CBD Hemp Oil now legal in all 50 states
Mr. Chairman, Ms. Chairwoman, and Members of the Senate Drug Caucus, thank you for inviting 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 restorative impacts of cannabidiol (CBD), one of the main active chemical compounds discovered in cannabis. Because of the quickly developing interest in the prospective use of marijuana and its acquired substances for medical functions, it is important to take stock of what we understand and do not know about the restorative potential of CBD.
CBD Biology and Therapeutic Rationale
CBD is among more than 80 active cannabinoid chemicals in the marijuana plant.ii Unlike the primary psychoactive cannabinoid in marijuana, tetrahydrocannabinol (THC), CBD does not produce euphoria 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, discovered on nerve cells and glial cells in numerous parts of the brain, and the CB2 receptor, discovered mainly in the body's immune system. The blissful impacts of THC are brought on by its activation of CB1 receptors. CBD has a very low affinity for these receptors (100 fold less than THC) when it binds it produces little to no impact. There is also growing proof that CBD acts upon other brain signaling systems, and that these actions may be very important factors to its healing effects.ii
Preclinical and Clinical Evidence
Rigorous scientific research studies are still needed to examine the clinical potential of CBD for particular conditions.i However, pre-clinical research study (consisting of both cell culture and animal models) has actually revealed CBD to have a series of effects that might be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties.
Anti-Seizure Effects
A variety of studies over the last 20 years or more have reported that CBD has anti-seizure activity, decreasing the seriousness of seizures in animal models.vi, vii In addition, there have been a variety of case studies and anecdotal reports recommending that CBD may work in dealing with children with drug-resistant epilepsy.viii, ix, x However, there have actually just been a few small randomized medical trials taking a look at the effectiveness of CBD as a treatment for epilepsy; the total variety of subjects registered in these research studies was 48. 3 of the four research studies reported favorable outcomes, consisting of reduced frequency of seizures. However, the studies suffered from significant design defects, including failure to totally quantify standard seizure frequency, insufficient analytical analysis, and an absence of enough information to sufficiently evaluate and translate the findings.viii Therefore, the currently offered information is inadequate to draw firm conclusions regarding the effectiveness of CBD as a treatment for epilepsy; a recent Cochrane evaluation concluded, there is a requirement for “a series of effectively developed, high quality, and properly powered trials.” xi.
NIDA is presently teaming up with the National Institute on Neurological Disorders and Stroke to assess CBD in animal designs of epilepsy in order to comprehend the hidden systems and enhance the conditions under which CBD might deal with seizure conditions, and identify whether it works synergistically with other anti-seizure medications. In addition, medical trials are presently underway by GW Pharmaceuticals, testing the efficacy of Epidiolex, a purified CBD extract, for treatment of pediatric epilepsy.
Neuroprotective and Anti-Inflammatory Effects.
CBD has likewise been revealed to have neuroprotective residential or commercial properties in cell cultures along with in animal designs of numerous neurodegenerative illness, consisting of Alzheimer's, xii, xiii, xiv stroke, xv glutamate toxicity, xvi several sclerosis (MS), xvii Parkinson's disease, xviii and neurodegeneration brought on by alcohol abuse.xix Nabiximols (brand name Sativex), which consists of THC and CBD in roughly equivalent proportions, has been authorized throughout most of Europe and in a variety of other nations for the treatment of spasticity connected with MS. It has actually not been approved in the United States, however clinical trials are ongoing, and 2 recent studies reported that nabiximols reduced the intensity of spasticity in MS patients.xx, xxi There have been restricted medical trials to examine the potential efficacy of CBD for the other signs highlighted; nevertheless, a current small double-blind trial in clients with Parkinson's disease discovered the CBD enhanced quality-of-life scores.xxii.
Analgesic Effects.
There have actually been numerous clinical trials showing the effectiveness of nabiximols on main 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 pain unresponsive to opioid therapy. However, the existing evidence suggests that the analgesia is mediated by THC and it is uncertain whether CBD adds to the healing effects.xxiv THC alone has been revealed to minimize discomfort; xxv, xxvi we are uninformed of clinical research studies that have actually checked out the efficacy of CBD alone on discomfort. Nevertheless, the anti-inflammatory homes of CBD (discussed above) could be anticipated to contribute in the analgesic impacts of nabiximols. Current research study has actually also suggested that cannabinoids and opioids have various mechanisms for decreasing pain and that their effects might be additive, which suggests that combination treatments might be developed that might have lowered risks compared to existing opioid treatments. However, this work is extremely preliminary.xxvii.
Anti-Tumor Effects.
In addition to the research on the use of cannabinoids in palliative treatments for cancer– lowering discomfort and queasiness and in increasing appetite– there are likewise a number of pre-clinical reports revealing anti-tumor effects of CBD in cell culture and in animal models.xxviii These research studies have actually found reduced cell practicality, increased cancer cell death, reduced tumor growth, and inhibition of transition (examined in McAllister et al, 2015). xxix These impacts might be because of the antioxidant and anti-inflammatory results of CBD; xxx however these findings have actually not yet been checked out in human clients. There are several industry sponsored scientific trials underway to start to check the efficacy of CBD in human cancer clients.
Anti-Psychotic Effects.
Cannabis can produce intense psychotic episodes at high dosages, and a number of research studies have actually connected marijuana use to increased risk for chronic psychosis in individuals with particular genetic threat elements. Research study recommends that these effects are moderated by THC, and it has been recommended that CBD might alleviate these effects.xxxi There have been a few small scientific trials where clients with psychotic signs were treated with CBD, consisting of case reports of clients 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 medical trial reporting medical improvement in clients with schizophrenia treated with CBD.xxxii Large randomized medical trials would be had to totally evaluate the therapeutic potential of CBD for patients with schizophrenia and other kinds of psychosis.
Anti-Anxiety Effects.
CBD has actually shown therapeutic efficacy in a variety of animal models of stress and anxiety and stress, minimizing both behavioral and physiological (e.g., heart rate) steps of tension and anxiety.xxxiii, xxxiv In addition, CBD has revealed effectiveness in small human lab and clinical trials. CBD minimized anxiety in clients with social anxiety subjected to a difficult public speaking task.xxxv In a lab procedure developed to design trauma, CBD enhanced “consolidation of extinction knowing”, in other words, forgetting of traumatic memories.xxxvi The anxiety-reducing impacts of CBD appear to be moderated by modifications in serotonin receptor 1a signaling, although the exact system remains to be illuminated and more research study is needed.xxxvii.
Effectiveness for Treating Substance Use Disorders.
Early preclinical findings also recommend that CBD might have therapeutic worth as a treatment of substance use conditions. CBD decreased the rewarding impacts of morphinexxxviii and reduced cue-induced heroin seekingxxxix in animal designs. A couple of little clinical trials have actually examined CBD and/or nabiximols (THC/CBD) for the treatment of compound usage disorders; however, the readily available information are not enough to reason. NIDA is supporting numerous ongoing clinical trials in this area.
Security of CBD.
For factors gone over formerly, regardless of its molecular resemblance to THC, CBD just interacts with cannabinoid receptors weakly at extremely high doses (100 times that of THC), xl and the alterations in believing and understanding brought on by THC are not observed with CBD.iii.iv, v The various pharmacological homes of CBD provide it a different security profile from THC.
An evaluation of 25 research studies on the security and effectiveness of CBD did not determine substantial adverse effects across a vast array of doses, including intense and chronic dose programs, utilizing various modes of administration.xli CBD is present in nabiximols which, as noted previously, is authorized throughout most of Europe and in other countries. Since of this, there is extensive details readily available with regard to its metabolic process, toxicology, and safety. However, extra safety screening among particular patient populations may be warranted ought to an application be made to the Food and Drug Administration.
Research Opportunities and Challenges.
This is an important location for brand-new research. While there is preliminary evidence that CBD may have restorative worth for a number of conditions, we need to beware 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 recently revealed removal of the PHS evaluation of non-federally moneyed research procedures including marijuana is an essential first step to improve carrying out research on cannabis and its components such as CBD. Still, it is essential to attempt to understand the factors for the absence of well-controlled medical trials of CBD including: the regulatory requirements connected with doing research with Schedule I compounds, including a requirement to demonstrate institutional evaluation board approval; and the absence of CBD that has actually been produced under the guidance of Current Good Manufacturing Processes (cGMP)– required for testing in human scientific trials– offered for researchers. Moreover, the chance to gather crucial info on scientific outcomes through useful (non-randomized) trials for patients using CBD products offered in state marijuana dispensaries is complicated by the variable quality and pureness of CBD from these sources.
Ongoing CBD Research.
The NIH acknowledges the need for additional research on the restorative impacts of CBD and other cannabinoids, and supports continuous efforts to reduce barriers to research in this location. NIH is currently supporting a number of research studies on the healing impacts in addition to the health dangers of cannabinoids. These consist of studies of the therapeutic worth of CBD for:.
Treatment of compound usage conditions (opioids, alcohol, cannabis, methamphetamine).
Attenuation of the cognitive deficits triggered by THC.
Neuropathic discomfort due to spinal cord injury.
Reducing the effect of cannabis use on risk for schizophrenia.
Examination of the potential of CBD as an antiepileptic treatment.
It is essential to keep in mind that NIDA's mission is concentrated on substance abuse; studies related to the restorative effects of CBD in other locations would be moneyed by the Institute or Center accountable for that program location. For instance, studies associated with 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 studies associated with schizophrenia will likely be moneyed by the National Institute on Mental Health.
Conclusion.
There is substantial preliminary research study supporting the possible healing value of CBD, and while it is not yet enough to support drug approval, it highlights the requirement for rigorous clinical research in this location. There are barriers that need to be dealt with to facilitate more research study in this location. We appreciate the opportunity to affirm on the potential use of CBD for restorative functions.
References
- i Welty et al. Cannabidiol: promise and pitfalls. Epilepsy Curr. 14(5):250-2. (2014).
- ii Borgelt et al. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy (Review) 33 (2): 195–209 (2013).
- iii 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.
- iv Fusar-Poli et al. Distinct Effects of Ξ9-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 exerts 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 comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977 Apr;201(1):26-32.
- viii 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.
- ix Press et al. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior 45 (2015) 49–52.
- x 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.
- xi Gloss and Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 3:CD009270. (2014).
- xii 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).
- xiii MartΓn-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 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).
- xv Pazos et al. Mechanisms 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 antioxidants. 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 GarcΓa-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).
- xix 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.
- xx 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).
- xxi 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)
- xxii 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).
- xxiii Russo EB. Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management. 4(1):245-259.(2008).
- xxiv 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).
- xxv 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.
- xxvi 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.
- xxvii Neelakantan et al. Distinct interactions of cannabidiol and morphine in three 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 systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res. 162(1-3):153-61. (2015).
- xxxiii Guimaraes et al. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559 (1990).
- xxxiv 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).
- xxxv Bergamaschi et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 2011;36:1219–1226.
- xxxvi Das et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013 Apr;226(4):781-92.
- xxxvii 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.
- xxxviii 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.
- xxxix 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.
- xl Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Ξ9-tetrahydrocannabinol, cannabidiol and Ξ9-tetrahydrocannabivarin. Br J Pharmacol. 2008 Jan; 153(2): 199–215.
- xli 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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