The pain management community’s go-to – Mark Wallace, MD, of UC San Diego – answers questions surrounding cannabis effects, safety, formulations, and promise as a therapeutic tool. Plus, why he feels medical cannabis should be offered to patients before opioids.

The answers to crucial questions surrounding cannabis effects, safety, formulations, and promise as a therapeutic tool. Plus, why medical cannabis should be offered to patients before opioids.

This discussion is part of a conversation series led by Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD, in honor of PPM’s 20th anniversary of publication. A condensed transcript follows. Access the full conversation audio file.

Dr. Fudin: Going back in time a bit, what led you to dig into the potential of cannabinoids as analgesics?

Dr. Wallace: Well, I was in California when it was first legalized in 1996. At that time, I was on the fence as to which way we should go. I had questions about the source and the quality. Shortly after it was legalized, the state of California allocated a substantial amount of money for research, which led to the creation of the Center for Medicinal Cannabis Research, stationed here at UC San Diego. I was interested in researching it and got my first grant.

Fast forward, and the center has completed seven randomized, double-blind placebo-controlled studies, all with inhaled cannabis. Over time, I started learning more about it and started integrating it into medical practice. Today, it is integrated into the therapies we provide our patients.

Dr. Gudin: I have talked to some clinicians who say patients absolutely cannot use marijuana products and be part of their practice, and, yet, when you look at some of the data, it actually supports the fact that we may be able to spare opioids, NSAIDs, or other adjuvants that have side effects. What’s your thinking along these lines? Is there a happy middle ground?

Dr. Wallace: My view is we have over 60,000 deaths annually from opioids in this country – that’s a combination of prescription and abused opioids. There’s never been a reported death from cannabis so we don’t even know if there are any lethal doses of cannabis.

Where does it fit in practice? I place it before opioids in my practice. Patients want it before opioids. They look at opioids and think, ‘Oh my gosh, they’re risky and do they even work?’ You’re right that we’re still divided as a clinical community, but I’ve seen a major trend moving from the majority against it to the majority in favor of it – but we still have a long ways to go.

We need more research to understand how to use it. We need better quality control. We need better sources. We need get closer to medical-grade cannabis.

Dr. Gudin: Have you found any specific types of pain or types of patients it works for? If clinicians were going to start allowing patients to use marijuana products as analgesics, where should they start?

Dr Wallace: It’s a difficult question to answer because when we think of what medical cannabis encompasses, it’s a large variety of compounds – from the flower itself to specific extracts to specific extracts within the flower. There are over 100 active cannabinoids that could possibly be effective.

Most of our evidence is with THC. In fact, we have almost no evidence with CBD even though there’s this big hype with CBD.

You have to understand that the therapeutic range of THC is quite narrow, going from beneficial effects to negative effects, and that range of effects goes from 1 to 20 milligrams whereas CBD ranges from 10 to 800 milligrams, as far as the range of effects. So, to get to what we think is the beneficial effects of CBD would be cost-prohibitive – it would cost thousands of dollars a month because you would have to take 400, 600, or 800 milligrams a dose – that’s what Epidiolex (cannabidiol)is, which is CBD for seizures and children.

As far as the specific types of pan, most of our evidence is with THC and neuropathic pain – and with cancer pain. But over time, I have started opening up its use to different pain problems, such as fibromyalgia, osteoarthritis, chronic low back pain, headaches… we have a grant right now to look at the randomized placebo-controlled crossover design as a migraine abort. So there’s a wide ranges of therapies we can use it for but keep in mind that most of the evidence is in neuropathic pain. We have very little evidence for all these other pain syndromes – but I think we’re getting there.

I will say it’s very hard to do research with cannabis because it’s a Schedule I substance. I can’t do a multi-site placebo-controlled randomized trial design when we’re limited to single site, placebo-controlled small numbers. It’s not like we don’t want to do multicenter trials –it’s just very difficult to do them across state lines.

Dr. Fudin: My concern with any of these cannabis products is drug interactions, not just with opioids but all medications. Some listeners may not be familiar with the original research by John W. Hoffman (known as JWH) – he was an organic chemist who, in 1984, started synthesizing synthetic cannabinoid compounds that led to important discoveries around the endocannabinoid system.

The synthetic compounds that were developed, such as the commonly known Spice or K2, wreaked around the world because of their toxicity. Can you elucidate for us how the toxicity of those street compounds differs from the newer synthetic approved C2 compounds, and how the CB1 and CB2 receptors differ?

Dr. Wallace: So, let’s focus first on the naturally occurring THC, which is a very weak agonist and has a very low affinity for the CB1 and CB2 receptors – that’s a good thing because when you start overstimulating the cannabinoid receptors, you get pretty major negative effects with psychosis. The synthetic compounds are probably stimulating the receptors too much.

We know that the endocannabinoid system is very important to our body’s ability to handle stress and pain. It helps us with sleep and memory. And if you start messing with that system, you have major negative effects. An example is the cannabinoid receptor antagonist, which they were trying to develop for weight loss but had negative effects and had to stop development. If you start blocking the cannabinoid receptor system, it can wreak havoc on your body. We need that system.

I think those synthetic compounds that were having such negative effects were way too potent.

We even see that now with dosing THC. When we use medical doses, we’re using very small doses; I’m starting with 1 or 2 milligrams per dose. At night, we may bump it up to about 5 milligrams, maybe 7 or 8 milligrams, per dose because it helps with sleep.

If you go above 10 milligrams, you start getting paranoia. When you get to 20 milligrams, you get psychosis. So you can see how you have this biphasic effect – and the same holds for CBD. Low doses of CBD can be stimulating and activating while high doses are calming, anxiety-reducing, anti-seizure.

So with these biphasic-like effects of the cannabinoid system, you have to make sure you’re in the lower end to get the positive effects. And I think that’s what was happening with K2 and Spice –they were going right through to those very high-dose, high stimulations of the cannabinoid system and you got negative effects.

Now the difference between CB1 and CB2 – CB1 is the most abundant receptor in our nervous system; it is found all over the place, except for very low levels in the brainstem. And that’s probably why we don’t have any respiratory depression with cannabinoids. The CB2 receptors are located mainly on the inflammatory cells so that leads to the anti-inflammatory effects of the cannabinoids

Dr. Gudin: You discussed dosing, but what kind of formulations are you using?

Dr. Wallace: So, remember, I’m in California and California has been doing this for 20 years. The quality control is getting so much better here. Everything that gets to the shelves has to be batch tested for content, contaminants, water content, molds. As far as the product, most of our patients are using edibles and oil extracts. It gets complicated because if they start medical cannabis use, their insurance isn’t going to cover it. And so the cost is going to be on the patients.

The cheapest way to do it is with the flower – that is, inhalation. But we don’t like our patients to smoke it and we don’t recommend inhalation of smoke. However, we’re okay with inhalation of the organically grown flower in a vaporizer. So we teach them how to get the proper content of the product (eg, 2% THC, 2% CBD and they can mix it). For the extracts, we tend to tell them to change the ratio of CBD to THC based on the time of day.

During the daytime, they usually go with a 20:1 THC:CBD ratio and they start with a quarter of a dropper full – that’s only going to give them about 1 to 2 milligrams of THC.

At night, we tell them to go to a 1:1 ratio and still to start with a quarter of a dropper, drop it under their tongue, let it sit there, and then swallow it.

The key is to start low and go slow and then to slowly titrate it up because if they go too fast, they’ll blow right through the positive effects into the negative effects.

Dr. Gudin: So I’m going to change gears a little bit….we work with residents and fellows and we’ve hired a number of graduating pain clinicians over the years and many have gotten so pharmacology phobic – many just want to do procedures.

Do you think medicinal marijuana analgesic cannabinoids is a way to kind of draw them back in to look at the patient from a holistic approach? What would you say to the young residents and fellows pursuing careers in pain management?

Dr. Wallace: One unique about our training program is all of our fellows get a lot of exposure to medical cannabis. They always ask, ‘How can I use it,’ and I tell them, ‘You have to be realistic. It’s going to vary depending on what state you’re in, what part of the country you’re in, and even where it’s legal, you may not know the source or quality of the cannabis… .’ I tell them to look at the state regulations where they practice and to visit the state medical board sites for guidelines.

I do feel cannabis should be used before opioids and I do agree with you that our fellows are being pushed too much on the interventional side. We’re pain medicine physicians – we do care across the spectrum from non-invasive psychological therapies to very highly invasive therapies. As for where cannabis fits in – it’s somewhere in the middle of all that and it should be integrated into the multimodal, multidisciplinary model.

Mark Wallace, MD

Mark Wallace, MD, received his MD from Creighton University School of Medicine in 1987.  He completed an Anesthesiology residency at the University of Maryland followed by an NIH training grant fellowship and a Clinical Pain Fellowship in the Department of Anesthesiology, University of California San Diego (UCSD).  He is currently a Professor of Anesthesiology and the Chair, Division of Pain Medicine in the Department of Anesthesiology, UCSD School of Medicine and Director, Division of Clinical Research in the UCSD Clinical and Translational Institute (CTRI).

Dr. Wallace is the recipient of numerous awards including the Award for Excellence in Clinical Care, American Pain Society Center of Excellence Award, and the Leonard Tow Humanism in Medicine Award.  Dr. Wallace has authored and co-authored more than 300 articles, abstracts, books, and book chapters concerning pain research and management, including research on the use of medical cannabis to treat pain.  He has also authored numerous book chapters and review articles on medical cannabis to treat chronic pain.  He has extensive experience with all phases of clinical trials.

Chronic Pain and the Short-term Effects of Medical Cannabis

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