exp Neurol 229:440-449.

Castillo PE et al. (2012) Endocannabinoid signaling and synaptic function. Neuron 76:70-81.

Consroe P et al. (1991) Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav 40:701-708.

Curtis A & Rickards H (2006) Nabilone could treat chorea and irritability in Huntington’s disease. J Neuropsychiatry Clin Neurosci 18:553-554.

Curtis A et al. (2009) A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov Disord 24:2254-2259.

Chiarlone A et al. (2014) A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci USA 111:8257-8262.

Chiodi V et al. (2012) Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington’s disease. Neurobiol Dis 45:983-991.

Denovan-Wright EM & Robertson HA (2000) Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience 98:705-713.

Dowie MJ et al. (2010) Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience 170:324-336.

Fernández-Ruiz J et al. (2011) Prospects for cannabinoid therapies in basal ganglia disorders. Br J Pharmacol 163:1365-1378.

Glass M et al. (2000) The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience 97:505-519.

Laprairie RB et al. (2015) Components of the endocannabinoid and dopamine systems are dysregulated in Huntington’s disease: analysis of publicly available microarray datasets. Pharmacol Res Perspect 3:e00104.

López-Sendón Moreno JL et al. (2016) A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol 263:1390-1400.

Maccarrone M et al. (2007) The endocannabinoid pathway in Huntington’s disease: A comparison with other neurodegenerative diseases. Prog Neurobiol 81:349-379.

McCaw EA et al. (2004) Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice. Eur J Biochem 271:4909-4920.

Mievis S et al. (2011) Worsening of Huntington disease phenotype in CB1 receptor knockout mice. Neurobiol Dis 42:524-529.

Muller-Vahl KR et al. (1999) Nabilone increases choreatic movements in Huntington’s disease. Mov Disord 14:1038-1040.

Naydenov AV et al. (2014) Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in EH mice. Neurobiol Dis 71C:140-150.

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Huntington's disease (HD) is a devastating neurodegenerative disease that begins with choreic movements and goes on to include serious motor, behavioural and cognitive alterations (Walker, 2007). There is currently no known cure for HD. It leads to the death of the patient between 10 and 20 years from the onset of the symptoms. The disease has an approximate prevalence of 1

Huntington’s Disease & CBD Oil: Possible Neuroprotection & Motor Control

Huntington’s Disease & CBD Oil: Possible Neuroprotection & Motor Control

Huntington’s disease is a neurodegenerative disorder without any known cures.

Huntington’s disease is a progressive brain disorder, inherited at birth, with no known cure. Symptoms usually appear when patients reach middle-age and show many similarities to that of Parkinson’s, amyotrophic lateral sclerosis (ALS), and Alzheimer’s. Only with Huntington’s, these symptoms often happen all at once.

Patients suffering from this disease gradually lose control of their body and minds as parts of the brain degenerate. Uncontrolled body movements, muscle spasms, and fits of uncontrolled rage are common. As the disease progresses, patients may become immobile and oftentimes lose the ability to even eat.

With no way of stopping the disease, the best that sufferers can do is manage their symptoms to improve their quality of life. Medications are available to treat some of the symptoms but they typically come with many unwanted side effects.

Due to complications associated with these medications, patients often seek alternative options. One option that is beginning to show some promise for managing Huntington’s disease symptoms is CBD oil.

Benefits of CBD Oil for Huntington’s Disease

While no cure is available for Huntington’s disease, there are many medications that treat its various symptoms.

Medications such as Tetrabenazine, Haloperidol, and Clonazepam are available to treat the movement disorders associated with Huntington’s. Unfortunately, they come with the risk of triggering psychiatric conditions such as depression, and may even make symptoms like muscle rigidity and involuntary movements worse.

For the mental symptoms of Huntington’s disease, antidepressants, antipsychotics, and mood stabilizers are often prescribed. These, too, aren’t without their side effects. Nausea, diarrhea, and the chance of making movement disorders worse are all possible side effects.

In contrast to the many side effects that these medications may produce, CBD oil offers potential relief with relatively few negatives. According to The World Health Organization (WHO), “CBD is generally well tolerated with a good safety profile” and “no public health related problems associated with the use of pure CBD.”

But, as with any medication or treatment, it’s important you do your research and speak to your doctor before adding CBD oil to your wellness regimen. Certain medications you may be taking to manage the symptoms of Huntington’s disease, like antidepressants, can interact with cannabidiol (CBD). To avoid potential complications, it’s imperative that you consult with your doctor ahead of time.

Effectiveness of CBD Oil for Huntington’s Disease

CBD oil has shown much potential in treating the various symptoms associated with Huntington’s disease.

For example, CBD oil has antidepressant properties, which could potentially help reduce the severity of depression that accompanies this disease. CBD oil has also been found to be an effective anticonvulsant, so it may be able to help reduce the occurrence of uncontrolled body movement. There’s extensive research being done on CBD’s ability to help people with movement disorders like Parkinson’s and dyskinesia, but when it comes to Huntington’s disease, studies tend to combine CBD with other cannabinoids like tetrahydrocannabinol (THC).

One study, published in the Journal of Huntington’s Disease, monitored seven patients suffering in the early stages of Huntington’s disease. The study found that those who consumed cannabinoids enjoyed noticeable improvements in their motor symptoms, as a result of calming their dystonia, or involuntary muscle contractions. The researchers also noticed, “less irritability and apathy” in the patients, a promising sign of cannabis’ potential to address Huntington’s symptoms that are both physical and mental.

Another study, conducted in 2017, examined the effects of a 1:1 ratio of CBD:THC on a model of Huntington’s disease in mice test subjects. Huntington’s and other movement disorders have been linked to decreased metabolic function in the basal ganglia and deterioration of the striatum, which are the parts of the brain responsible for smooth and voluntary bodily movements. In the study, the combined CBD and THC were shown to reduce the decrease in metabolic activity at the basal ganglia, and even reversed some of the neurodegenerative effects of Huntington’s. In the end, the study concludes, “A…combination of phytocannabinoids administered to…mice at the onset of motor symptoms produced certain benefits on the progression of striatal deterioration in these mice, which supports the interest of this cannabinoid-based medicine for the treatment of disease progression in HD [Huntington’s disease] patients.”

CBD and other cannabinoids’ neuroprotective properties, especially as they pertain to neurodegenerative diseases like Huntington’s, were studied in Spain in 2011. In the study, researchers found that cannabis-based medications like Sativex (containing both THC and CBD) were effective at slowing the progression of Huntington’s disease in mice by exerting neuroprotective properties.

While the results of the studies so far are promising, much more research and clinical trials on humans are needed to conclusively say whether CBD, or a CBD-THC hybrid, is a viable treatment for Huntington’s.

How to Use CBD Oil for Huntington’s Disease

If you decide to try using CBD oil to manage the symptoms of Huntington’s disease, there are a variety of different ways you can take it. Some options available include vaporizers, edibles, CBD oil drops or tinctures, and capsules.

Depending on how far Huntington’s disease has progressed, some of these options may be off the table. Patients with motor impairment, or who have trouble eating will likely find CBD oil capsules preferable to gummies, drops, or vaporizers. CBD capsules are especially easy to take alongside other medications, and can be incorporated into your daily wellness routine.

One thing to keep in mind is that each CBD delivery format has a slightly different time of onset. CBD oil edibles and capsules, for example, must pass through the digestive system, which means you may not feel their effects for an hour or so.

Vaped CBD oil is absorbed directly into the bloodstream through the lungs, and goes to work within minutes. If this is an accessible method of administration for you, a CBD vape could be great for on-the-go and on-the-spot relief from sudden onset of symptoms like dystonia or muscle contractions. The only downside to CBD vapes is the effects typically wear off within an hour.

CBD oil drops and tinctures provide a nice middle-of-the-road option: they are also absorbed quickly, typically within 30 minutes, and their effects last 2 to 4 hours. Placed under the tongue, the CBD is absorbed through the thin skin of the mouth. Though, if you’re experiencing severe motor symptoms, administering CBD drops or tinctures could present a challenge if someone isn’t there to help.

A final aspect to consider when choosing your CBD product is the research that has been done, and the results that have been obtained using a mix of CBD and THC. The effects of cannabidiol and THC together may prove more beneficial than using CBD on its own. For this reason, you may want to consider a full-spectrum product, which is made from an extract containing all of the cannabis plant’s cannabinoids, including CBD and THC. The one precaution to take here is to verify it’s legal for you to purchase a product containing THC.

CBD Oil Dosage for Huntington’s Disease

While there is no single CBD dose that works for everyone, reading the instructions and following the recommended dosage on the product at hand is a good start.

We at CBD Oil Review have reviewed hundreds of different CBD products, and come up with the following suggestion to get you started:

The CBD Oil Review Serving Standard is 25mg of CBD, taken twice daily

If you find no relief at this dose, increase the dose in 25 mg increments every 3 to 4 weeks.

The delivery formats that allow for the easiest increase (or decrease) in dosage are CBD oil drops and tinctures. You can adjust the number of milligrams of cannabidiol you’re ingesting down to the literal drop! CBD oil capsules come in set concentrations, and can provide you with your ideal dose of CBD on a consistent basis.

It is important to remember that there is no official standard dosage for CBD oil, and what works for one person may not work for another. For more detailed information about CBD dosing and tips for getting it right, check our dosing guide. You might also consider speaking with a naturopathic doctor who can provide the most personalized dosage and CBD action plan for your needs.

While CBD oil has shown great potential in treating the various symptoms of Huntington’s disease, it is not a cure and there’s no guarantee that it is going to work for everyone. But, with few side effects, CBD oil is starting to look like a great addition to current treatment options.

If prescription medication isn’t working or the side effects are becoming more trouble than they’re worth, consider giving CBD oil a try.

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A terrifying, progressive and degenerative condition, Huntington’s Disease is difficult to treat and has no cure. Could CBD oil offer some relief?