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Cannabidiol: Promise and Pitfalls Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has More than 60 percent of CBD users were taking it for anxiety, according to a survey of 5,000 people. Does it help?

Cannabidiol: Promise and Pitfalls

Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy—especially in children with Dravet syndrome—using cannabidiol (CBD). Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products.

Cannabidiol is the major nonpsychoactive component of Cannabis sativa. Over the centuries, a number of medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesics by Western medical practitioners in the 19 th century (1). More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis (1).

Basic Pharmacological Mechanisms

Cannabidiol pharmacological effects are mediated through G protein coupled receptors, cannabinoid type I (CB1) and cannabinoid type II (CB2), which are highly expressed in the hippocampus and other parts of the central nervous system (2). When activated, CB1 receptors inhibit synaptic transmission through action on voltage-gated calcium and potassium channels, which are known to modulate epileptiform and seizure activity (3). CB2 receptors are primarily expressed in the immune system and have limited expression in the central nervous system. The effects of CBD are CB2 receptor independent (3).

Studies have demonstrated that CBD has a low affinity for the CB1 receptors, but even at low concentrations, CBD decreases G-protein activity (3). CB1 receptors are expressed on many glutamatergic synapses that have been implicated in seizure threshold modulation. CBD may act at CB1 receptors to inhibit glutamate release (4). Studies have shown changes in the expression of CB1 receptors during epileptogenesis and after recurrent seizures (5). CB1 receptor expression is upregulated at GABAergic synapses and shown to be downregulated at glutamatergic synapses in epilepsy, contributing to lowering seizure thresholds.

Other targets for CBD include transient receptor potential (TRP) channels that are involved with the modulation of intracellular calcium (1, 6). Cannabinoids are highly lipophilic, allowing access to intracellular sites of action, resulting in increases in calcium in a variety of cell types including hippocampal neurons. CBD actions on calcium homeostasis may provide a basis for CBD neuroprotective properties.

Evidence in Animal Models

When administered alone, CBD is an effective anticonvulsant in maximal electrical shock (MES), magnesium-free, 4-aminopyridine, and audiogenic models (7, 8). Co-administration with AEDs leads to various effects; anticonvulsant effects of CBD are enhanced with phenytoin or phenobarbital but decreased with chlordiazepoxide, clonazepam, trimethadione, and ethosuximide. In a recent study using an acute pilocarpine model, although CBD administration reduced the number of animals displaying seizure activity, CBD did not appear to have any significant effect on the number of seizures per animal (7).

Clinical Evidence in Epilepsy

While animal experimental data clearly suggest a potential benefit, supportive clinical data are quite sparse. In a case-control study of 308 cases of new onset seizures, Brust and colleagues found that marijuana use was significantly less prevalent among men who had unprovoked seizures compared to case controls (9). This difference was not significant in women. The authors suggest a potential protective effect against seizures with marijuana use; however, this should be considered speculative.

A survey of patients seen in a tertiary epilepsy center found that 21% of patients admitted to using marijuana in the last year, and 24% of patients believed marijuana to be effective for their seizures (10). While interesting, this anecdotal observation does not rise to the level of evidence needed to evaluate a potential new therapeutic modality.

Gloss and Vickrey conducted a Cochrane systematic review of the use of CBD in the treatment of epilepsy (11). Their methodology included only those trials that were randomized and controlled and excluded case series, case reports, and expert opinion. They were able to identify only 4 randomized controlled studies reported in the literature, and they included a letter to the editor and an abstract. The total number of subjects enrolled in these studies was 48 (11–14). While only four studies and a letter to the editor were in the actual analysis, the authors included a complete reference listing of all articles reviewed for inclusion.

These reports suffered from a number of design flaws, including incomplete baseline quantification of baseline seizure frequency, indeterminate time periods for outcome determination and, in some cases, inadequate (or missing) statistical analysis—in general, a lack of sufficient detail to adequately evaluate and interpret the findings. Limitations aside, several studies did report that administration of adjunctive CBD did not result in meaningful changes in seizure frequency (11–13).

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Cunha et al. reported a 2-phase pilot study of CBD versus placebo in normal volunteers and patients with refractory secondarily generalized epilepsy (14). In the first phase, 8 normal volunteers received CBD or placebo in a doubled-blind fashion, at a dose of 3 mg/kg for 30 days. The second phase was also double-blinded in 15 patients with epilepsy receiving 200 to 300 mg daily of CBD or placebo for 135 days. Patients continued baseline AED. All subjects tolerated CBD well, with no serious adverse events. Four of the epilepsy patients receiving CBD were “almost free of convulsive crisis” for the duration of the study. Three other patients receiving CBD had a partial reduction in seizures, and 1 subject had no response. Of the 7 patients receiving placebo, seizure frequency was unchanged in 6, and 1 had clear improvement in seizure control.

Using rigorous review methodology, Gloss and Vickery conclude that based on the low quality of the reports available, there is insufficient data available to draw any conclusions regarding the efficacy and or long-term safety of CBD in treating epilepsy (11). From the data available, it does appear that daily doses of 200 to 300 mg were safe in this small group of patients for a short period of time (14).

Tolerability and Drug Interactions

CBD is well tolerated in humans with doses up to 600 mg not resulting in psychotic symptoms (15). In the few small placebo-controlled studies performed, no significant CNS effects were noted. Oral CBD undergoes extensive first-pass metabolism via CYP3A4, with a bioavailability of 6%. Following single doses in humans, the half-life of CBD when taken orally is about 1 to 2 days.1 In vitro studies have shown that CBD is a potent inhibitor of multiple CYP isozymes, including CYP 2C and CYP3A (16, 17). Whether these in vitro observations are relevant at plasma concentrations likely to be seen in patients is unclear. In addition, given its metabolism via CYP3A4, clinical trials of CBD in patients receiving enzyme-inducing AEDs, such as carbamazepine or phenytoin, will require detailed pharmacokinetic studies.

A number of difficulties exist in evaluating published data on CBD or marijuana use for epilepsy. The extremely limited published studies were small, poorly described, and not well designed. Contributing to the difficulty of interpreting published studies, CBD products are not produced under the guidance of good manufacturing practices (GMP) and are not subject to regulations governing labeling, purity, and reliability. In other words, currently, there is no guarantee of consistency between products, or even differing lots produced by the same manufacturer. Without independent testing (e.g. USP certification) of CBD products for content and purity, as well as bioavailability testing of specific products, uncertainty surrounds the use of available CBD products in routine clinical settings.

Conclusions

At this time, there does seem to be a growing body of basic pharmacologic data suggesting there may be a role for CBD, especially in the treatment of refractory epilepsy. However, given the lack of well-controlled trials, we must also ask if we are getting ahead of ourselves. Clearly, this is an emotionally and politically charged issue. If this were any other uninvestigated pharmaceutical compound, would we feel as compelled to make the agent widely available before statistically valid class 1 evidence was available for review? Until data from well-designed clinical trials are available and reliable, and standardized CBD products that are produced using GMP are available, caution must be exercised in any consideration of using CBD for the treatment of epilepsy. In the meantime, based upon promising preliminary data, further clinical research should be wholeheartedly pursued.

What Are the Benefits of CBD?

More than 60 percent of CBD users were taking it for anxiety, according to a survey of 5,000 people. Does it help?

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By Dawn MacKeen

The CBD industry is flourishing, conservatively projected to hit $16 billion in the United States by 2025. Already, the plant extract is being added to cheeseburgers, toothpicks and breath sprays. More than 60 percent of CBD users have taken it for anxiety, according to a survey of 5,000 people, conducted by the Brightfield Group, a cannabis market research firm. Chronic pain, insomnia and depression follow behind. Kim Kardashian West, for example, turned to the product when “freaking out” over the birth of her fourth baby. The professional golfer Bubba Watson drifts off to sleep with it. And Martha Stewart’s French bulldog partakes, too.

What is CBD?

Cannabidiol, or CBD, is the lesser-known child of the cannabis sativa plant; its more famous sibling, tetrahydrocannabinol, or THC, is the active ingredient in pot that catapults users’ “high.” With roots in Central Asia, the plant is believed to have been first used medicinally — or for rituals — around 750 B.C., though there are other estimates too.

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Cannabidiol and THC are just two of the plant’s more than 100 cannabinoids. THC is psychoactive, and CBD may or may not be, which is a matter of debate. THC can increase anxiety; it is not clear what effect CBD is having, if any, in reducing it. THC can lead to addiction and cravings; CBD is being studied to help those in recovery.

Cannabis containing 0.3 percent or less of THC is hemp. Although last year’s Farm Bill legalized hemp under federal law, it also preserved the Food and Drug Administration’s oversight of products derived from cannabis.

What are the claims?

CBD is advertised as providing relief for anxiety, depression and post-traumatic stress disorder. It is also marketed to promote sleep. Part of CBD’s popularity is that it purports to be “nonpsychoactive,” and that consumers can reap health benefits from the plant without the high (or the midnight pizza munchies).

Just as hemp seedlings are sprouting up across the United States, so is the marketing. From oils and nasal sprays to lollipops and suppositories, it seems no place is too sacred for CBD. “It’s the monster that has taken over the room,” Dr. Brad Ingram, an associate professor of pediatrics at the University of Mississippi Medical Center, said about all the wild uses for CBD now. He is leading a clinical trial into administering CBD to children and teenagers with drug-resistant epilepsy.

Is This A Scam?

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Does CBD work?

“It’s promising in a lot of different therapeutic avenues because it’s relatively safe,” said James MacKillop, co-director of McMaster University’s Michael G. DeGroote Center for Medicinal Cannabis Research in Hamilton, Ontario.

Last year, the F.D.A. approved Epidiolex, a purified CBD extract, to treat rare seizure disorders in patients 2 years or older after three randomized, double-blind and placebo-controlled clinical trials with 516 patients that showed the drug, taken along with other medications, helped to reduce seizures. These types of studies are the gold standard in medicine, in which participants are divided by chance, and neither the subject nor the investigator knows which group is taking the placebo or the medication.

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While there is hope for treating other conditions with the plant extract, Epidiolex remains the only CBD-derived drug approved by the F.D.A. Most of the research on cannabidiol has been in animals, and its current popularity has outpaced science. “We don’t have the 101 course on CBD quite figured out yet,” said Ryan Vandrey, an associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine.

Does CBD help anxiety and PTSD?

For students with generalized social anxiety, a four-minute talk, with minimal time to prepare, can be debilitating. Yet a small experiment in the journal Neuropsychopharmacology found that CBD seemed to reduce nervousness and cognitive impairment in patients with social anxiety in a simulated public speaking task.

However, a double-blind study found healthy volunteers administered CBD had little to no change in their emotional reaction to unpleasant images or words, compared to the placebo group. “If it’s a calming drug, it should change their responses to the stimuli,” said Harriet de Wit, co-author of the study and a professor in the University of Chicago’s department of psychiatry and behavioral neuroscience. “But it didn’t.”

Many soldiers return home haunted by war and PTSD and often avoid certain activities, places or people associated with their traumatic events. The Department of Veterans Affairs is funding its first study on CBD, pairing it with psychotherapy.

“Our top therapies attempt to break the association between reminders of the trauma and the fear response,” said Mallory Loflin, an assistant adjunct professor at the University of California, San Diego and the study’s principal investigator. “We think that CBD, at least in animal models, can help that process happen a lot faster.” While large clinical trials are underway, psychologists say there isn’t compelling evidence yet as to whether this is a viable treatment.

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Does CBD help sleep and depression?

Up in the wee hours of the night, stuck watching videos of puppies? CBD may be promising as a sleep aid; one of the side effects of the Epidiolex trials for epilepsy was drowsiness, according to Mr. MacKillop, a co-author of a review on cannabinoids and sleep. “If you are looking for new treatments for sleep, that may be a clue,” he said.

But he cautions that the side effects could have been because of an interaction with other medications the children were taking to control the seizures. So far, there hasn’t been a randomized, placebo-controlled, double-blind trial (the gold standard) on sleep disorders and CBD.

A recent chart review of 72 psychiatric patients treated with CBD found that anxiety improved, but not sleep. “Over all, we did not find that it panned out as a useful treatment for sleep,” said Dr. Scott Shannon, assistant clinical professor of psychiatry at the University of Colorado, Denver and the lead author of the review in The Permanente Journal.

Sleep can be disrupted for many reasons, including depression. Rodents seemed to adapt better to stressful conditions and exhibited less depressive-like behavior after taking CBD, according to a review in Journal of Chemical Neuroanatomy. “Surprisingly, CBD seems to act faster than conventional antidepressants,” wrote one of the authors of a new review, Sâmia Joca, a fellow at the Aarhus Institute of Advanced Studies in Denmark and an associate professor at the University of São Paulo in Brazil, in an email interview. Of course, it’s difficult to detect depression in animals, but the studies that Ms. Joca and her colleagues reviewed suggested that in models of chronic stress exposure, the mice and rats treated with CBD were more resilient.

But without clinical trials in humans, psychologists say CBD’s effect on depression is still a hypothesis, and not an evidence-based treatment.

Is CBD harmful?

“If you take pure CBD, it’s pretty safe,” said Marcel Bonn-Miller, an adjunct assistant professor at the University of Pennsylvania’s Perelman School of Medicine. Side effects in the Epidiolex trial included diarrhea, sleepiness, fatigue, weakness, rash, decreased appetite and elevated liver enzymes. Also, the safe amount to consume in a day, or at all during pregnancy, is still not known.

Recently, the F.D.A. sent a warning letter to Curaleaf Inc. about its “unsubstantiated claims” that the plant extract treats a variety of conditions from pet anxiety and depression to cancer and opioid withdrawal. (In a statement, the company said that some of the products in question had been discontinued and that it was working with the F.D.A.)

Dr. Smita Das, chair of the American Psychiatric Association’s Council on Addiction Psychiatry’s cannabis work group, does not recommend CBD for anxiety, PTSD, sleep or depression. With patients turning to these to unproven products, she is worried that they may delay seeking appropriate mental health care: “I’m dually concerned with how exposure to CBD products can lead somebody into continuing to cannabis products.”

Some CBD products may contain unwanted surprises. Forensic toxicologists at Virginia Commonwealth University examined nine e-liquids advertised as being 100 percent natural CBD extracts. They found one with dextromethorphan, or DXM, used in over-the counter cough medications and considered addictive when abused; and four with a synthetic cannabinoid, sometimes called Spice, that can cause anxiety, psychosis, tachycardia and death, according to a study last year in Forensic Science International.

Earlier research found fewer than a third of 84 products studied contained the amount of CBD on their labels. Some users of CBD have also failed drug tests when the product contained more THC than indicated.

This year, 1,090 people have contacted poison control centers about CBD, according to the American Association of Poison Control Centers. Over a third are estimated to have received medical attention, and 46 were admitted into a critical care unit, possibly because of exposure to other products, or drug interactions. In addition, concern over 318 animals poured into the American Society for the Prevention of Cruelty to Animals’ Animal Poison Control Center.

Is CBD a scam or not?

A few drops of CBD oil in a mocha or smoothie are not likely to do anything, researchers contend. Doctors say another force may also be at play in people feeling good: the placebo effect. That’s when someone believes a drug is working and symptoms seem to improve.

“CBD is not a scam,” said Yasmin Hurd, director of the Addiction Institute of Mount Sinai in New York City who led a double-blind study of 42 recovering heroin addicts and found that CBD reduced both cravings and cue-based anxiety, both of which can cycle people back into using. “It has a potential medicinal value, but when we are putting it into mascara and putting it into tampons, for God’s sake, to me, that’s a scam.”

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