Anxiety, Depression, Post-Traumatic Stress Disorder, Uncategorized

Cannabidiol and tetrahydrocannabinol: effectiveness in post-traumatic stress disorder, anxiety and depression

Virginia Thornley, M.D., Neurologist, Epileptologist

March 20, 2018

Post-traumatic stress disorder is the silent disorder that could be affecting the co-worker who sits one cubicle over from you. When one hears of post-traumatic stress disorder, one thinks of traumatizing incidents such as war, abuse or some other devastating event but can occur even in situations such as car accidents or a spouse of many decades suddenly leaving. It is the quiet disorder that if you do not expound on it, nobody really knows about it. Because of the stigma surrounding psychological disorders, often times, help is not sought in a timely manner.

It is often characterized by nightmares waking someone up in the middle of the night or sudden flashbacks when placed in a situation similar to the traumatic event.  Management includes working with a psychiatrist using conventional medications and a psychologist using behavioral therapy. It is not uncommon for a patient to have to go through many different anti-depressants or anxiolytics before one finds the correct drug and titration. But sometimes even the best medications fail to treat someone with Post-traumatic stress disorder adequately. Psychotherapy may be helpful in some patients depending on the patient. In others,  there is less benefit and some dislike the thought of reliving the experience in order to learn coping mechanisms.

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Alternatives include non-pharmacologic measures including relaxation techniques such as doing yoga, Tai Chi or meditation. Exercise can often boost the mood and doing enjoyable activities may help alleviate symptoms without the addition of pharmacologic agents. Doing something one enjoys or taking joy in the simple activities in life such as writing poetry, art therapy, taking up a sport may help alleviate some of the stress. Great tips can be found on Psychiatrist, Dr. Welby’s site found here: https://drmelissawelby.com/exercise-depression-get-started-want-stay-bed/

More and more patients are turning towards alternative measures, finding that conventional medications are not always optimal. Cannabidiol works through the endocannabinoid pathway and modulates its effect through the CB1 receptor which is predominantly found in the nervous system. The CB2 receptor is found mostly in the immune system. In some studies, it was found that cannabidiol may help reduce fearful memory if taken in the conditioning phase so that rather than reacting to the stimulus with fear, the stimulus is then associated with a different reaction and may help mitigate the symptoms of post-traumatic stress disorder through this mechanism (1). In another study, it was found to influence synaptic dendrites and may contribute towards learned memory in the hippocampus (2).

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Cannabidiol interacts with the 5HT-A receptor which is an important receptor in mitigating the symptoms of anxiety. Serotonin works through the 5HT1-A receptors. Some anxiolytics and anti-depressants work through an increase in serotonin which boosts the mood. Cannabidiol itself is known to have a calming effect with none of the euphoria found in THC alone.   Cannabidiol is non-intoxicating and when combined with low dose tetrahydrocannabinol has great medical effects.

In summary, when medications and therapy are found to be ineffective for post-traumatic stress disorder, anxiety or depression, cannabidiol which is non-intoxicating may be an effective therapeutic option alone or in conjunction with low dose THC and should be considered.

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References

  1. Uhernik, et al, “Learning and memory are modulated by cannabidiol when administered during trace fear-conditioning,” Neurobiology of Learned Memory, 2018, Feb., 9, 149:58-76. doi: 10.1016/j.nlm.2018.02.009 (Epub ahead of print)
  2. Lee, et al, “Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorder,” British Journal of Pharmacology, 2017, Oct., 174 (19): 3242-3256. doi: 10.1111/bph.13724. (Epub. 2017 Mar. 9.)
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multiple sclerosis

Sativex (tetrahydrocannabinol and cannabidiol) and the European experience in medically refractory spasticity in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist
March 12, 2018

Introduction

Sativex has been available in Europe since 2010. It is a combination of tetrahydrocannabinol and cannabidiol at a ratio of 1:1 and has been found to be effective in spasticity resistant to medications in patients with multiple sclerosis. Spasticity is the increased tone seen in the muscles due to abnormalities in the central nervous system such as the white matter lesions seen in multiple sclerosis.

Sativex and medically refractory spasticity in multiple sclerosis

Sativex is a THC:CBD (tetrahydrocannabinol:cannabidiol) preparation taken oromucosally which was approved in European countries for the treatment of medically refractory spasticity in patients with multiple sclerosis. Sativex contains a 1:1 ratio of THC to CBD, where THC interacts with CBD receptors to reduce spasticity while CBD ameliorates the side effects often seen with THC. In one large clinical trial of 1615 patients, 42% showed improvement of spasticity in the first 4 weeks, defined as > or = to 20% reduction in spasticity. The responders were double-blinded and grouped under placebo or THC:CBD, a larger proportion of patients had significant response compared to placebo, > or = to 30% reduction of NRS score for spasticity. 47% had adverse effects including fatigue and dizziness. Reported side effects included psychiatric disturbances, 55 had cognitive (attention problems, cognitive worsening and memory problems) and psychiatric issues (confusion, panic attacks, hallucinations, depression and suicidal ideations). Fatigue, drowsiness, dizziness, gastrointestinal symptoms, mouth discomfort and allergic reactions were other reported side effects. There was no evidence of abuse or addiction in the patients. There were significant side effects deemed unrelated to Sativex including, myocardial infarct, hypertensive crisis (2).

In the original MOVE 2 trial in Italy, in the 322 patients studied, the NRS numerical rating scale decreased by -19.1% from baseline time to 3 months of treatment with Sativex. At visit 3 at 3 months, 24.6% were considered relevant responders to the medication with 30% or more reduction in spasticity. Side effects of >1% included somnolence, dizziness, and fatigue. 41 patients reported side effects 3 were serious side effects of which one was not related (3).

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Sativex and studies in Germany, United Kingdom, Switzerland and Spain

Sativex was first approved in Spain and the United Kingdom in 2010 for use in spasticity related to multiple sclerosis. Data were collected to study continued efficacy and safety profiles.  941 patients (761 from the UK, 178 from Germany and 2 from Switzerland) were studied. Data was collected up until January of 2015.  A patient registry was set up as per guidelines before new medications are approved. Patients from the UK were 22% of the patients registered in the UK using that medication since 2010. Continuation rates were 1 year for 68% of patients. Among those who stopped it, 30% cited lack of effectiveness and 25% described side effects. Some significant side effects include suicidality in 2% and depression in 6%. There was no evidence of abuse, addiction or misuse. The fatigue was within the known safety margins of the drug. The patients used on average 5.9 +/- 4.9 sprays per day

In Spain, 204 patients were evaluated. After 6 months, 143 (70.1%) had benefited from using it for spasticity. After 12 months 64.7% derived beneficial effects. The average dose was 6.6 sprays a day. 41 patients had side effects consisting of psychiatric events, falls, reduced the ability to drive and others. Both study groups in the UK, Germany, Switzerland and in Spain both derived benefits justifying continued used of Sativex. Adverse effects were low, and the mean use of sprays was between 5.9-6.6 which was lower than the clinical trial using 8 sprays (4).

Sativex and timeline when it is found to be ineffective

In one large study in Italy involving 30 multiple sclerosis centers, the discontinuation profile was studied. Patient data from 30 MS centers were collected from a period of January 2014 to January 2015. 39.5% of patients disconnected treatment with Sativex. Spasticity was studied using the EDSS or expanded disability status scale and the patient NRS numerical rating scale 0-10 for spasticity. Information was collected at baseline (T0), 4 weeks (T1), 3 months (T2) and 6 months (T3).

Spasticity was noted in 1615 patients. 1597 (39.5%) discontinued treatment. Of those, 24.8% did not reach 20% effectiveness using the NRS scale. Reasons of discontinuing include lack of effectiveness 23%, side effects 16.3% and lack of compliance 0.8%, lost to follow-up 0.4%, patient choice 0.3% and unknown reasons 2%. Analysis showed that an increase in the NRS scale by 1 point at baseline time corresponded to a lower rate of discontinuation. While an increase in the NRS scale at timeline 2 or at 4 weeks corresponded with worsening spasticity and a higher non-responder rate. They concluded that Sativex is a good option for spasticity and by 4-6 weeks, patients can be reliably identified as responders or non-responders to avoid the cost burden on the healthcare system (1).

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Introduction/Disclaimer

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Reference

  1. Messina, et al, “Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study), Public Library of Science PLoS One, 2017, 12(8) e0180651
  2. Patti, et al, “Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, 2016, Sep., 87(9):944-951.
  3. Trojano, et al, “Effectiveness and tolerability of THC/CBD oromucosal spray for multiple sclerosis spasticity in Italy: first data from a large observational study,” European Neurology, 2015, 74:178-185,https://doi.org/10.1159/000441819
  4. Fernandez, et al, “THC:CBD in daily practice: available data from UK, Germany and Spain,”European Neurology, 2016, 75 (supp 1);1-3, https://doi.org/10.1159/000444234
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Amyotrophic lateral sclerosis

Non-pharmacologic aspects of ALS: correlation of higher BMI with greater survival, beneficial use of cannabidiol, respiratory evaluation, exercise and anesthetic considerations 

Virginia Thornley, M.D., Neurologist, Epileptologist

March 4, 2018

ALS is a progressive neurodegenerative illness which affects the lower motor neurons causing progressive weakness and eventually respiratory failure. There are currently only 2 prescription agents available for slowing the progression of the disease. Management is largely symptomatic treatment of debilitating symptoms.  Much consideration is being directed towards alternative treatments such as dietary considerations and use of cannabidiol.

ALS and supplements and BMI

Based on one large review of studies, there was not enough evidence to support recommendations of Vitamin A, and C or Coenzyme Q10. For Vitamin B complex, Homocysteine, Vitamin D, there is limited data which is not enough to support or refute recommendation, more clinical trials are needed. Vitamin E may be beneficial in preclinical patients with a familial tendency. Omega-3 was found to accelerate disease progression with increased vacuolization of anterior horn cells and are deleterious in presymptomatic patients. L-Carnitine may increase survival time with a slower ALSFRS or ALS functional revised score and greater FVC volumes but more trials are needed (1). Body mass index of less than 18.5kg/m is found with less survival time, while those with a higher BMI have greater survival time. One small study suggested a high calorie, hypercaloric enteral diet was tolerable in patients but unclear if associated with better outcome in terms of survival time.

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Cannabidiol as a novel therapeutic agent

Cannabidiol is known in animal models to be anti-inflammatory and anti-oxidant. In the G93A SOD-1 mouse model, it was found to slow progression of the disease and increase survival time. In a study of 13 patients, it reduced drooling, loss of appetite, pain, and spasticity.

In one study, cannabidiol was used in human gingiva-derived mesenchymal stromal cells. The transcriptomic sequence in the next generation shows a change in gene expression in ALS related genes. There was a change in the genes connected to ALS regarding oxidative stress, mitochondrial dysfunction and excitotoxicity in the human gingiva-derived mesenchymal stromal cells when treated with cannabidiol. This suggests that cannabidiol may serve as a modulatory role in the early pathogenesis of ALS (2).

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Other aspects of ALS

Exercise 

Studies regarding exercise showed flaws in methodology or were in small numbers. Therefore, based on available studies it is unclear if exercise benefits a patient’s long-term outcome.

 

Sialorrhea

Sialorrhea should be addressed. Aside from conventional medications, other options include botulinum toxin and small doses of radiation therapy delivered to the salivary glands.

Anesthesia 

Anesthetic agents such as neuromuscular blockers are contraindicated in patients with ALS due to the risk of increased potassium release. In one study of 51 patients with ALS, general anesthesia was safely administered.

Pulmonary function 

Pulmonary function tests are monitored every few months depending on the rapidity of the progression of the disease. Non-invasive positive pressure ventilation is used in patients with ALS with an oral or nasal mask. As force vital capacity (FVC) declines, it may be administered through a bi-level positive airway ventilation machine continuously at night(1).

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References

1. Karam, et al, “Palliative care issues in amyotrophic lateral sclerosis: an evidence-based review,” American Journal of Palliative Care, 2016, Feb., 33(1):84-92.

2. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.

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Epilepsy, pain

Cannabidiol: Is there any scientific evidence? Review of some of the novel mechanisms of action in analgesic, anti-epileptic, anti-inflammatory, anti-tumorigenic and anxiolytic effects 

Virginia Thornley, M.D., General Neurologist and Epileptologist

@VThornleyMD

February 16, 2018

Introduction

Cannabidiol (CBD) is the little known medical component without the euphoria used for medical indications such as analgesic, anti-inflammatory, anti-epileptic and anxiolytic effects. In the pathway for endocannabinoids, cannabinoid exerts its therapeutic effects by binding to the CBD1 receptor found in the brains and the nerves exerting their analgesic effects. CBD does not have the same euphoriant effect as THC its counterpart which is better known to the public with much stigma. CBD will need to be 100 times more potent to have the same euphoria as THC making it relatively safe to give without the intoxicating effects. THC or delta-tetrahydrocannabidiol is the main psychoactive component in the marijuana plant, the one finds in the street drugs which has caused such a stigma shadowing the beneficial effects of the plant. Cannabidiol is also thought to work on the 5HT1 receptor giving its anxiolytic properties. This review seeks to understand some of the laboratory research that study the underlying mechanisms for its beneficial actions.

Cannabidiol works on CBD1 receptor and is thought to have an analgesic and anti-inflammatory role in diseases. In many states, it still outlawed to have in possession but growing clinical evidence shows that it can be used in pain syndromes. In the state of Florida there are 10 conditions recognized that can be treated with CBD. It is most commonly used in pain from stage IV metastatic cancer. Cannabidiol has been found to have anti-inflammatory, anti-tumorigenic, analgesic, anti-epileptic and anxiolytic properties.

Analgesic effects

CB1 receptors are found to be expressed in anterior horn cells. The CB2 receptors possibly reduce pain by acting on the neutrophil accumulation and mast cell degranulation which can reduce pain both of these processes increase inflammatory algesia(1).Analgesia has been demonstrated with cannabinoids in visceral inflammation and pain due to peripheral neuropathies, important areas of therapeutic considerations.

Anti-seizure effects

Some of the vast scientific research for cannabinoid is found in the animal models for epilepsy. Cannabinoids exert effects on CB1 and CB2 receptors in the hippocampus where it has a weak affinity(5). CBD1 receptors affect transmission in the synapses through the voltage-gated calcium and potassium channels. There are studies on the effects of CBD in refractory types of epilepsy such as Dravet’s syndrome one of the SCN1a genetic disorders affecting the sodium channel manifesting as severe myoclonic epilepsy. Mechanisms of CBD include increasing excitation of the inhibitory effect of the hippocampus where seizures are propagated.  At low doses, it helps with autism and impaired cognition.  It may exert its effect by working against GPR55(7), TRPV1 in addition to voltage-gated voltage-gated potassium and sodium channels. Another study supports the role that cannabinoids may play in shifting the inhibition of glutamatergic effects and GABAergic effects in the hippocampus mediated by CB1 receptors. In the rat model, it was suggested that seizures can upset the balance of these glutamate and GABA systems (4). 15 minutes after an induced seizure, there is increased 2-arachidonylycerol which is a CB1 agonist suggesting cannabinoids act as a negative feedback loop for seizures(4). In addition, it was found there are more CB1 receptors in the hippocampi with induced seizures compared to control suggesting plasticity of the brain with a compensatory increase in CB1 receptors in response to increased seizures(4). CB2 receptors are related to the immune system and are limited in the CNS. Cannabinoids affect calcium homeostasis and may provide its neuroprotective effects. Growing evidence shows case series, case reports and anecdotal reports on patients having fewer seizures on cannabidiol. Large case-controlled clinical randomized trials are needed.

Anti-tumor effects

There appears to be increased cancel cell death, reduced viability and reduced numbers of metastatic cells. In one study, it is found to reduce epidermal growth factor-induced multiplication and chemotaxis of cells in breast cancer. In mouse models, it inhibits macrophage recruitment in tumor-related cells.n It can potentially inhibit metastasis and proliferation and may provide a novel therapeutic option in breast cancer(2).

Anxiolytic effects

It works on the 5HT1 receptor by altering effects on this receptor the exact mechanism is unknown accounting for anxiolytic properties(6).

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Anti-psychotic effects

CBD may alter the effects of THC and reduce its psychoactive properties (6).

 

Alternative treatment in opioid use

CBD might also work in place of opioids with the growing epidemic of chronic pain and overuse of opioids, CBD may be an alternative analgesic for chronic pain without the effect of tolerance or sedating properties. CBD was found to reduce the reward effects of morphine and does not have the same properties of tolerance. CBD does not have the same euphoria and THC and works on pain(6).

In summary, it is an exciting time for research in the use of cannabinoids. There are innumerable basic science research studies demonstrating the therapeutic effects at the cellular level. Large randomized clinical trials are still needed to gain information in using cannabinoids in humans.

Introduction/Disclaimer

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References

1. Rice, AS, et al, “Endocannabinoids and pain: peripheral and spinal analgesia in inflammation and neuropathy, ” Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002, Feb., 66(2-3)246-256.

2. Elbaz, E. et al, ” Modulation of tumor microenvironment and inhibition of EGF/EGFR pathway: novel mechanisms of Cannabidiol on breast cancer,”Molecular Oncology, 2015, Apr., 9(4):906-919.

3. Welty, W.E., et al, “Cannabinoids: the promises and pitfalls,” Epilepsy Currents, 2014, Sep.-Oct., 14(5):250-252.

4. Wallace, MJ, et al, ” The endogenous Cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy, ” The Journal of Pharmacology and Experimental Therapeutics, 2003, Oct., 307(1):129-137.

5. Gaston, T. et. al, “Pharmacology of cannabinoids in the treatment of epilepsy, ” Epilepsy Behavior, 2017, May, 70:313-318.

6. Volkow, Nora, “The biology and potential therapeutic effects of cannabidiol,” National Institute on Drug Abuse Senate Caucus on International Narcotics Control, 2015, June.

7. Kaplan, et.al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome, “Proceedings of the National Academy of Science, 2017, Oct.

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