Mr. Chairman, Ms. Chairwoman, and Members of the Senate Drug Caucus, thank you for welcoming the National Institute on Drug Abuse (NIDA), a part of the National Institutes of Health (NIH), to take part in this hearing to share exactly what we understand about the biology and the potential corrective impacts of cannabidiol (CBD), among the main active chemical compounds discovered in marijuana. Due to the fact that of the quickly establishing interest in the potential usage of cannabis and its acquired substances for medical functions, it is very important to take stock of exactly what we understand and do unknown about the restorative capacity of CBD.
CBD Biology and Therapeutic Rationale
CBD is among more than 80 active cannabinoid chemicals in the cannabis plant.ii Unlike the primary psychoactive cannabinoid in marijuana, tetrahydrocannabinol (THC), CBD does not produce ecstasy or intoxication.iii, iv, v Cannabinoids have their impact primarily by engaging with particular receptors on cells in the brain and body: the CB1 receptor, found on nerve cells and glial cells in many parts of the brain, and the CB2 receptor, discovered generally in the body’s immune system. The euphoric effects of THC are caused by its activation of CB1 receptors. CBD has a really low affinity for these receptors (100 fold less than THC) when it binds it produces little to no impact. There is also growing evidence that CBD acts upon other brain signaling systems, which these actions may be extremely important elements to its recovery effects.ii
Preclinical and Clinical Evidence
Extensive clinical research studies are still needed to examine the medical potential of CBD for particular conditions.i However, pre-clinical research study (consisting of both cell culture and animal designs) has in fact revealed CBD to have a series of impacts that might be therapeutically useful, consisting of anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety homes.
A variety of studies over the last 20 years or more have reported that CBD has anti-seizure activity, reducing the seriousness of seizures in animal models.vi, vii In addition, there have actually been a variety of case research studies and anecdotal reports recommending that CBD might work in handling children with drug-resistant epilepsy.viii, ix, x However, there have in fact just been a few little randomized medical trials having a look at the efficiency of CBD as a treatment for epilepsy; the total variety of topics registered in these research study studies was 48. 3 of the 4 research study studies reported favorable results, including minimized frequency of seizures. Nevertheless, the studies suffered from significant design problems, including failure to absolutely measure standard seizure frequency, inadequate analytical analysis, and a lack of enough information to sufficiently evaluate and translate the findings.viii Therefore, the currently used details is inadequate to draw firm conclusions relating to the efficiency of CBD as a treatment for epilepsy; a current Cochrane assessment concluded, there is a requirement for “a series of efficiently developed, high quality, and correctly powered trials.” xi.
NIDA is currently partnering with the National Institute on Neurological Disorders and Stroke to assess CBD in animal designs of epilepsy in order to understand the covert systems and improve the conditions under which CBD might deal with seizure conditions, and recognize whether it works synergistically with other anti-seizure medications. In addition, medical trials are currently in progress by GW Pharmaceuticals, testing the efficacy of Epidiolex, a purified CBD extract, for treatment of pediatric epilepsy.
Neuroprotective and Anti-Inflammatory Effects.
CBD has also been exposed to have neuroprotective residential or business homes in cell cultures along with in animal styles of many neurodegenerative health problem, consisting of Alzheimer’s, xii, xiii, xiv stroke, xv glutamate toxicity, xvi a number of sclerosis (MS), xvii Parkinson’s disease, xviii and neurodegeneration brought on by alcohol abuse.xix Nabiximols (brand name Sativex), which includes THC and CBD in approximately comparable percentages, has actually been authorized throughout most of Europe and in a range of other nations for the treatment of spasticity connected with MS. It has really not been authorized in the United States, nevertheless medical trials are ongoing, and 2 recent research studies reported that nabiximols lowered the strength of spasticity in MS patients.xx, xxi There have actually been limited medical trials to analyze the possible efficacy of CBD for the other signs highlighted; however, an existing small double-blind trial in customers with Parkinson’s illness discovered the CBD improved quality-of-life scores.xxii.
There have really countlessed medical trials showing the efficiency of nabiximols on primary and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain.xxiii In addition, nabiximols is currently approved in Canada for the treatment of central neuropathic pain in MS and cancer discomfort unresponsive to opioid treatment. Nevertheless, the existing evidence recommends that the analgesia is mediated by THC and it doubts whether CBD adds to the recovery effects.xxiv THC alone has been revealed to reduce pain; xxv, xxvi we are uninformed of clinical research studies that have in fact taken a look at the effectiveness of CBD alone on pain. Nonetheless, the anti-inflammatory homes of CBD (talked about above) might be prepared for to contribute in the analgesic impacts of nabiximols. Present research study has in fact likewise suggested that cannabinoids and opioids have various systems for decreasing pain and that their impacts may be additive, which recommends that combination treatments might be established that may have reduced threats compared to existing opioid treatments. Nevertheless, this work is exceptionally preliminary.xxvii.
In addition to the research on using cannabinoids in palliative treatments for cancer– decreasing discomfort and queasiness and in increasing cravings– there are likewise a variety of pre-clinical reports exposing anti-tumor effects of CBD in cell culture and in animal models.xxviii These research studies have in fact discovered minimized cell practicality, increased cancer cell death, reduced tumor development, and inhibition of shift (analyzed in McAllister et al, 2015). xxix These effects might be because of the antioxidant and anti-inflammatory outcomes of CBD; xxx nevertheless these findings have really not yet been checked out in human clients. There are numerous industry sponsored clinical trials underway to start to check the effectiveness of CBD in human cancer customers.
Cannabis can produce extreme psychotic episodes at high doses, and a number of research studies have actually connected cannabis use to increased danger for chronic psychosis in people with specific hereditary risk elements. Research research study suggests that these effects are moderated by THC, and it has been recommended that CBD may reduce these effects.xxxi There have actually been a few small scientific trials where customers with psychotic signs were treated with CBD, consisting of case reports of customers with schizophrenia that reported conflicting results; a small case research study in clients with Parkinson’s illness with psychosis, which reported favorable results; and one small randomized medical trial reporting medical improvement in clients with schizophrenia treated with CBD.xxxii Large randomized medical trials would be had to absolutely evaluate the therapeutic capacity of CBD for patients with schizophrenia and other sort of psychosis.
CBD has really shown healing effectiveness in a range of animal designs of stress and anxiety and stress, reducing both behavioral and physiological (e.g., heart rate) steps of stress and anxiety.xxxiii, xxxiv In addition, CBD has actually revealed effectiveness in small human laboratory and scientific trials. CBD decreased stress and anxiety in customers with social anxiety subjected to a hard public speaking task.xxxv In a lab procedure established to develop injury, CBD improved “combination of extinction understanding”, to puts it simply, forgetting of traumatic memories.xxxvi The anxiety-reducing effects of CBD seem moderated by modifications in serotonin receptor 1a signaling, although the specific system remains to be lit up and more research study is needed.xxxvii.
Effectiveness for Treating Substance Use Disorders.
Early preclinical findings also recommend that CBD may have restorative worth as a treatment of substance usage conditions. CBD decreased the rewarding effects of morphinexxxviii and lowered cue-induced heroin seekingxxxix in animal designs. A number of little scientific trials have really examined CBD and/or nabiximols (THC/CBD) for the treatment of compound use conditions; nevertheless, the readily available info are not enough to reason. NIDA is supporting numerous ongoing medical trials in this location.
Security of CBD.
For factors discussed previously, despite its molecular resemblance to THC, CBD simply connects with cannabinoid receptors weakly at incredibly high dosages (100 times that of THC), xl and the changes in believing and comprehending induced by THC are not observed with CBD.iii.iv, v The different pharmacological houses of CBD supply it a various security profile from THC.
An examination of 25 research study studies on the security and effectiveness of CBD did not identify substantial negative effects throughout a vast range of dosages, consisting of intense and persistent dosage programs, utilizing various modes of administration.xli CBD exists in nabiximols which, as noted formerly, is authorized throughout most of Europe and in other nations. Considering that of this, there is comprehensive information readily available with regard to its metabolic process, toxicology, and safety. Nevertheless, additional security screening among particular patient populations might be called for should an application be made to the Food and Drug Administration.
Research study Opportunities and Challenges.
This is a crucial location for new research. While there is initial evidence that CBD may have corrective worth for a number of conditions, we need to be careful to not get ahead of the proof. Ninety-five percent of drugs that move from promising preclinical findings to scientific research study do not make it to market. The just recently revealed removal of the PHS evaluation of non-federally moneyed research procedures consisting of marijuana is an essential primary step to enhance carrying out research study on cannabis and its parts such as CBD. Still, it is vital to attempt to comprehend the elements for the absence of well-controlled medical trials of CBD consisting of: the regulative requirements gotten in touch with researching with Schedule I substances, including a requirement to demonstrate institutional examination board approval; and the absence of CBD that has in fact been produced under the assistance of Current Good Manufacturing Processes (cGMP)– required for screening in human clinical trials– provided for researchers. Additionally, the chance to collect crucial info on scientific outcomes through useful (non-randomized) trials for clients utilizing CBD items offered in state cannabis dispensaries is complicated by the variable quality and pureness of CBD from these sources.
Continuous CBD Research.
The NIH acknowledges the requirement for extra research on the restorative effects of CBD and other cannabinoids, and supports continuous efforts to decrease barriers to research in this area. NIH is currently supporting a number of research studies on the recovery impacts in addition to the health threats of cannabinoids. These consist of studies of the therapeutic worth of CBD for:.
Treatment of substance usage conditions (opioids, alcohol, cannabis, methamphetamine).
Attenuation of the cognitive deficits activated by THC.
Neuropathic discomfort due to spinal cord injury.
Minimizing the effect of cannabis usage on risk for schizophrenia.
Evaluation of the potential of CBD as an antiepileptic treatment.
It is vital to keep in mind that NIDA’s objective is focused on drug abuse; research studies related to the restorative results of CBD in other locations would be moneyed by the Institute or Center responsible for that program location. For instance, research studies related to epilepsy will likely be funded by the National Institute of Neurological Disorders and Stroke or by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, while research study studies associated with schizophrenia will likely be moneyed by the National Institute on Mental Health.
There is considerable initial research study supporting the possible recovery value of CBD, and while it is not yet enough to support drug approval, it highlights the requirement for strenuous clinical research in this location. There are barriers that have to be handled to help with more research study in this area. We appreciate the chance to verify on the potential usage of CBD for restorative functions.
i Welty et al. Cannabidiol: promise and pitfalls. Epilepsy Curr. 14( 5):250 -2. (2014).
ii Borgelt et al. The pharmacologic and medical impacts of medical cannabis. Pharmacotherapy (Review) 33 (2): 195– 209 (2013).
iii Martin-Santos et al. Severe 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.
iv Fusar-Poli et al. Unique Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing. Arch Gen Psychiatry. 2009; 66( 1):95 -105.
v 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.
vi Jones et al. Cannabidiol applies anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun; 21( 5):344 -52.
vii Consroe P and Wolkin A. Cannabidiol– antiepileptic drug contrasts and interactions in experimentally caused seizures in rats. J Pharmacol Exp Ther. 1977 Apr; 201( 1):26 -32.
viii Porter BE and Jacobson C. Report of a moms and dad study of cannabidiol-enriched marijuana usage in pediatric treatment-resistant epilepsy. Epilepsy & Behavior 29 (2013) 574– 577.
ix Press et al. Adult reporting of response to oral marijuana extracts for treatment of refractory epilepsy. Epilepsy & Behavior 45 (2015) 49– 52.
x Hussain et al. Perceived effectiveness of cannabidiol-enriched marijuana extracts for treatment of pediatric epilepsy: A possible function for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav. 2015 Apr 29. pii: S1525-5050( 15) 00157-2.
xi Gloss and Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 3: CD009270. (2014).
xii Esposito G et al. The cannabis element cannabidiol prevents beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med (Berl). 84( 3):253 -8. (2006).
xiii 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).
xiv Iuvone et al.Neuroprotective impact of cannabidiol, a non-psychoactive part from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 89( 1):134 -41. (2004).
xv Pazos et al. Systems of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT( 1A) and CB2 receptors. Neuropharmacology. 71:282 -91. (2013).
xvi Hampson et al. Cannabidiol and (-) Delta9-tetrahydrocannabinol are neuroprotective anti-oxidants. Proc Natl AcadSci U S A. 95( 14):8268 -73. (1998).
xvii 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] xviii García-Arencibia et al. Assessment of the neuroprotective impact of cannabinoids in a rat design of Parkinson’s disease: significance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 1134( 1):162 -70. (2007).
xix Hamelink et al. Contrast of cannabidiol, anti-oxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther. 2005 Aug; 314( 2):780 -8.
xx Di Marzo and Centonze. Placebo effects in a several sclerosis spasticity enriched medical trial with the oromucosal cannabinoid spray (THC/CBD): measurement and possible causes. CNS Neurosci Ther. 21( 3):215 -21. (2015).
xxi Flachenecker et al. Nabiximols (THC/CBD oromucosal spray, Sativex ®) in clinical practice– results of a multicenter, non-interventional research study (MOVE 2) in clients with numerous sclerosis spasticity. Eur Neurol.71( 5-6):271 -9. (2014).
xxii Chagas et al. Impacts of cannabidiol in the treatment of clients with Parkinson’s illness: an exploratory double-blind trial. J Psychopharmacol. 28( 11):1088 -98. (2014).
xxiii Russo EB. Cannabinoids in the management of difficult to deal with discomfort. Rehabs and Clinical Risk Management. 4( 1):245 -259.( 2008).
xxiv Iskedjian et al. Meta-analysis of cannabis based treatments for neuropathic and numerous sclerosis-related pain. Curr Med Res Opin. 23( 1):17 -24.( 2007).
xxv Svendsen et al. Does the cannabinoid dronabinol lower main pain in numerous sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004 Jul 31; 329( 7460):253.
xxvi Portenoy et al. Nabiximols for opioid-treated cancer clients with poorly-controlled persistent discomfort: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012 May; 13( 5):438 -49.
xxvii Neelakantan et al. Distinct interactions of cannabidiol and morphine in 3 nociceptive behavioral models in mice. Behav Pharmacol. 26( 3):304 -14. (2015).
xxviii McAllister et al. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. J Neuroimmune Pharmacol. 2015 Apr28. [Epub ahead of print] xxix McAllister et al. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. J Neuroimmune Pharmacol. 2015 Apr28. [Epub ahead of print]
xxx 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.
xxxi Wilkinson et al. Impact of Cannabis Use on the Development of Psychotic Disorders. Curr Addict Rep. 2014 Jun 1; 1( 2):115 -128.
xxxii Iseger and Bossong. A methodical evaluation of the antipsychotic homes of cannabidiol in human beings. Schizophr Res. 162( 1-3):153 -61. (2015).
xxxiii Guimaraes et al. Antianxiety effect of cannabidiol in the raised plus-maze. Psychopharmacology (Berl) 100:558– 559 (1990).
xxxiv Lemos et al. Participation of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 207:105– 111( 2010).
xxxv Bergamaschi et al. Cannabidiol decreases the anxiety caused by simulated public speaking in treatment-naive social phobia clients. Neuropsychopharmacology 2011; 36:1219– 1226.
xxxvi Das et al. Cannabidiol improves consolidation of explicit fear extinction in human beings. Psychopharmacology (Berl). 2013 Apr; 226( 4):781 -92.
xxxvii Campos et al. Involvement of serotonin-mediated neurotransmission in the dorsal periaqueductal noodle on cannabidiol persistent effects in panic-like actions in rats. Psychopharmacology (Berl). 2013 Mar; 226( 1):13 -24.
xxxviii Katsidoni et al. Cannabidiol prevents the reward-facilitating result of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013; 18( 2):286– 96.
xxxix Ren et al. Cannabidiol, a nonpsychotropic element of marijuana, prevents cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009; 29( 47):14764– 9.
xl 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.
xli Bergamaschi et al. Safety and negative effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011 Sep 1; 6( 4):237 -49.