Project CBD Releases Educational Primer on Cannabinoid-Drug Interactions

New: This report is now available in Spanish and Japanese translations! See bottom of this article for downloads.

Project CBD, a California-based educational non-profit, has published an in-depth primer on Cannabinoid-Drug Interactions for health professionals, patients, and public policy-makers. The 33-page report, summarized below, is available for free download at the bottom of the page.

Drug interactions are a significant consideration in modern medicine. More than half of U.S. adults regularly take prescription meds and at least 75 percent of Americans take at least one over-the-counter drug. Many people, including most seniors (the fastest growing demographic of cannabis users), take multiple drugs, and these compounds can interact and affect the metabolism of each other.

Cannabis is one of the most widely consumed substances in the United States and throughout the world, and a huge number of cannabis users also consume pharmaceutical products. Given the increasing acceptance and prevalence of cannabis as a therapeutic option, it’s important for physicians and patients to understand how various cannabis components, including cannabidiol (CBD) and tetrahydrocannabinol (THC), the major phytocannabinoids, may interact with commonly consumed pharmaceuticals.

But pertinent information about cannabinoid-drug interactions is difficult to obtain because of marijuana prohibition and consequent restrictions on clinically relevant research. Hence the need for Project CBD’s primer, which was written not only to help health professionals and patients anticipate and avoid problematic outcomes but also to take advantage of situations where cannabis and pharmaceuticals can act synergistically in a positive way.

A complicated issue

“It’s a complicated issue,” says research chemist Adrian Devitt-Lee, the author of the Project CBD primer. “Although drug interactions are rarely so dangerous as to entirely preclude the use of a medication, they can have serious impacts on a patient’s treatment and wellbeing.”

The Project CBD primer includes a discussion of various “substrates” or drugs that are metabolized by cytochrome P450, a large family of non-specific enzymes that are involved in breaking down an estimated 60 to 80 percent of all pharmaceuticals. Cytochrome P450 enzymes may be inhibited or amplified by CBD, THC and other plant cannabinoids, thereby reducing or prolonging the activity of another drug.

By suppressing or inducing specific cytochrome P450 enzymes, CBD and THC can alter how one metabolizes a wide range of substances. Much depends on the particular substrate involved in the drug interaction. Some pharmaceuticals, known as “prodrugs,” don’t become functional until they are metabolized into an active component. If CBD or THC inhibits the breakdown of a prodrug, the latter will remain inactive – whereas inhibiting the metabolism of a regular drug will result in higher blood levels of the active substance.

Several variables make precise predictions about drug interactions difficult, even for practiced physicians. “It is much easier to assess whether drug interactions are likely than to predict their exact effect,” the Project CBD primer asserts.

The CBD paradox

Thus far, based on observations regarding the widespread use of raw cannabis flower and full-spectrum cannabis oil, it does not appear that there have been many problems because of cannabinoid-drug interactions. The clinical use of Sativex (a 1:1 CBD:THC sublingual tincture) and Marinol (a pure, synthetic THC pill) has resulted in few, if any, reported adverse events attributable specifically to interactions with pharmaceuticals.

To the extent that there have been problematic drug interactions with cannabinoids, these have involved high doses of nearly pure CBD isolates, not cannabis in general. Even though THC is an intoxicant and CBD is not, the fact that people tend to use much higher doses of pure CBD makes it a much riskier player in metabolic drug interactions.

Consider the numbers: Ten milligrams of THC in a cannabis product is a hefty dose for a naive patient and sufficiently psychoactive for the occasional recreational user. Ten mgs of THC combined with an equal amount of CBD in a Sativex tincture hit the analgesic sweet spot in clinical trials. These are moderate doses compared to the amount of single-molecule CBD administered to epileptic children in clinical trials – up to 50 mg per kilogram – with CBD doses as high as 2000 mg not uncommon among patients who obtain CBD isolates from internet storefronts and other unregulated sources.

THC has its own built-in guard rails – consume too much and you’ll know you’ve hit your limit. With CBD, there are no guard rails, no dysphoric feedback loop that says you’ve had enough. CBD is intrinsically safe, but when extracted from the plant and concentrated as an isolate, high doses are necessary for therapeutic efficacy – unlike whole plant CBD-rich extracts, which have a broader therapeutic window and are effective at lower doses than single-molecule CBD.

Drug interactions are much more likely with high dose CBD therapy than other forms of cannabis consumption. Physicians and patients should be concerned about this, given that the current regulatory regime privileges CBD isolates over artisanal, plant-derived, multicomponent formulations.

Mode & sequence of administration

The way cannabinoids are administered (smoking, eating, etc.) also has a major impact on whether or not drug interactions occur. Interactions are far more likely when both drugs are taken orally and processed by the liver before being distributed through the body. Cannabinoids are absorbed more if ingested on a full stomach. Ingested cannabinoids will have higher peak liver concentrations than inhaled cannabinoids, so ingested cannabinoids should have more potent drug interactions.

The Project CBD primer notes that the sequence as well as the route of administering cannabidiol can influence how another drug is metabolized. One study disclosed that CBD has a stronger inhibitory impact on a particular cytochrome P450 enzyme if it’s administered 20 minutes before the second drug.

CBD also interacts with THC. By taking CBD and THC together, individuals may find that the effects of THC are tempered but prolonged slightly. It is known that 11-OH-THC, a THC breakdown component, is more potent than THC at the CB1 cannabinoid receptor, which mediates psychoactivity. 11-COOH-THC, another THC metabolite, has anti-inflammatory effects without causing a high.

Some people can hardly tolerate any THC. The wide range of reactions to THC-rich cannabis may be influenced by genetic factors. A common polymorphism (or variant) of a gene that encodes a particular cytochrome P450 enzyme alters how one metabolizes THC so it breaks down more slowly and stays active longer, resulting in hypersensitivity to THC’s psychoactive effects.

That may be one of the reasons why some people find THC-rich cannabis to be unpleasant, while hundreds of millions smoke it to relax. This genetic variant exists among 20% in European & Middle Eastern populations, meaning one in five Caucasians are THC-averse. Less than 10% of Africans have this genetic variant and among Asians it’s less than 5%.

Positive synergies

Other noteworthy findings in the Project CBD primer:

  • THC v. lung cancer. When cannabis is smoked, cytochrome P450 enzymes in the lungs convert inhaled ash into potent carcinogens, including highly toxic polycyclic aromatic hydrocarbons (PAHs). But THC may protect against lung cancer by inhibiting the same metabolic enzymes that PAHs induce.
  • Cannabinoid-opiate interactions. Supplementing an opioid-based pain-management regimen with cannabis could result in lower doses of opioids required for adequate analgesia. Lower doses of opioids will reduce the number of overdose deaths. This is an example of a potentially beneficial cannabinoid-drug interaction.
  • CBD, THC & chemotherapy. Limited preclinical research indicates that administering CBD and/or THC in conjunction with first-line chemotherapy drugs could potentiate the latter, thereby reducing the dosage of highly toxic chemo necessary to treat the cancer. If this translates to human experience, it would be a huge benefit. But if pure CBD delays chemo metabolism, dangerously high levels of a toxic drug could accumulate unless the dose of chemotherapy is reduced and properly managed. The fact that cannabinoids make radiation and chemotherapy both more tolerable and seemingly more effective is an area worth studying.
  • Blood thinners. Both THC and CBD delay the metabolism of warfarin, a widely prescribed blood thinner. Mis-dosing warfarin causes tens of thousands of ER visits every year because of excessive bleeding. The Project CBD primer reviews a recent case study as an example of how physicians can successfully adjust the dose of warfarin for a patient who is also taking a CBD isolate.

Research barriers

The information presented in the Project CBD primer is intended to help doctors and patients understand if and when drug interactions with cannabis or cannabinoids are likely. “It is not meant to stoke fears about drug interactions or add to decades of ill-advised, anti-marijuana hysteria,” the author emphasizes.

How dangerous are cannabinoid-drug interactions? As dangerous as mis-dosing the other drug(s) that a patient is taking. Problems are more likely to arise when a patient combines a high dose of an otherwise benign CBD isolate with a pharmaceutical that has a very narrow window between its therapeutic and toxic levels.

In GW Pharmaceuticals’ clinical trials of Epidiolex, an almost pure CBD compound, there were potentially dangerous interactions with Clobazam, an anti-epilpetic drug, which necessitated a dosage adjustment of the latter. The FDA recently approved Epidiolex as a medication for children with refractory seizure disorders. And the DEA classified Epidiolex as a schedule V substance in September 2018.

Epidiolex would surely command a lot of “off label” attention if not for the potent price tag. And just as surely a huge unregulated market for hemp-derived CBD isolates will continue to flourish in a tenuous legal environment. An already massive consumer demand for CBD products has far outpaced the gathering of clinical data on cannabinoid interactions with pharmaceuticals for pain, cancer, autism, heart disease and many other chronic ailments.

The longstanding barrier to requisite research is the Schedule I status of cannabis, a category reserved for dangerous substances with no medical value, according to federal law. But the paucity of federally sanctioned clinical research, a consequence of cannabis prohibition, should not be an excuse for physicians or patients to shun nonlethal cannabinoid therapies, which show promise for a wide range of conditions.

Project CBD hopes that “as cannabis therapeutics continues to gain acceptance among physicians and patients, adequate resources will become available for clinical studies involving drug interactions with CBD, THC and other plant cannabinoids.”

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Dr. Ethan Russo: CBD, the Entourage Effect and the Microbiome

Project CBD: I’m Martin Lee with Project CBD, and this is another edition of Cannabis Conversations. Today, we’re very pleased to have Dr. Ethan Russo come back in the studio with us. Dr. Ethan Russo is a neurologist, a scientist, widely published author in many peer-reviewed journals and currently a director of research and development for the International Cannabis and Cannabinoid Institute, which is located in Prague, in the Czech Republic. Thanks for joining us, Ethan.

Russo: It’s a pleasure to be here.

Project CBD: Ethan, there’s been an explosion of interest in CBD lately. Explain what the excitement is about. What is CBD?

Russo: Well, first of all, this has been long in coming. For probably 40 years now the real concentration in breeding has been toward THC, the main psychoactive ingredient of cannabis. Unfortunately, a lot of that is a by-production of prohibition. The market was driven by people in the recreational sphere that were looking for escape or sometimes medical use. In the process, a lot of the benefit of cannabis was lost genetically because customarily, in many parts of the world where cannabis was grown, it was typically a plant that had equal amounts of tetrahydrocannabinol – the main psychoactive ingredient in cannabis – and cannabidiol.

So what is cannabidiol? Cannabidiol is frequently mischaracterized as being non-psychoactive. Rather, it is psychoactive. It is an anti-anxiety agent, and anti-psychotic agent. But it also complements a great number of the effects of THC, in that both are analgesics, painkillers, both are anti-inflammatory, and because cannabidiol has this ability to counteract some of the prominent side effects of THC it’s a very valuable thing to have in any cannabis preparation – whether it’s predominant or in conjunction with THC. It is a very versatile compound. It has a lot of effects. But unlike most drugs that have multiple effects, in this instance it’s very hard to pick out any particular side effect of CBD that’s problematic. The only thing that we can really point to is that in extreme doses, when it’s used in isolation, it can produce some drug-drug interactions such as producing sedation with drugs like Clobazam that are used to treat severe seizure disorders. But, on its own, it does not product anxiety – rather treats it. It’s really hard to come up with a significant side effect that we need to warn people about. Of course, it depends on the preparation, and other ingredients may be prone to side effects, so we have to be careful in that regard.

Project CBD: You refer to both THC (the high causer, so to speak) and CBD in the same breath. That suggests that they work together in some way. There’s this phrase, “the entourage effect” or “ensemble effect,” explain what that is in terms of the cannabis plant.

Russo: So, cannabis is a botanical. This is a way of saying that it’s a plant-based medicine. And, although the thrust of pharmaceutical development for decades has been on single molecules, often synthetic, this is the more common concept in medicine historically. What I mean is, traditionally people have used plant drugs to treat their problems. It’s only been in the last 75 years there’s been this shift toward synthetics. So, a botanical doesn’t rely on one compound to produce the beneficial effects. Rather there may be many – and that’s certainly the case in cannabis where we know that there are actually over 100 related molecules, we call cannabinoids, but in addition there are aromatic compounds, the same things that you’d find in lemon and pine needles called terpenoids that alter the effects of the cannabinoids in a way that often is synergistic. Synergy is a boosting of effect. So, it would be the idea that 2 + 2, instead to equaling 4, it gives you an 8 in terms of the benefit. So, for example, as we’ve mentioned, cannabidiol treats pain. But there are other ingredients in cannabis that also treat pain or may limit the side effects of other components and so it is sort of like an ensemble of musical instruments where you might think if THC as the soloist with an important part provided by cannabidiol, but you also have these other components producing a harmony that really increases the overall effect and makes hopefully the best possible medicine.

Project CBD: And you referred to pain: we are in the midst of a painkiller epidemic really. It’s well known now we have many overdoses due to addiction to opioids. Maybe you could talk a little bit about that in terms of what cannabis might bring to the table in terms of addressing this crisis.

Russo: This is an absolute medical crisis in that 72,000 Americans died of opioid-related overdoses in 2017. We have known – and this may come as a surprise to almost everyone – it’s been known for 150 years that cannabis is capable of acting in concert with opioids to treat pain and allowing what’s called “opioid sparing.” This means a lower dose producing the same or better level of pain control. Additionally, it was observed in the 19th century that cannabis could treat withdrawal symptoms from opioids and other addictive drugs, reduce craving, and allow people to get off of them entirely. The same thing has been observed for decades in people who have used cannabis medicinally. But, again, until recently that was primarily with THC predominant cannabis, which did work in this regard. But the real missing ingredient until say the last decade has been cannabidiol. Because cannabidiol on its own acts as an anti-addictive substance. It actually works on an area of the brain called the insula that reduces craving. Particularly in combination with THC, we’ve seen a really amazing response in patients to reduce their opioid doses and often get off of opioids that they may have used chronically. Additionally, there’s another component in cannabis, a terpenoid called caryophyllene, that also is anti-addictive through a totally different mechanism than CBD. It’s working on another receptor called the CB2 receptor that’s involved in addiction. So, a preparation that had THC, CBD, and caryophyllene may be an ideal way of dealing with chronic pain and particularly people who are addicted to opioids.

Project CBD: You mentioned CB2 receptor – you’re referring to a cannabinoid receptor which is part of something we refer to as the endocannabinoid system. Could you basically define that or describe what that is, and why it’s important.

Russo: So, we have this thing in our bodies and all mammals and a lot of lower animals, anything that has a spinal cord basically, has an endocannabinoid system. This came about through research on cannabis and specifically THC. So in 1998 it was discovered that there were endogenous cannabinoids; the first one was called anandamide (“Ananda” in Sanskrit means bliss), then a couple of years later it was observed that there was a cannabinoid receptor that was named CB1 (cannabinoid 1). Very shortly thereafter, a second receptor – a non-psychoactive receptor – called CB2 was discovered that is involved in inflammatory responses, pain control, and limiting fibrosis (the buildup of scar tissue in the body). So, THC works on CB1 and CB2. Caryophyllene works just on CB2 with no effect on CB1. Certainly, with adequate amounts of it, it has this ability to treat pain, inflammation, and addiction, without producing any unwanted psychoactive side effects. And when I say that, I mean anxiety, paranoia, the things that we associate with a situation where someone has too much THC.

Project CBD: What about CBD? Does it also bind or activate these receptors that you refer to? Or how does it work?

Russo: Well that’s really interesting – a little complicated. CBD does not bind directly to the regular sites on either CB1 or CB2. On CB1 it does bind to another site called the allosteric site (“allo” means other). When it does bind to these allosteric receptors it produces what’s called a negative modulation. Functionally what this means is when CBD is present it’s a little harder for THC to bind to the CB1 receptor. Now that really would make it sound like it’s going to interfere with the benefits of THC on pain and other conditions, but that’s not what we see. What we see, though, when CBD is combined with THC is a blunting of the peak high. If someone smoked material with both THC and CBD, they’re not going to get quite as high if they would with THC alone. But, much more importantly, the effect is prolonged. In medical settings, this is very important because it allows people to, say, dose with an oral preparation, perhaps two or three times a day, as opposed to smoking medicine where they might have to utilize it every two to three hours because of a higher peak and – peaks and valleys of activity – rather than a smoother contour of effect, which is much preferable in a medical setting.

Project CBD: I have lots of questions I’d love to ask, but I think we have time for one more. I believe in the Ayurvedic Indian medical tradition, and traditional Chinese medicine, there’s an emphasis on the gut. The idea that health is rooted in the gut. And we hear a lot these days, the buzzword about the microbiome, the bacteria beneficial or otherwise, in the gut and the role that that plays in terms of health. Does the endocannabinoid system play into this at all? And if so, how?

Russo: Well, yes it does in a very important way. There’s been some very interesting work done recently that shows that the microbiome, which is a collection of natural bacterium in the gut, has a great deal to do with our health overall. Whether someone has problems with inflammation or not, it provides neurotransmitters that go to the brain, effects our moods in a very key way, it’s very involved in autoimmune diseases. What it was found is that THC actually stimulates production of some of the more beneficial bacterium and suppresses the disease-causing bacteria like clostridia that produces severe diarrhea syndrome.

Project CBD: That’s THC in particular does that.

Project CBD: And CBD? Do they know how it plays into it?

Russo: We’ve got a little less knowledge. And yet, however, there seems to be a key role for the microbiome, or gut bacteria, in endocannabinoid tone. Endocannabinoid tone is a function of how many receptors, say CB1 receptors, are active in the brain. The amount of the endocannabinoids like anandamide and 2-Arachidonoylglycerol, and also the function of the enzymes that make these substances and break them down. So, it’s a very important concept. We can define it – right now we don’t have good methods of measuring it. We can do serum levels of endocannabinoids in the blood, but it might not reflect what’s going on in the brain. And today, I’m afraid we don’t have a scan of the brain yet to show the activity of the receptors. But these are research projects that hopefully are going to give us better diagnostics in the future.

Project CBD: The implication is that – and maybe it’s too obvious we don’t have to say it – but our diet is key to our health, and that the endocannabinoid system mediates that whether for good or ill in some way.

Russo: That’s absolutely right. And this is one of the reasons you see a lot of emphasis now, people may see ads on TV for what are called probiotics. This is a way of taking a supplement by mouth that’s going to provide, hopefully, more of these beneficial bacteria. But those beneficial bacteria need something to eat, and it isn’t always what we have in the American diet. The American diet, I’m afraid, with a lot of fried food and carbohydrates upsets the balance of the bacteria in the gut and favors the production of inflammation. If, however, people are eating certain foods called prebiotics, they tend to be non-digestible fibers. This is what the beneficial bacteria really like. And when they’re functioning well, we have good evidence now, it’s going to increase the endocannabinoid tone and really contribute to overall health.

Project CBD: I think that’s good food for thought. I want to thank you Dr. Russo, you’ve been a great educator for our community and when we appreciate it very much. It’s been another edition of Cannabis Conversations, hopefully we’ll do more with you in the future.

Russo: Thank you.

Dr. Ethan Russo can be contacted at

Copyright, Project CBD. May not be reprinted without permission.

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Feds To Spend $1.5 Million On Research Into Marijuana’s Lesser Known Components

The federal government plans to award $1.5 million in grants during the 2019 fiscal year to researchers who study how components of marijuana other than THC affect pain.

In a notice about the funding opportunity published on Thursday, the National Center for Complementary and Integrative Health (NCCIH) said that it was seeking applications from researchers to conduct studies on “minor cannabinoids and terpenes.” The aim of the grants will be to learn how these components work–separately and when combined–as potential pain-relieving agents.

The research is especially important given the widespread use of addictive opioid-based painkillers for pain management, NCCIH said. While THC has known analgesic properties, very little is known about the hundreds of other constituents in cannabis, which could represent viable alternatives to popular painkillers.

“Early clinical data suggest that cannabis may enhance the potency of opioids in relieving pain; and the synergy from using these products together may result in more effective pain relief with lower doses of opioids,” the agency wrote. “Yet, it is unclear which components of cannabis may have these properties. In particular, few studies have examined whether and which cannabinoids and/or terpenes interact with the opioid pain pathways.”

NCCIH, which is part of the National Institutes of Health, said that of particular interest are studies looking at cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), nyrcene, ?-caryophyllene, Limonene, ?-terpineol, linalool, ?-phellandrene, ?-pinene, ?-pinene, ?-terpinene and ?-humulene.

“A growing body of literature suggests that the cannabis plant may have analgesic properties; however, research into cannabis’s potential analgesic properties has been slow,” the funding opportunity says. “One key mechanism to investigate is whether potential analgesic properties of cannabis can be separated from its psychoactive properties. To address this question, more research is needed into the basic biological activity of the plant’s diverse phytochemicals, specifically minor cannabinoids and terpenes.”

NCCIH listed 11 areas of interest for prospective applicants:

* To investigate the potential analgesic properties and adverse effects of minor cannabinoids, alone or in combination with each other or terpenes;

* To investigate the mechanisms by which minor cannabinoids and terpenes may affect pain pathways, including ascending and/or descending neural pathways, cellular and molecular signaling pathways, neuroimmune interactions, or other innovative regulatory pathways related to pain;

* To explore the impact of sex, age and ethnicity on potential analgesic properties of minor cannabinoids and terpenes;

* To explore analgesic potential of minor cannabinoids and terpenes for different pain types (e.g., acute pain, chronic pain, inflammatory pain, neuropathic pain);

* To investigate the pharmacology (pharmacokinetic and pharmacodynamic profiles) of minor cannabinoids and terpenes;

* To explore binding affinities of minor cannabinoids and terpenes to cannabinoid and opioid and other pain-related receptors;

* To investigate the impact of dose and/or route of administration on potential analgesic effects of minor cannabinoids and terpenes;

* To characterize if/how specific terpenes may influence potential analgesic properties of cannabinoids;

* To explore potential opioid sparing effects of minor cannabinoids and terpenes;

* To explore the interaction between the microbiome and minor cannabinoids or terpenes;

* To improve methods to quantify systemic levels of minor cannabinoids and terpenes

Applicants are encouraged to submit letters of intent about their research proposals 30 days before the March 15 application deadline. The $1.5 million will be distributed among four grant recipients.

The agency first announced its intent to launch the funding opportunity in November.

“The mechanisms and processes underlying potential contribution of minor cannabinoids and terpenes to pain relief and functional restoration in patients with different pain conditions may be very broad,” NCCIH said. “This initiative encourages interdisciplinary collaborations by experts from multiple fields–pharmacologists, chemists, physicists, physiologists, neuroscientists, psychologists, endocrinologists, immunologists, geneticists, behavioral scientists, clinicians, and others in relevant fields of inquiry.”

The research opportunity is one of several marijuana-related projects the federal government has recently promoted. For example, NCCIH has four other grants available to researchers to study “natural products” such as cannabis, the National Institute on Drug Abuse is calling for bulk marijuana cultivators to supply research-grade cannabis and the Agency for Healthcare Research and Quality has asked the public to send them information about marijuana and Alzheimer’s disease.

Feds Call For Even More Marijuana Research After Hosting Cannabis Workshop

Photo courtesy of Brian Shamblen.

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