(Cannabidiol)

There is an increasing awareness, with more states passing bills to legalize CBD, many people are wondering just what CBD is and what benefits it may have.

Given that just about all topics nowadays are politicized, CBD being one of them, this post will attempt to shed a little light on some of the many health benefits attributed to CBD.

To date, 30 States and the District of Columbia have passed laws allowing marijuana to be used for a variety of medical conditions. Many other States have enacted laws intended to allow access to CBD oil and/or high-CBD strains of marijuana. Interests in the potential therapeutic effects of CBD has been growing rapidly, partially in response to media attention surrounding the use of CBD oil in young children with intractable seizure disorders including Dravet syndrome and Lennox-Gastaut syndrome, but also personal testimonials on social media. While there is promising preliminary data, the scientific literature is currently insufficient to either prove or disprove the benefits and safety of CBD in patients with epilepsy and further clinical evaluation is definitely warranted.

{Welty et al. Cannabidiol: promise and pitfalls. Epilepsy Curr. 14(5):250-2. (2014)}

 In addition to epilepsy, the therapeutic potential of CBD is currently being explored for a number of indications including anxiety disorders, substance use disorders, schizophrenia, and the list keeps growing.

Just a few other illnesses that are helped with CBD:

• Relieves pain and inflammation.
• Helps to fight cancer
• Has anti-psychotic effects
• Reduces anxiety
• Relieves nausea and headaches
• Possible lessening of seizures and other neurological disorders
• Promotes cardiovascular health
• Helps stabilize glucose levels for diabetes
• Stop smoking
• Helps with Opioid withdrawal
• Helps with insomnia
• Restless leg syndrome

On June 24 2015 Nora D. Volkow, director of the National Institute on Drug Abuse, NIDA, addressed the Senate Caucus on International Narcotics Control. In this lengthy meeting several items came up including the acknowledging of the need to further clinical research. She stated rigorous clinical studies are still needed to evaluate the clinical potential of CBD for specific conditions, however pre-clinical research has shown CBD to have a range of effects that may be therapeutically useful.

Volkow also continued with some rather interesting information:

Seizures

A number of studies over the last two decades or more have reported that CBD has anti-seizure activity, reducing the severity of seizures in animal models.

{ Jones et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52 } and { Consroe P and Wolkin A. Cannabidiol–anti-epileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977 Apr;201(1):26-32 }.  

In addition there have been a number of case studies and anecdotal reports suggesting that CBD may be effective in treating children with drug-resistant epilepsy.

{Porter BE and Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior 29 (2013) 574–577 }, { Press et al. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior 45 (2015) 49–52 }, { Hussain et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav. 2015 Apr 29. pii: S1525-5050(15)00157-2. }.

NIDA is currently collaborating with the National Institute on Neurological Disorders and Stroke to evaluate CBD in animal models of epilepsy in order to understand the underlying mechanisms and optimize the conditions under which CBD may treat seizure disorders, and determine whether it works synergistically with other anti-seizure medication.

Neuroprotective and Anti-Inflammatory Effects

Neuroprotective, meaning just that it is able to protect nerve cells against damage, degeneration, and or impairment of function.  CBD has also been shown to have neuroprotective properties in cell cultures as well as in animal models of several neurodegenerative diseases including,

Alzheimer’s. {Esposito G et al. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.} {J Mol Med (Berl). 84(3):253-8. (2006),} {Martín-Moreno et al. Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer’s Disease.} {Molecular Pharmacology. 79(6):964-973. (2011),} {Iuvone et al.Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 89(1):134-41. (2004).}

Stroke. {Pazos et al. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs:role of 5HT(1A) and CB2 receptors. Neuropharmacology. 71:282-91. (2013)},

Glutamate toxicity.  {Hampson et al. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl AcadSci U S A.95(14):8268-73. (1998)} 

Multiple Sclerosis. {Pryce et al. Neuroprotection inExperimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J Neuroimmune Pharmacol. 2014 Dec 24. [Epub ahead of print] }

Parkinson’s Disease.  {García-Arencibia et al. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 1134(1):162-70. (2007) }

Neurodegeneration caused by alcohol abuse. {Hamelink et al. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther. 2005 Aug;314(2):780-8}

Nabiximols (trade name Sativex), which contains THC and CBD in roughly equal proportions, has been approved throughout most of Europe and in a number of other countries for the treatment of spasticity associated with MS. It has not been approved in the United States, but clinical trials are ongoing, and two recent studies reported that nabiximols reduced the severity of spasticity associated with MS patients.  {Di Marzo and Centonze . Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. CNS Neurosci Ther. 21(3):215-21. (2015)} {Flachenecker et al. Nabiximols (THC/CBD oromucosal spray,Sativex®) in clinical practice–results of a multi center, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur Neurol.71(5-6):271-9. (2014) }

There have been limited clinical trials to assess the potential efficacy of CBD for the other indications highlighted: however, a recent small double-blind trial in patients with Parkinson’s disease found the CBD improved quality-of-life scores. {Chagas et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 28(11):1088-98. (2014) }

Analgesic Effects

There have been multiple clinical trials demonstrating the efficacy of nabiximols on central and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain. {Russo EB. Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management. 4(1):245-259.(2008)}

In addition, nabiximols is currently approved in Canada for the treatment of central neuropathic pain in MS and cancer pain uresponsive to opioid therapy. However, the current evidence suggests that the analgesia is mediated by THC and it is unclear whether CBD contributes to the therapeutic effects. {Iskedjian et al. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin. 23(1):17-24.(2007)}

I will state personal observation here and include that the Social Media consensus of those whom have claimed a cure for their various types of cancer, have all used a THC, CBD combination.

THC alone has been shown to reduce pain, {Svendsen et al. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomized double blind placebo controlled crossover trial. BMJ. 2004 Jul 31;329(7460):253.}  {Portenoy et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012 May;13(5):438-49.}

and The National Institute on Drug Abuse is unaware of clinical studies that have explored the efficacy of CBD alone with pain. But one must be aware of the anti-inflammatory properties of CBD (discussed above) could be predicted to play a role in the analgesic effects of nabiximols. Recent research has also suggested that cannabinoids and opioids have different mechanisms for reducing pain and that their effects may be additive, which suggests that combination therapies may be developed that may have reduced risks compared to current opioid therapies. However, this work is very preliminary. {Neelakantan et al. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behav Pharmacol. 26(3):304-14. (2015) }

Anti -Tumor Effects

 

In addition to the research on the use of cannabinoids in palliative treatments for cancer; reducing pain and nausea and the increase in appetite; there are also several pre-clinical reports showing anti-tumor effects of CBD in cell culture and in animal models. {McAllister et al. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. J Neuroimmune Pharmacol. 2015 Apr28. [Epub ahead of print]}

These studies have found reduced cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis (reviewed in McAllister et al, 2015) {McAllister et al. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. J Neuroimmune Pharmacol. 2015 Apr28. [Epub ahead of print] }

These effects may be due to the antioxidant and anti-inflammatory effects of CBD, however these findings have not yet been explored in human patients. There are multiple industry sponsored clinical trials underway to begin to test the efficacy of CBD in human cancer patients. {Massi et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the anti tumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem. 2008 Feb;104(4):1091-100 }

Anti-Psychotic Effects

Marijuana can produce acute psychotic episodes at high doses, and several studies have linked marijuana use to increase risk for chronic psychosis in individuals with specific genetic risk factors. Research suggests that these effects are mediated by THC, and it has been suggested that CBD may mitigate these effects.

{Wilkinson et al. Impact of Cannabis Use on the Development of Psychotic Disorders. Curr Addict Rep. 2014 Jun 1;1(2):115-128 }

There have been a few small-scale clinical trials in which patients with psychotic symptoms were treated with CBD, including case reports of patients with schizophrenia that reported conflicting results; a small case study in patients with Parkinson’s disease with psychosis, which reported positive results; and one small randomized clinical trial reporting clinical improvement in patients with schizophrenia treated with CBD. Again, large randomized clinical trials would be needed to fully evaluate the therapeutic potential of CBD for patients with schizophrenia and other forms of psychosis. {Iseger and Bossong. A systematic review of the anti-psychotic properties of cannabidiol in humans. Schizophr Res. 162(1-3):153-61. (2015) }

Anti-Anxiety Effects

CBD has shown therapeutic efficacy in a range of animal models of anxiety and stress, reducing both behavioral and physiological (e.g., heart rate) measures of stress and anxiety. {Lemos et al. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 207:105–111(2010) } {Guimaraes et al. Anti-anxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559 (1990) }

In addition, CBD has shown efficacy in small human laboratory and clinical trials. CBD reduced anxiety in patients with social anxiety subjected to a stressful public speaking task. {Bergamaschi et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 2011;36:1219–1226 }

In a laboratory protocol designed to model post-traumatic stress disorders, CBD improved “consolidation of extinction learning” put another way, forgetting of traumatic memories. {Das et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013 Apr;226(4):781-92 }

The anxiety-reducing effects of CBD appear to be mediated by alterations in serotonin receptor 1a signaling, although the precise mechanism remains a mystery and more research is needed. {Campos et al. Involvement of serotonin-mediated neurotransmission in the dorsal periaqueductal gray matter on cannabidiol chronic effects in panic-like responses in rats. Psychopharmacology (Berl). 2013 Mar;226(1):13-24 }

Efficacy for Treating Substance Use Disorders

Early pre-clinical findings also suggest that CBD may have therapeutic value as a treatment of substance use disorders. CBD reduced the rewarding effects of morphine, {Katsidoni et al. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013;18(2):286–96. } and reduced cue-induced heroin seeking in animal models. {Ren et al. Cannabidiol, a non-psychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009;29(47):14764–9 }

A few small clinical trials have examined CBD and or nabiximols (THC/CBD) for the treatment of substance use disorders; however the available data are not sufficient to draw conclusions. NIDA is supporting multiple ongoing clinical trails in the area.

Safety of CBD

For reasons discussed previously, despite its molecular similarity to THC, CBD only interacts with cannabinoid receptors weakly at very high doses (100 times that of THC), { Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008 Jan; 153(2): 199–215 } and the alterations in thinking and perception caused by THC are not observed with CBD.  { Martin-Santos et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18(32):4966-79.}, {Fusar-Poli et al. Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing. Arch Gen Psychiatry. 2009;66(1):95-105.} {Winton-Brown et al. Modulation of Auditory and Visual Processing by Delta-9-Tetrahydrocannabinol and Cannabidiol: an fMRI Study. Neuropsychopharmacology. 2011 Jun;36(7):1340-8.}

The different pharmacological properties of CBD give it a different safety profile from THC.

A review of 25 studies on the safety and efficacy of CBD did not identify significant side effects across a wide range of dosages, including acute and chronic dose regimens, using various modes of administration. {Bergamaschi et al. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011 Sep 1;6(4):237-49.}

CBD is present in nabiximols which, as noted earlier, is approved throughout most of Europe and in other countries. Because of this, there is extensive information available with regard to its metabolism, toxicology, and safety. However, additional safety testing among specific patient populations may be warranted should an application be made to the Food and Drug Administration.

Research Opportunities and Challenges

This is a critical area for new research. While there is preliminary evidence that CBD may have therapeutic value for a number of conditions, we need to be careful to not get ahead of the evidence. Ninety-five percent of drugs that move from promising pre-clinical findings to clinical research do not make it to market.

A personal side note here would be to say the ethical stability of the FDA is questionable at times.  The recently announced elimination of the PHS review of non-federally funded research protocols involving marijuana is an important first step to enhance conducting research on marijuana and its components such as CBD. Still, it is important to try to understand the reasons for the lack of well-controlled clinical trials of CBD including: the regulatory requirements associated with doing research with Schedule I substances, including a requirement to demonstrate institutional review board approval; and the lack of CBD that has been produced under the guidance of Current Good Manufacturing Processes (cGMP) – required for testing in human clinical trials – available for researchers. Furthermore, the opportunity to gather important information on clinical outcomes through practical (non-randomized) trials for patients using CBD products available in state marijuana dispensaries is complicated by the variable quality and purity of CBD from these sources.

Conclusion

There is significant preliminary research supporting the potential therapeutic value of CBD, and while it is not yet sufficient to support drug approval, it highlights the need for rigorous clinical research in this area. There are barriers that should be addressed to facilitate more research in this area.

Be Healthy.