Cannabis Medicine

Patient Survey: Cannabis in the Treatment of Age-Related Pain

Patient Survey: Cannabis for the treatment of age-related pain
By on November 03, 2016

Pain affects one’s mood, memory, relationships, and overall quality of life. Chronic pain can cause frustration, depression, anger, social isolation, anxiety, poor sleep, and other health risks. Fifty percent of older adults who live on their own and 75-85 percent of the elderly in care facilities reportedly suffer from chronic pain.

This survey—a collaboration between Care By Design and Project CBD—sought to answer several questions: How satisfied are patients with cannabis as an analgesic? How does medical marijuana compare to other pain management approaches, in particular, opiates? How do the most common pain management therapies compare in terms of their impact on quality of life?

Eight hundred people, most between 50 to 70 years old, responded to the survey. Over 80 percent reported that they were suffering from chronic pain; close to half reported suffering from acute pain.

A significant decrease in opiate usage among elderly patients on cannabis therapy was the study’s most notable finding. Over half of respondents reported that they had used both cannabis and opiates for pain management. Of this subgroup, 91 percent said they used fewer or no opiates after beginning cannabis therapy. Sixty-three percent said that they went off opiates altogether.

Other Key Findings:

  • A striking number of patients (around half) reported that opiates had a negative impact on overall wellbeing, and resulted in worsening mood, energy, functional ability and sleep.
  • Cannabis was the only therapeutic approach for which there were no reports of worsening pain. In contrast, surgery, exercise, and nerve blockers benefited some but resulted in increased pain in a significant minority of survey participants.
  • There were no significant differences in outcomes for patients using plant-derived high THC products compared to whole plant CBD-rich products; both types of cannabis were found to be highly effective in managing pain.
  • The most common method of cannabis administration was vaporization, which is generally a safe mode of administration—barring additives and thinning agents that can be found in low quality vaping products.

According to this patient survey, cannabis therapy appears to be an effective pain management tool with few negative side effects. Patient-reported outcomes of cannabis’ efficacy together with its low side effect profile suggest that it should be considered as a first-line treatment for pain and/or as an adjunct treatment to opiates rather than as a medication of last resort.

Read the full report here.

Clinical Endocannabinoid Deficiency Reconsidered

endocannabinoid tone russo
By on August 02, 2016

Abstract (Cannabis and Cannabinoid Research) 2016

Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

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Cannabis as Medicine Has Strong Roots in Science

greg gerdeman opinion piece
By on July 18, 2016

A version of this article was published in South Florida Hospital News and Healthcare Report

The use of cannabis as medicine is not going away. Testimonials from patients, families and physicians continue to fuel a swing in public support for reintroducing cannabis to widespread use in the American medicine cabinet. Regardless of the pace of change in cannabis policy, it is critical that physicians and other allied health workers attend with an open mind to the real world rationales for cannabis used as a medicine, its risks with respect to other widely used medicines, and the ethical question of whether honest medical access to cannabis should be prohibited by law.

Clinicians should also know that an important aspect of the popularity and staying power of medical marijuana is its scientific credibility. Biomedical research has yielded a trove of discovery about the endocannabinoid system (ECS). Endocannabinoids are arachidonic acid-derived lipid signaling molecules that are produced throughout the body, not at all confined to nervous tissue as once imagined, and which mostly act as paracrine signals serving a wide variety of homeostatic functions. These range from the neuroendocrine control over feeding and metabolism, to bone remodeling, to pleiotropic effects on inflammatory immune function, to the more familiar anti-seizure effects, to name but a few. Numerous authoritative books and literature reviews demonstrate the scope of endocannabinoids’ physiological importance to be vastly beyond that of a brief commentary.

This body of research is of course powerfully relevant to cannabis. In some ways it’s ironic that many of the most compelling discoveries about the neuroprotective properties of cannabinoids, for example, have arisen out of funding priorities to study the presumed risk of marijuana. However, the field has expanded well beyond the prerogatives of drug abuse research, as presaged by seminal findings showing the extraordinary abundance of CB1 cannabinoid receptor expression throughout the mammalian brain, and how the endocannabinoids behave as cellular negative feedback signals to dampen excitotoxicity.

The scientific consensus that has arisen from this body of data is exciting. The human ECS can be viewed as an intrinsic system of neuroprotection, a homeostatic defense of the brain and spinal cord to excitotoxicity, seizure, traumatic injury and ischemia. Cannabinoids also defend against many facets of immune responses that exacerbate brain injury, such as microglial activation. Moreover, chronic neuroinflammation is now believed to be central to the etiologies of many age-related neurodegenerative diseases.

Inflammation is a key cause of chronic neuropathic and rheumatic pain, and clinical data increasingly support the use of cannabinoids as a potential therapeutic strategy. The central neural circuitries of pain are also regulated actively by cannabinoids and at multiple levels; indeed the very same can be said for the neural systems of fear, stress and emotional affect.

The scientific literature supporting these broad claims is extensive and of high caliber, and is actively disseminated to the public at various degrees of sophistication. While it is true that only a relatively small fraction of cannabinoid research has been from clinical trials – clearly a consequence of obstructing policies of prohibition – the research continues at a rapid pace to demonstrate mechanistic plausibility for a range of conditions that still surprises me after 20 years in the field.

It is also universally recognized that in modest doses cannabis and its extracts are well tolerated, and that even very high doses will cause distress but not death. Thus it shouldn’t be taken with surprise or cynicism that so many patients have the perception that cannabis does or might help them. The response of the healthcare community should instead be to stay ahead of the educational curve.

It is also time for healthcare professionals to engage in critical evaluation and engaged commentary on the systems of prohibition that force honest patients to become criminals should they try cannabis. Educate yourselves to form an opinion and ethical position on the use of criminal sanctions to deny access to medical marijuana. As for me, I believe that measures like Amendment 2 in Florida are a cautious approach and a moral imperative.

Dr. Gregory L. Gerdeman is Assistant Professor of Biology at Eckerd College in Saint Petersburg and Chief Science Officer for 3 Boys Farm in Ruskin, Florida. He has researched the neuroscience and pharmacology of cannabis and the endocannabinoid system since 1996.

Greg Gerdeman: Brain Science & the Endocannabinoid System

Greg Gerdeman cannabis science
By on January 20, 2016

Professor Greg Gerdeman on brain science, the neurobiology of stress, and how the discovery of the endocannabinoid system has liberated cannabis from the drug abuse paradigm.

Transcript

Project CBD: We’re speaking with Greg Gerdeman, a neuroscientist and professor of biology at Eckerd College in Florida. Greg Gerdeman is one of the few professors that we know of who actually teaches classes on something called the “endocannabinoid system.” What is the endocannabinoid system? Why do you teach classes on that, and what’s its significance?

Greg Gerdeman: The endocannabinoid system is an area of research that’s been my focus for 20-some years. It was discovered by understanding how cannabis works. So cannabis works at the endocannabinoid system. It’s a broad way to speak about it. But partly what’s so exciting is that as scientists have studied the endocannabinoid system to understand cannabis, we’ve really come to learn a tremendous amount more about how our brains, our bodies work. How we work, not just how cannabis works. So to the education piece, I’m a neuroscientist and now teaching about how the brain works and processes information, how different circuits work in the brain, endocannabinoids are such an integral part of that, that it should be part of neuroscience curriculums, let alone a course in and of itself.

Project CBD: So what do we specifically mean by endocannabinoid system?

Gerdeman: Well, it means, first and foremost I think the receptors by which THC and other cannabinoids act. So, the targets of how cannabis works and an intrinsic set of neuromodulators called endocannabinoids that are released by cells and act at the receptors. So, although the system is distributed throughout the body, I tend to think about the brain and it’s very highly utilized by the brain. And, as an example of how the brain works with endocannabinoids, a given neuron – a cell within the brain receiving thousands of different inputs – will release endocannabinoids, these small signaling molecules, to fine-tune the strength of their own synaptic inputs. So the endocannabinoids are signaling molecules that are created and broken down by enzymes in the body. They act at cell surface receptors that change the activity of cells. And all of this – the signaling molecules, the enzymes that make them and break them down, the receptors that exert the effects of the compounds – are bundled up into what we call the endocannabinoid system.

Project CBD: So when you talk about “endocannabinoids,” you’re talking about molecules that exist in our own brains and bodies.

Gerdeman: Right.

Project CBD: Would it be correct to say they’re marijuana-like molecules? How do they relate to THC and CBD, or other components of the plant, these endocannabinoids in our own body?

Gerdeman: In some ways, it’s fair to say that. And people say it’s like the body’s own marijuana. A structural chemist they might take some objection to that because the structures [of the molecules] don’t look that much alike. But functionally, which is what a physiologist thinks about, the physiology of how anandamide binds to and changes cellular activity binding a cannabinoid receptor is actually quite similar to THC.

Project CBD: Anandamide is an endocannabinoid.

Gerdeman: That’s right. “Endo” is short for endogenous cannabinoid, molecules within our own body. They primarily are represented by anandamide and a compound called 2-AG. There are probably several others. We know there are other endocannabinoid-like molecules that are released in an entourage sort of way. And, regulate in a concerted way a great many cellular functions. It’s quite variable, but it seems to be a system that promotes homeostasis well being, keeping the body within an optimal set range. The endocannabinoids modulate the body in that way.

Lee: So you talk about homeostasis and about other crucial functions that the endocannabinoid system plays in the body; homeostasis balancing physiological systems is one. What other aspects of human physiology and biology is the endocannabinoid system affecting or interacting with?

Gerdeman: Well, it certainly interacts with processes of learning and memory and how we integrate sensory, motor information. In a way, as a physiologist, I can think of that all as homeostasis. Like if you’re hungry and go get cues through your body to seek food, that’s a complex process of homeostasis – the human organism is sensing deficit and seeking to restore balance by eating food. And the endocannabinoid system in fat tissue and the hypothalamus of the brain, in the brain pleasure centers (as they get called) that motivate behavior – they’re all being choreographed, sort of orchestrated by endocannabinoids.

Project CBD: In your own research, I know you’ve done work on exercise and how physical exercise affects the endocannabinoid system or the cannabinoid receptor signaling. What drew you into that research? What did you find essentially?

Gerdeman: Well I got drawn into that because, being a cannabinoid brain guy, I had an interaction with an anthropologist named David Raichlen and we started teaming up because he has a long interest in what drove endurance running behavior as an evolutionary force in human evolution. And, so the question of why do people engage in distance running, anthropologists get caught up on the notion that it’s energy intensive, it has risk of damage to your body, and to make what can be kind of a long story short, we started investigating what others had already seen, that with aerobic exercise, anandamide (not 2-AG), anandamide goes up in the blood in humans. We found it in dogs, another group of animals that have evolved to run distances. And we relate it to sort of the runners joy, the runners high. When you get a sense of wellness, elevated mood, wellbeing, the kinds of things that make exercise a good compliment to just healthy lifestyle and well being, the endocannabinoids are related to this. We think that the anandamide levels that go up with exercise are really important for how running and other forms of exercise helps to maintain a robust, resilient physiology – resilient to stress and disease.

Project CBD: So it’s kind of like a feedback loop. It gives you kind of a pleasure, like the runners high, you’re saying, and that’s related to the endocannabinoids in our body, you specifically mentioned anandamide.

Gerdeman: Anandamide. 2-AG doesn’t seem to go up. And that’s part of the new and emerging complexities of the endocannabinoids – what’s the difference between these two. But in the biology, in studies of the neurobiology of stress, it’s interesting that keeping a solid anandamide tone, having a healthy level of anandamide, at least within certain brain areas, seems to be very important to one’s resilience to stress. And the neurobiology of sensing fear and perceiving fear is related to that anandamide level transiently dropping. This is work by Matt Hill. When an organism senses fear, anandamide levels in the amygdala drop, and that triggers the fight or flight immune response. And it also triggers sort of higher level coding of the fearful experience. Higher anandamide levels – and this could be oversimplified – but higher anandamide levels or a healthy anandamide level seems to be, in some very mechanistically clear ways. This is high-end scientific research, related to resilience, to stress, and overcoming and forgetting stress and stressful cues that provoke anxiety from past trauma, for example.

Project CBD: And what do we mean by “stressful cues” in this instance, because so many different things can act as stressors in the body. Are there only certain kinds of stress, like psychological stress, that the endocannabinoid system will mediate in some ways? Or would that be a plethora of different stressful cues that the endocannabinoid system in some way will be involved in helping the organism cope?

Gerdeman: Well, I think more the latter. Because I look at it as a brain scientist, and the neural circuitry involved in perceiving stress, sensing it, responding to it, communicating to the body to elevate the heart rate, the whole suite of stress sensation, responsing, remembering -- those are complex neural circuits and they regulate themselves on a moment-to-moment basis with endocannabinoids. So the system is involved. Now, as far as real close investigation, real fine investigation of stress, the best evidence is for what in jargon you might call homotypic stress, the kind of repeated day-in, inescapable stress that describes some people’s conditions in life that lead to chronic anxiety.

Project CBD: Stress is understood to underline many different diseases or aberrant medical conditions. In general terms or in broad terms, the advances that have been made in understanding brain science through studying the endocannabinoid system -- what are the implications just in terms of understanding disease and health and how we function? What light does studying the endocannabinoid system, or what light has it shed on these basic challenges that we confront in life, on a day-to-day basis? Because most people aren’t scientists, we don’t think it terms of molecules and these things, it’s just we want to improve our health. What does the endocannabinoid system tell us about that?

Gerdeman: Well, I mean, I think we’ve learned enough to say it’s incredibly promising and fascinating focus to look into. The endocannabinoids are implicated in so many different disease states. And it fits in with the whole area of cannabis as medicine, and botanical cannabis products tweaking or interacting with the system in a way that there’s just so much potential for, you know, pain states and stress states and chronic disease. Part of what fascinates me, as a neuroscientist that looks at how endocannabinoids like allow cells to fine tune their own inputs, I can think of how this relates to motor control, for example. And there’s really high-level research showing that endocannabinoids are related in Huntington’s Disease and Parkinson’s Disease, different kinds of tremor. But these same molecules that interact with these electrical neurocircuits are like controlling tumor growth and are signaling in the gastric, the intestinal cell lining, to regulate healing and scarring. There’s so much we don’t know yet. But it’s fascinating that this system acts at so many different levels that are related to health and wellbeing.

Project CBD: So the implication would be that if cannabis interacts with this very subtle and important physiological system, the endocannabinoid system, that it could be used to improve health, to bring the system back into balance if there are some deficits in our own physiology, that for some reason this particular plant interacts in a very profound and deep way with our own physiology and to understand that relationship somehow the endocannabinoid system in crucial.

Gerdeman: Yeah, like no other. The endocannabinoid system, sort of crystallized by the cannabinoid CB1 and CB2 receptors, the evolution of these genes that appeared at sort of the base of the vertebrae tree of life, they weren’t there before, these receptors. And now you look at human animals and we’ve got this extraordinarily complex brain, extraordinarily adaptive immune system, that really fine tunes itself all the time with endocannabinoids, the endocrine system that works with endocannabinoids, something really works with endocannabinoid signaling. And the cannabis plant interacts with it in such incredibly diverse ways, surprisingly subtle ways. You know the notion that you don’t get more serious side effects from using a medicine that interacts at such an integral level with your neurocircuitry, is pretty amazing. It’s pretty amazing.

Project CBD: Opens up whole new vistas, it seems, to understanding human biology with great implications for medicine.

Gerdeman: It does. And that’s why different avenues of research – I mean, when I got into it, the National Institutes of Health really only funded endocannabinoid research under the National Institute on Drug Abuse. Nobody – if you told people, hey you’re interested in the circuitry of the amygdala and fear, learning, and stress, what do you think about endocannabinoids because they’re all over that circuit, the response among scientists would still be kind of like well I don’t study marijuana! I don’t study drug abuse. They didn’t get yet. But now, I like to say that the scientific discovery of the endocannabinoid system has, in some important ways, liberated cannabis from the drug abuse paradigm that’s been locking it in for so many, several decades here – which in the long span of cannabis as medicine is a short period of time – but it’s been enormous. And the endocannabinoid system has liberated cannabis more into the biomedical health and wellbeing – not just for terminal illness, not just as a last resort – but there’s so much value to researching the endocannabinoids and cannabis-derived botanicals as medicines for wellness and resilience.

Project CBD: Well fortunately there are some scientists such as yourself who are not simply operating within the drug abuse paradigm, but have been really doing cutting-edge research that has advanced our understanding of health and disease. And hopefully that can be used to make a better life. Thank you, Greg Gerdeman for speaking with us at Project CBD.

Gerdeman: Thanks Martin.

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

Audio-visual category: 

O’Shaughnessy’s (Winter 2015/16)

O’Shaughnessy’s- The Journal of Cannabis in Clinical Practice
By on January 04, 2016

The Winter 2015/16 issue of O’Shaughnessy’s—the journal that was instrumental in launching Project CBD six years ago—is now available.

There are too many highlights to highlight in this 72-page publication, which chronicles the recent history of medical marijuana as a dynamic social movement from the perspective of cannabis health specialists and their patients.

The lead story tracks the paths by which CBD-rich products are reaching medical patients. Both Bonni Goldstein, MD, in California and Margaret Gedde, MD, in Colorado have monitored the progress of hundreds of pediatric epilepsy patients utilizing unregulated high CBD/low THC cannabis oils (extracted from strains such as ACDC and Charlotte’s Web) with results similar to what doctors are seeing in FDA-approved treatment programs using GW Pharmaceuticals’ Epidiolex.

More than half the children who are given CBD-rich oil experience significantly fewer and less-severe seizures. For a small group at one end of the curve, seizures are eliminated. For a small group at the other end, cannabis doesn’t help at all, or exacerbates symptoms. Medical scientists are investigating why CBD-rich oil works for some patients but not for others. Most pediatric epilepsy cases involve genetic mutations. Some but not all gene-based epilepsies are amenable to treatment with CBD. Some are proving amenable to treatment with CBD plus THC and other cannabinoids.

O’Shaughnessy’s was conceived by Tod Mikuriya, MD, as a journal in which doctors monitoring cannabis use by patients could share their findings and observations and be kept up to date on the relevant science and politics. Dr. Mikuriya wanted physicians in the emerging specialty to share O’Shaughnessy’s with patients “by way of thanks, because almost all we know about cannabis as medicine comes from patients.”

Order O’Shaughnessy’s          

Open Letter to NFL Commisioner Roger Goodell

Lester Grinspoon and Project CBD, cannabis and NFL
By on January 04, 2016

Originally published by O'Shaughnessy's (BeyondTHC.com)

I am among the millions of people who enjoy football as a spectator sport. However, I am becoming increasingly uncomfortable with the growing specter that many of these athletes will pay the price of developing Chronic Traumatic Encephalopathy (CTE) to a greater or lesser extent as they grow older. I believe that any change in the rules of the game which would accommodate these concerns would also diminish its popularity. I also believe that attempts to improve protective equipment can only go so far without seriously diminishing the skills and capacities of the player. Football is a violent game and every one involved in it knows that there will certainly be injuries. However, most injuries manifest themselves immediately, are orthopedic, not life-threatening, and with the help of nature and orthopedic medicine, will sooner or later heal. Injury to the brain is another matter.

The skull is nature’s way of protecting this most important organ, the brain. However, strong as this container is, it cannot protect the contents from concussion. And most assuredly it offers no protection against the consequences of repeated concussions which can lead to the development of CTE. And unlike orthopedic injuries, the effects of this syndrome only manifest themselves over the course of years and they are always irreversible and often devastating. The piece of equipment meant to protect the head is the helmet, which is excellent at protecting the container but not the contents. Furthermore, given the limitations imposed by physics, anatomy and neurophysiology, I question whether there is any helmet design which can do much more to limit the frequency or severity of concussions. It is for this reason that I believe it is important to look for internal protection against this kind of devastation.

Over the last two decades interest, knowledge and use of marijuana as a medicine has grown exponentially. People who are knowledgeable about cannabinopathic medicine believe that marijuana is neuroprotective. This understanding has grown from both clinical experience and animal research. It is also well known that it is remarkably free of toxicity. Furthermore, it is been learned relatively recently that one of the constituents of marijuana is a cannabinoid known as cannabidiol (CBD), which has no psychoactive properties; in other words, no amount of it would lead to a “high.” Increasingly, it is being sought as a medicine because it is both an anti-inflammatory and an antioxidant and it is free of psychoactivity. It is a very promising development, but the kind of research that will be necessary to establish this as a general medicine useful preventively in patients who are more likely to develop strokes because they suffer from heart arrhythmias or with patients who are subjected to other kinds of brain trauma will have to await the funding of this research. Funding for this kind of research is usually provided by a pharmaceutical company which wants to develop a new medicine for the market and, in order to do so, has to provide the Food and Drug Administration (FDA) with the research data which establishes both efficacy and safety. It is highly unlikely that a pharmaceutical company will get involved in this expensive research in this instance because a high ratio CBD/THC is now available in those states which have legalized the medicinal use of cannabis. The only other source of funding would be the US government which is not likely to provide it.

I would propose two actions for the NFL which have a good chance of decreasing the devastation of CTE. The NFL pockets are deep enough to support a crash research program to determine that this combination of cannabinoids is effective in preventing the consequences of concussion so that we will know for sure whether or not it will protect against this threat to the players. Secondly, I would also urge the NFL to drop its urine testing marijuana program so that players who believe that a high ratio CBD/THC substance may be useful to them in this regard will be free to use it without objection by the NFL.

Sincerely,

Lester Grinspoon M.D.
Emeritus Professor of Psychiatry
Harvard Medical School
Author of Marihuana Reconsidered (Harvard University Press, 1971) and Marijuana, the Forbidden Medicine (Yale University Press, 1993, 1997)

Veterans Drop Hundreds of Empty Pill Bottles at the White House

Veterans call for medical marijuana
By on November 12, 2015

Published in full on the Washington Post.

A couple dozen servicemen and women marched to the White House this Veterans Day and dumped a large box of empty pill containers, calling on the president and other federal officials to make medical marijuana accessible to veterans.

“Here’s what the over-medication of our veterans looks like,” they said as they spilled the canisters onto the floor. “We don’t want it.”

The veterans and protesters—affiliated with various veteran and marijuana advocacy organizations—argued that Veterans Affairs hospitals are over-medicating veterans, prescribing them a large number of psychoactive medications to treat PTSD. They marched from McPherson Square to the Department of Veterans Affairs headquarters, then to the White House, some smoking joints along the way, which is illegal in D.C.

Read full article


See the report on the Care By Design survey on cannabis in the treatment of PTSD.

READ REPORT

Illuminating Results of CBD Patient Survey

Care By Design
By on September 15, 2015

Care By Design surveyed thousands of patients who had been using CBD-rich cannabis medicines for over 30 days. They asked patients what they were taking CBD-rich cannabis for, the ratio of CBD-to-THC they were using, and about its impact on pain, discomfort, energy, mood, and overall wellbeing. 

Here's what they learned:

READ FULL REPORT

WHAT PATIENT'S SAY

Key Findings

  1. Medical marijuana patients are using CBD-rich cannabis for a wide variety of conditions, including serious and incurable diseases, and conditions that may respond poorly to FDA-approved pharmaceuticals. Over 12% are using it to address the side effects of cancer treatment.
  2. Patients with psychiatric illnesses, mood disorders, neurological diseases and CNS injuries favor CBD-dominant cannabis medicines. Patients with pain and inflammation favor CBD-rich cannabis medicines with more equal levels of CBD and THC.
  3. THC matters. Patients using the 4:1 CBD-to-THC were the most likely to report a reduction in pain or discomfort, and improvements in mood and energy. Patients using the 2:1 CBD-to-THC ratio reported the greatest improvement in overall wellbeing. This finding is consistent with scientific research indicating that CBD and THC interact synergistically to enhance one another’s therapeutic effect.
  4. CBD-rich cannabis appears to be remarkably good at ameliorating pain (particularly in patients with fibromyalgia, headaches and migraines), and at improving patients’ sense of wellbeing, particularly for patients with PTSD.
  5. Given that people using CBD-rich cannabis for “general wellbeing” are the only group who reported a decreased feeling of wellbeing and the most likely to report a worsening mood, it's possible that CBD products may not be appropriate as a supplement for people who are otherwise healthy.

Project CBD director Martin A. Lee served as a product development consultant for Care By Design. He did not participate in the preparation of this report.

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CBD-Drug Interactions: Role of Cytochrome P450

Cytochrome P450
By on September 08, 2015

With cannabidiol (CBD) poised to become widely available in pharmaceutical, nutraceutical, and herbal preparations, medical scientists are taking a closer look at CBD-drug interactions.

Cannabidiol is a safe, non-intoxicating, and non-addictive cannabis compound with significant therapeutic attributes, but CBD-drug interactions may be problematic in some cases.

CBD and other plant cannabinoids can potentially interact with many pharmaceuticals by inhibiting the activity of cytochrome P450, a family of liver enzymes. This key enzyme group metabolizes most of the drugs we consume, including more than 60 percent of marketed meds.

At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds, including tetrahydrocannabinol (THC), which causes the high that cannabis is famous for.

Metabolizing THC

When THC or any other foreign compound enters the body, it is metabolized. This process is generally very complicated. Metabolizing something properly can involve multiple molecular pathways and various enzymes that enable the body to get rid of the compound (often done by adding something to the original compound). Or metabolism can entail breaking down a compound into a more basic molecule that the body then uses.

Products of a drug’s metabolism are called its metabolites. These metabolites can have very different properties than the initial drug. Ethanol, for example, owes some of its effects, including much of the hangover, to its two-step metabolism. The buildup of acetaldehyde in the liver—while ethanol is converted first to acetaldehyde and then to acetic acid—is a major reason for ethanol’s liver toxicity and the nausea and vomiting caused by excessive consumption.

THC metabolites contribute significantly to the effects of cannabis consumption. Eleven-hydroxy-THC (11-OH-THC), for example, is a THC metabolite that activates the CB1 cannabinoid receptor in the brain and induces a high more potently than THC itself. This means that the body’s metabolism of THC can make it more potent.

Cytochrome P450 enzymes contribute to the metabolism of drugs by oxidizing them, which generally means incorporating an oxygen atom into the drug’s molecular structure. Oxidation will usually make a compound more water soluble and therefore easier for the kidneys to filter out. Both steps in the metabolism of ethanol, mentioned above, and the conversion of THC into 11-OH-THC involve oxidation (though ethanol is not oxidized specifically by cytochrome P450).

Different routes of cannabinoid administration have different effects. Inhaled THC enters capillaries in the lungs, passes into general circulation through the pulmonary arteries, and quickly crosses the blood-brain barrier. When ingested orally, however, THC is absorbed in the small intestine and then carried to the liver, where it is metabolized by subclasses of cytochrome P450 (abbreviated CYP), specifically the CYP2C and CYP3A enzymes.

These liver enzymes also metabolize CBD, converting it into 7-OH-CBD and 6-OH-CBD. But there has been relatively little research into the properties of these CBD metabolites.

Metabolizing CBD

The way CBD interacts with cytochrome P450 is pivotal; in essence, they deactivate each other. Preclinical research shows that CBD is metabolized by cytochrome P450 enzymes while functioning as a “competitive inhibitor” of the same liver enzymes. By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents cytochrome P450 from metabolizing other compounds.

The extent to which cannabidiol behaves as a competitive inhibitor of cytochrome P450 depends on how tightly CBD binds to the active site of the metabolic enzyme before and after oxidation. This can change greatly, depending on how—and how much—CBD is administered, the unique attributes of the individual taking this medication, and whether isolated CBD or a whole plant remedy is used.

If the dosage of cannabidiol is low enough, it will have no noticeable effect on CYP activity, but CBD may still exert other effects. There is no clearly established cut-off dose, below which CBD does not interact with other drugs. A 2013 report on a clinical trial using GW Pharmaceutical’s Sativex, a whole plant CBD-rich sublingual spray, found no interactions with CYP enzymes when approximately 40mg of CBD were administered. A subsequent clinical trial, however, found that 25mg of orally administered CBD significantly blocked the metabolism of an anti-epileptic drug.

How do CBD-generated changes in cytochrome P450 activity impact the metabolic breakdown of THC? Animal studies indicate that CBD pretreatment increases brain levels of THC. That’s because CBD, functioning as a competitive inhibitor of cytochrome P450, slows down the conversion of THC into its more potent metabolite, 11-OH-THC. Consequently, THC remains active for a longer duration, but the peak of the extended buzz is blunted somewhat under the influence of cannabidiol.

Other factors figure prominently in CBD’s ability to lessen or neutralize the THC high.

Grapefruit and Ganja

Lester Bornheim, a research pharmacologist at the University of California in San Francisco, was among the first scientists to study the metabolism of CBD. In 1987, he was awarded a NIDA grant to investigate the effects of phytocannabinoids on cytochrome P450 enzymes. THC and cannabinol (CBN) also inhibit CYP activity, but CBD, of all the plant cannabinoids studied, is the strongest cytochrome P450 deactivator.

“It’s a very unusual enzyme. Almost all other enzymes are designed to fit a single substrate and carry out a single chemical process resulting in a single product,” Bornheim noted, whereas numerous drugs are substrates for cytochrome P450, which seems to function like a generic breakdown mechanism for a wide range of exogenous and endogenous substances.

In 1999, Bornheim addressed the annual gathering of the International Cannabinoid Research Society (ICRS) and drew attention to the possibility that CBD could interfere with the metabolism of many medications. A year earlier, a team of Canadian scientists identified certain compounds in grapefruit that inhibit the expression of some cytochrome P450 enzymes—which is why physicians often warn patients not to eat grapefruit before taking their meds. CBD, it turns out, is a more potent inhibitor of cytochrome P450 enzymes than the grapefruit compound Bergapten (the strongest of several grapefruit components that inhibit CYPs).

What does this mean in practical terms for a medical marijuana patient on a CBD-rich treatment regimen who takes a prescription blood-thinner like warfarin, for example? CBD reduces the enzymatic degradation of warfarin, thereby increasing its duration of action and effect. A person taking a CBD-rich product should pay close attention to changes in blood levels of warfarin, and adjust dosage accordingly as instructed by their doctor.

Cancer and Epilepsy

In cancer treatment, the precise dosing of chemotherapy is extremely important; doctors often struggle to find the maximum dose that will not be catastrophically toxic. Many chemotherapy agents are oxidized by CYPs before their inactivation or excretion. This means that for patients using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the cytochrome-mediated metabolism of the chemotherapy and dosage adjustments aren’t made, the chemotherapy agent could accumulate within the body to highly toxic levels.

By and large, however, there have been few reported adverse cannabinoid-drug interactions among the many cancer patients who use cannabis to cope with the wrenching side effects of chemotherapy. It is possible that whole plant cannabis, with its rich compensatory synergies, interacts differently than the isolated CBD that is administered in most research settings. As well, the cytoprotective effects of the cannabinoids may mitigate some of the chemotherapeutic toxicity.

Some epileptic patients have encountered issues with how CBD interacts with their anti-seizure medication. A small clinical study at Massachusetts General Hospital involving children with refractory epilepsy found that CBD elevated the plasma levels and increased the long-term blood concentrations of clobazam, an anticonvulsant, and norclobazam, an active metabolite of this medication. A majority of these children needed to have their dose of clobazam reduced due to side effects. Given that both clobazam and CBD are metabolized by cytochrome P450 enzymes, a drug-drug interaction is not surprising. Published in May 2015, the study concluded that “CBD is a safe and effective treatment of refractory epilepsy in patients receiving [clobazam].” But the report also emphasized the importance of monitoring blood levels for clobazam and norclobazam in patients using both CBD and clobazam.

Dr. Bonni Goldstein has observed cases in which small doses of high-CBD/low-THC cannabis oil concentrate seemed to aggravate seizure disorders rather than quell them. How could this happen, given CBD’s renown anti-epileptic properties?

A 1992 review by Lester Bornheim and his colleagues indicated that CBD inhibits some cytochrome P450 enzymes at smaller doses than what is required for CBD to exert an anti-epileptic effect. This means that a certain dose of CBD could alter the processing of an anti-epileptic drug taken by the patient, but this amount of CBD might not be enough to provide any anti-epileptic relief itself. The advice some physicians offer in this situation may seem counterintuitive: Increase the dose of CBD—perhaps even add a little more THC (or THCA, the raw, unheated, non-psychoactive version of THC)and this may be more effective for seizure control.

Enigmatic Enzymes

But why would preventing the breakdown of an anti-epileptic drug reduce its effect? There are a number of possible answers, depending on the drug in question. The active component of the drug (the chemical that exerts an anti-epileptic effect) may be a breakdown product of the actual drug taken. So, by slowing the metabolism of the original drug, CBD would make that drug less active.

Other explanations are conceivable. For example, if the activity of certain CYPs is slowed, the drug may be broken down by another metabolic pathway, the products of which could then interfere with the drug’s activity. Or perhaps the inhibition of CYPs is not the predominant way that CBD interacts with certain anti-epileptic medications.

To complicate matters even further, a presentation by Dr. Kazuhito Watanabe at the 2015 International Cannabinoid Research Society meeting in Nova Scotia disclosed preliminary evidence that cannabidiol may “induce”—meaning amplify the activity ofsome cytochrome P450 enzymes. (Induction of a protein involves increasing the transcription of its corresponding mRNA, which leads to greater synthesis of the protein.) This suggests that CBD can either increase or decrease the breakdown of other drugs. Again, it depends on the drug in question and the dosages used.

Any pharmaceutical, nutraceutical or green rush scheme to exploit the therapeutic potential of CBD must reckon with the fact that cannabidiol can both inactivate and enhance various cytochrome P450 enzymes in the liver—and this can potentially impact a wide range of medications. Drug interactions are especially important to consider when using life-saving or sense-saving drugs, drugs with narrow therapeutic windows, or medications with major adverse side effects. In particular, those who utilize high doses of CBD concentrates and isolates should keep this in mind when mixing remedies.

Adrian Devitt-Lee is a senior at Tufts University, studying mathematics and chemistry.

Learn More:

AED Potential Interactions with CBD

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


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Nora Volkow on the “Potential Promise” of CBD

Nora Volkow on CBD
By on August 10, 2015

Originally published by O’Shaughnessy’s News Service.

The director of the National Institute on Drug Abuse, Dr. Nora Volkow, has just published an article in the Huffington Post entitled “Researching Marijuana for Therapeutic Purposes: The Potential Promise of Cannabidiol (CBD).” A pro-cannabis friend forwarded the link, calling it “a powerful statement.” 

Given NIDA’s history and prohibitionist mission, Volkow’s piece can be seen as a step in the right direction. She calls for “addressing barriers that slow clinical research”—a reference to CBD’s absurd status as a Schedule I substance. But that shy, sly allusion is hardly a powerful statement. In fact, “potential promise”—the blatantly redundant phrase in the title of Volkow’s CBD essay—reveals an almost laughable level of timidity. And it’s misleading to the point of dishonesty.

Yes, there are many potential uses of CBD for researchers to explore. But the ability of cannabidiol to alleviate symptoms in a wide range of illnesses has been proven—determined, established, QED, confirmed, made evident—in many studies involving animals, several trials with human patients, and thousands of cases monitored by physicians in California, Colorado, and other states where medical use is legal. 

To repeat: CBD provides medical benefit. That is a fact, not a “potential promise.”  

Nora Volkow is taking part in a stall with tragic consequences. Earlier this week the Occupational Safety and Health Administration proposed drastically limiting allowable exposure to beryllium, a metal used in electronics, dental implants, and other nuclear devices. Berylliium damages the lungs; workers exposed to it can develop a fatal disease (245 cases a year, OSHA estimates).

“OSHA first proposed lowering the beryllium workplace standard in 1975,” wrote Barry Meier in the New York Times, “but efforts to do so were beaten back over the years by industry resistance, technical debates and political stalling.” (Add misleading sentences. Industry resistance is solely to blame for all those years of excessive exposure to beryllium. Industry resistance took the form of technical debates and political stalling.)

OSHA expects the new limits on beryllium exposure will be in place by late 2016 and “will prevent close to 100 deaths annually.” Accepting OSHA’s numbers (which are likely to be low) means that 90 American workers have been killed by beryllium exposure each year since 1975. That’s 3,690 deaths—which means the honchos at Materion (formerly Brush Wellman, the only beryllium producer in the US), conspired to kill 3,690 Americans to enhance their profits. How many Americans did Osama bin Laden’s group kill on 911?  Why aren’t the Materion execs being charged with murder? 

Our local TV news recently showed a Black man working in a community garden in Oakland. He talked about the legal toxins we’re all exposed to in our food, air and water. “They’re killing us,” he warned the reporter, “but they’re killing us slow.”

It happens that 1975 was also the year that the first study showing that CBD has anti-seizure effects was published. Not “potential promise”—anti-seizure effects.