Major literature articles related to cannabidiol and cannabidiol-tetrahydrocannabinol combination for various indications.

Although clinical evidence is still needed to evaluate the potential of CBD as a drug for many specific conditions, pre-clinical research (including both cell culture and animal models) has shown CBD to have a range of effects that may be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties.  A list of publications against each indication below reflects the work done to date and highlights the potential of CBD working alone, or in conjunction with THC at times, in treating and managing various illnesses.

 

Anti-Seizure Effects

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.
  • Consroe P and Wolkin A. Cannabidiol--antiepileptic 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.

Neuroprotective and Anti-Inflammatory Effects

CBD has 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).
  • Luvone 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 (MS): 

  • Pryce et al. Neuroprotection inExperimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J Neuroimmune Pharmacol. 2014 Dec 24.

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 in MS patients, references below:

  • 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 multicenter, 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 unresponsive 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.
  • Svendsen et al. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised 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.

Although there are no controlled clinical studies that have explored the efficacy of CBD alone on pain, the anti-inflammatory properties of CBD 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 in increasing 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. 

These studies have found reduced cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis:

  • McAllister et al. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. J Neuroimmune Pharmacol. 2015 Apr28.

These effects may be due to the antioxidant and anti-inflammatory effects of CBD:

  • Massi et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem. 2008 Feb;104(4):1091-100.

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.

 

Anti-Psychotic Effects

Marijuana can produce acute psychotic episodes at high doses, and several studies have linked marijuana use to increased 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:

  • Iseger and Bossong. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res. 162(1-3):153-61. (2015). 

Large randomized clinical trials would be needed to fully evaluate the therapeutic potential of CBD for patients with schizophrenia and other forms of psychosis.


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:

  • Guimaraes et al. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559 (1990).
  • 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).

 

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”, in other words, 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 to be elucidated 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 preclinical 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 nonpsychotropic 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.

 

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

 

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