Clinical trials for cbd oil and opioid addiction

Cannabis (Marijuana) Research Report
Is marijuana safe and effective as medicine?

The potential medicinal properties of marijuana and its components have been the subject of research and heated debate for decades. THC itself has proven medical benefits in particular formulations. The U.S. Food and Drug Administration (FDA) has approved THC-based medications, dronabinol (Marinol ® ) and nabilone (Cesamet ® ), prescribed in pill form for the treatment of nausea in patients undergoing cancer chemotherapy and to stimulate appetite in patients with wasting syndrome due to AIDS.

In addition, several other marijuana-based medications have been approved or are undergoing clinical trials. Nabiximols (Sativex ® ), a mouth spray that is currently available in the United Kingdom, Canada, and several European countries for treating the spasticity and neuropathic pain that may accompany multiple sclerosis, combines THC with another chemical found in marijuana called cannabidiol (CBD).

The FDA also approved a CBD-based liquid medication called Epidiolex ® for the treatment of two forms of severe childhood epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. It’s being delivered to patients in a reliable dosage form and through a reproducible route of delivery to ensure that patients derive the anticipated benefits. CBD does not have the rewarding properties of THC.

Researchers generally consider medications like these, which use purified chemicals derived from or based on those in the marijuana plant, to be more promising therapeutically than use of the whole marijuana plant or its crude extracts. Development of drugs from botanicals such as the marijuana plant poses numerous challenges. Botanicals may contain hundreds of unknown, active chemicals, and it can be difficult to develop a product with accurate and consistent doses of these chemicals. Use of marijuana as medicine also poses other problems such as the adverse health effects of smoking and THC-induced cognitive impairment. Nevertheless, a growing number of states have legalized dispensing of marijuana or its extracts to people with a range of medical conditions.

An additional concern with “medical marijuana” is that little is known about the long-term impact of its use by people with health- and/or age-related vulnerabilities—such as older adults or people with cancer, AIDS, cardiovascular disease, multiple sclerosis, or other neurodegenerative diseases. Further research will be needed to determine whether people whose health has been compromised by disease or its treatment (e.g., chemotherapy) are at greater risk for adverse health outcomes from marijuana use.

Medical Marijuana Laws and Prescription Opioid Use Outcomes

A new study underscores the need for additional research on the effect of medical marijuana laws on opioid overdose deaths and cautions against drawing a causal connection between the two. Early research suggested that there may be a relationship between the availability of medical marijuana and opioid analgesic overdose mortality. In particular, a NIDA-funded study published in 2014 found that from 1999 to 2010, states with medical cannabis laws experienced slower rates of increase in opioid analgesic overdose death rates compared to states without such laws. 78

A 2019 analysis, also funded by NIDA, re-examined this relationship using data through 2017. Similar to the findings reported previously, this research team found that opioid overdose mortality rates between 1999-2010 in states allowing medical marijuana use were 21% lower than expected. When the analysis was extended through 2017, however, they found that the trend reversed, such that states with medical cannabis laws experienced an overdose death rate 22.7% higher than expected. 79 The investigators uncovered no evidence that either broader cannabis laws (those allowing recreational use) or more restrictive laws (those only permitting the use of marijuana with low tetrahydrocannabinol concentrations) were associated with changes in opioid overdose mortality rates.

These data, therefore, do not support the interpretation that access to cannabis reduces opioid overdose. Indeed, the authors note that neither study provides evidence of a causal relationship between marijuana access and opioid overdose deaths. Rather, they suggest that the associations are likely due to factors the researchers did not measure, and they caution against drawing conclusions on an individual level from ecological (population-level) data. Research is still needed on the potential medical benefits of cannabis or cannabinoids.

The Biology and Potential Therapeutic Effects of Cannabidiol

“Cannabidiol: Barriers to Research and Potential Medical Benefits”

Mr. Chairman, Ms. Chairwoman, and Members of the Senate Drug Caucus, thank you for inviting the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), to participate in this hearing to share what we know about the biology and the potential therapeutic effects of cannabidiol (CBD), one of the main active chemical compounds found in marijuana. In light of the rapidly evolving interest in the potential use of marijuana and its derivative compounds for medical purposes, it is important to take stock of what we know and do not know about the therapeutic potential of CBD.

Background

To date, 23 states and the District of Columbia have passed laws allowing marijuana to be used for a variety of medical conditions. Fifteen additional states have enacted laws intended to allow access to CBD oil and/or high-CBD strains of marijuana. Interest 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. While there are promising preliminary data, the scientific literature is currently insufficient to either prove or disprove the efficacy and safety of CBD in patients with epilepsy. i and further clinical evaluation is warranted. 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, cancer, pain, inflammatory diseases and others. My testimony will provide an overview of what the science tells us about the therapeutic potential of CBD and of the ongoing research supported by NIH in this area.

CBD Biology and Therapeutic Rationale

CBD is one of more than 80 active cannabinoid chemicals in the marijuana plant. ii Unlike the main psychoactive cannabinoid in marijuana, tetrahydrocannabinol (THC), CBD does not produce euphoria or intoxication. iii,iv,v Cannabinoids have their effect mainly by interacting with specific receptors on cells in the brain and body: the CB1 receptor, found on neurons and glial cells in various parts of the brain, and the CB2 receptor, found mainly in the body’s immune system. The euphoric effects of THC are caused by its activation of CB1 receptors. CBD has a very low affinity for these receptors (100 fold less than THC) and when it binds it produces little to no effect. There is also growing evidence that CBD acts on other brain signaling systems, and that these actions may be important contributors to its therapeutic effects. ii

Preclinical and Clinical Evidence

Rigorous clinical studies are still needed to evaluate the clinical potential of CBD for specific conditions. i However, 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.

Anti-Seizure Effects

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. vi,vii 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. viii,ix,x However, there have only been a few small randomized clinical trials examining the efficacy of CBD as a treatment for epilepsy; the total number of subjects enrolled in these studies was 48. Three of the four studies reported positive results, including decreased frequency of seizures. However, the studies suffered from significant design flaws, including failure to fully quantify baseline seizure frequency, inadequate statistical analysis, and a lack of sufficient detail to adequately evaluate and interpret the findings. viii Therefore, the currently available information is insufficient to draw firm conclusions regarding the efficacy of CBD as a treatment for epilepsy; a recent Cochrane review concluded, there is a need for “a series of properly designed, high quality, and adequately powered trials.” xi

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 medications. In addition, clinical trials are currently 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 also been shown to have neuroprotective properties in cell cultures as well as in animal models of several neurodegenerative diseases, including Alzheimer’s, xii,xiii,xiv stroke, xv glutamate toxicity, xvi multiple sclerosis (MS), xvii Parkinson’s disease, xviii and neurodegeneration caused by alcohol abuse. xix 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. xx,xxi 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. xxii

Analgesic Effects

There have been multiple clinical trials demonstrating the efficacy of nabiximols on central 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 current evidence suggests that the analgesia is mediated by THC and it is unclear whether CBD contributes to the therapeutic effects. xxiv THC alone has been shown to reduce pain; xxv,xxvi we are unaware of clinical studies that have explored the efficacy of CBD alone on pain. However, 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. xxvii

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. xxviii These studies have found reduced cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis (reviewed in McAllister et al, 2015). xxix These effects may be due to the antioxidant and anti-inflammatory effects of CBD; xxx 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. xxxi 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. xxxii 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. xxxiii,xxxiv 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. xxxv In a laboratory protocol designed to model post-traumatic stress disorders, CBD improved “consolidation of extinction learning”, in other words, forgetting of traumatic memories. xxxvi 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. xxxvii

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 xxxviii and reduced cue-induced heroin seeking xxxix in animal models. 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 trials in this 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), xl and the alterations in thinking and perception caused by THC are not observed with CBD. iii.iv,v 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. xli 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 preclinical findings to clinical research do not make it to market. 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.

Ongoing CBD Research

The NIH recognizes the need for additional research on the therapeutic effects of CBD and other cannabinoids, and supports ongoing efforts to reduce barriers to research in this area. NIH is currently supporting a number of studies on the therapeutic effects as well as the health risks of cannabinoids. These include studies of the therapeutic value of CBD for:

  • Treatment of substance use disorders (opioids, alcohol, cannabis, methamphetamine)
  • Attenuation of the cognitive deficits caused by THC
  • Neuropathic pain due to spinal cord injury
  • Mitigating the impact of cannabis use on risk for schizophrenia
  • Examination of the potential of CBD as an antiepileptic treatment

It is important to note that NIDA’s mission is focused on drug abuse; studies related to the therapeutic effects of CBD in other areas would be funded by the Institute or Center responsible for that program area. For example, 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 studies related to schizophrenia will likely be funded by the National Institute on Mental Health.

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. We appreciate the opportunity to testify on the potential use of CBD for therapeutic purposes. Thank you again for inviting me here today, and I look forward to any questions you may have.

Most Commonly Used Addictive Drugs

NIDA. “Media Guide.” National Institute on Drug Abuse, 2 Jul. 2018, https://archives.drugabuse.gov/publications/media-guide.

NIDA. Media Guide. National Institute on Drug Abuse website. https://archives.drugabuse.gov/publications/media-guide. July 2, 2018.

Most Commonly Used Addictive Drugs

Marijuana

Marijuana (cannabis) refers to the dried leaves, flowers, stems, and seeds from the Cannabis sativa or Cannabis indica plant and is the most commonly used illicit substance. It is now legal in some states for medical and recreational use. Some people use marijuana for its pleasurable high, but this drug also impairs short-term memory and learning, the ability to focus, and coordination. It also increases heart rate, can harm the lungs, and can increase the risk of psychosis in vulnerable people. Data suggest that 30 percent of those who use marijuana may have some degree of marijuana use disorder. People who begin using marijuana before the age of 18 are four to seven times more likely than adults to develop a marijuana use disorder. For more information, visit www.drugabuse.gov/drugs-abuse/marijuana.

Marijuana Research at NIDA and NIH

As part of its mandate to study drug use and addiction and other health effects of both legal and illegal drugs, NIDA funds a wide range of research on marijuana; its main mind-altering ingredient, THC; and other chemicals, such as cannabidiol (CBD). For more information about NIDA research on marijuana and cannabinoids, visit drugabuse.gov/drugs-abuse/marijuana/marijuana-research-nida. NIDA is one of 27 institutes and centers who could fund research on marijuana. For more information about NIH-funded research on marijuana, visit www.drugabuse.gov/drugs-abuse/marijuana/nih-research-marijuana-cannabinoids.

Medical Marijuana

Although many states have legalized marijuana for medical use, the scientific evidence to date is not sufficient for it to gain U.S. Food and Drug Administration (FDA) approval, for two main reasons.

First, there have not been enough clinical trials showing that marijuana’s benefits outweigh its health risks. The FDA requires carefully conducted studies (clinical trials) in hundreds to thousands of patients to determine benefits and risks.

Second, to be considered a legitimate medicine, a substance must have well-defined and measurable ingredients that are consistent from one unit to the next (such as a pill or injection). This consistency allows doctors to determine the dose and frequency. As the marijuana plant contains hundreds of chemical compounds that may have different effects and that vary from plant to plant, evaluating the whole plant as a medicine is difficult.

However, synthetic THC-based drugs to treat nausea caused by chemotherapy and increase appetite in patients with extreme weight loss caused by AIDS are already FDA-approved and prescribed. In addition, the FDA recently approved Epidiolex ® , the first medicine derived from the marijuana plant itself. Epidiolex ® is made using CBD, a non-pscyhoactive ingredient in the plant, and has shown efficacy in treating two rare and severe forms of epilepsy in children. For more information, see our Marijuana as Medicine DrugFacts at drugabuse.gov/publications/drugfacts/marijuana-medicine.

Synthetic Cannabinoids (K2/Spice)

Synthetic cannabinoids are human-made, mind-altering chemicals that are either sprayed on dried, shredded plant material so they can be smoked (herbal incense) or sold as liquids to be vaporized and inhaled in e-cigarettes and other devices (liquid incense) to produce a high.

These chemicals are called cannabinoids because they are related to chemicals found in the marijuana plant. Because of this similarity, synthetic cannabinoids are sometimes misleadingly called “synthetic marijuana” (or “fake weed”), and they are often marketed as “safe,” legal alternatives to that drug. In fact, they are not safe and may affect the brain more powerfully and differently than marijuana; their actual effects can be unpredictable and, in some cases, severe or even life-threatening.

Synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS). These are unregulated mind-altering substances that have become recently available on the market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity.

People taken to the emergency room after using synthetic cannabinoids report rapid heart rate, vomiting, violent behavior, and suicidal thoughts. These drugs can also raise blood pressure and reduce blood supply to the heart, as well as cause kidney damage and seizures. Synthetic cannabinoids have a high addictive potential and no medical benefit, so the U.S. Drug Enforcement Administration (DEA) has made it illegal to sell, buy, or possess them. However, manufacturers try to sidestep these laws by changing the chemical formulas in their mixtures. For more information, visit drugabuse.gov/drugs-abuse/synthetic-cannabinoids-k2spice.

Prescription and Over-the-Counter Medications

Some prescription and over-the-counter medications are increasingly being misused (used in ways other than intended or without a prescription). This practice can lead to addiction and, in some cases, overdose. Among the most disturbing aspects of this emerging trend is its prevalence among teenagers and young adults, as well as the common misperception that because these are used medically or prescribed by physicians, they are safe even when not used as intended. Commonly misused classes of prescription drugs include opioid pain relievers, stimulants, and central nervous system (CNS) depressants (sedatives and tranquilizers).

Opioids are a class of drugs naturally found in the opium poppy plant. Some prescription opioids are made from the plant directly, and others are made by scientists in labs using the same chemical structure. Opioids are often used as medicines because they contain chemicals that relax the body and can relieve pain. Prescription opioids are used mostly to treat moderate to severe pain, though some opioids can be used to treat coughing and diarrhea. Opioids can also make people feel very relaxed and high—which is why they are sometimes used for non-medical reasons. This can be dangerous because opioids can be highly addictive, and overdoses and death are common. Heroin is one of the world’s most dangerous opioids, and is never used as a medicine in the United States. Prescription opioids and heroin are chemically similar and can produce a similar high. In some places, heroin is cheaper and easier to get than prescription opioids, so some people switch to using heroin instead.

In the short term, opioids can relieve pain and make people feel relaxed and happy. However, opioids can also cause drowsiness, confusion, nausea, constipation, euphoria, and slowed breathing. Slowed breathing can cause hypoxia, a condition that results when too little oxygen reaches the brain. Hypoxia can have short- and long-term psychological and neurological effects, including coma, permanent brain damage, or death, resulting in increasingly higher overdose deaths in the U.S. Researchers are also investigating the long-term effects of opioid addiction on the brain, including whether damage can be reversed.

Stimulants such as Methylphenidate (Ritalin ® , Concerta ® ) and amphetamines (Adderall ® , Dexedrine ® ) are commonly prescribed for attention-deficit hyperactivity disorder (ADHD) and narcolepsy—uncontrollable episodes of deep sleep. Prescription stimulants increase alertness, attention, and energy. Stimulants enhance the effects of certain neurotransmitters in the brain, such as norepinephrine and dopamine. Dopamine affects feelings of pleasure. Norepinephrine affects blood vessels, blood pressure and heart rate, blood sugar, and breathing. People who use prescription stimulants report feeling a “rush” (euphoria) along with increased blood pressure and heart rate, increased breathing, decreased blood flow, increased blood sugar, opened-up breathing passages. At high doses, prescription stimulants can lead to a dangerously high body temperature, an irregular heartbeat, heart failure, and seizures. Repeated misuse of prescription stimulants, even within a short period, can cause psychosis, anger, or paranoia.

CNS Depressants are medicines that include sedatives, tranquilizers, and hypnotics. They are usually prescribed to treat anxiety, panic, acute stress reactions, and sleep disorders. Sedatives primarily include barbiturates (e.g., phenobarbitol) but also include sleep medications such as Ambien ® and Lunesta ® . Tranquilizers primarily include benzodiazepines, such as Valium ® and Xanax ® , but also include muscle relaxants and other anti-anxiety medications. These medications slow brain activity, which can cause drowsiness, slurred speech, poor concentration, confusion, dizziness, problems with movement and memory, lowered blood pressure, and slowed breathing, especially when misused.

Over-the-counter medicines that are commonly misused include dextromethorphan (DXM), a cough suppressant, and loperamide, an antidiarrheal. Products containing DXM can be sold as cough syrups, gel capsules, and pills that can look like candies. They are often misused by young people, who refer to the practice as “robotripping” or “skittling.” Loperamide is available in tablet, capsule, or liquid form. Both DXM and loperamide are opioids. DXM does not have effects on pain reduction or addiction and does not act on the opioid receptors. However, when taken in large doses, DXM can cause a depressant and hallucinogenic effect. Short-term effects of DXM misuse can range from mild stimulation to alcohol- or marijuana-like intoxication. Loperamide does not enter the brain; but when taken in large doses and combined with other substances, it may cause the drug to act in a similar way to other opioids. Loperamide misuse can cause euphoria, similar to other opioids, or lessen cravings and withdrawal symptoms, but other effects have not been well studied and reports are mixed.

For more information about misuse of prescription and over-the-counter medicines, view the following NIDA resources: