2. What can we learn about dosing from FDA-approved cannabinoids?
This is Part 2 in a 5-part series on Dosing & Administration: Dosing and administration of cannabinoids is a complex process. More complex than you may think.
(You can learn more about factors that influence dosing and administration of cannabinoids here)
When considering a starting dose, it is tempting to resort to units of measurement that are non-scientific: “one gummy”, “an eighth of a chocolate bar”, or “4 to 5 hits from a joint”, for example. This informal approach is reinforced by how we measure other psychotropic substances which are popular in our culture (e.g. Nicotine, caffeine, ethanol).
For contrast, there are roughly 10 grams of ethanol in a glass of wine, a beer or a cocktail. Ethanol is the “active ingredient” in alcoholic beverages. If you were asked, “How much alcohol did you drink last night?”, your answer would likely be measured in “Drinks”, “Glasses of wine” or “Beers”, as opposed to grams of ethanol. The same is true for nicotine (e.g. Cigarettes), caffeine (e.g. Cups of coffee) and other substances.
If dosing in scientific units doesn’t matter for alcohol, caffeine or nicotine, then why does it matter for cannabinoids?
Well, frankly, it may NOT matter. Human beings have been using Cannabis safely for thousands of years without any knowledge of a specific dose in scientific units. “One bong hit” has worked well for many people for many years.
Cannabis as medicine
When a specific clinical outcome is desired, however, understanding the dose in scientific units is important. For example, what if 1/10th (10%) of a 25mg bong hit was the therapeutic dose? What if taking 2.5mg, instead of 25mg, was enough to adequately manage symptoms? In that scenario, the other 90% would be unnecessary. It would be wasted “medicine” with a corresponding financial penalty and risk of adverse effects. The vast majority of adverse effects from drugs, including Cannabis, are dose-dependent. These unwanted, negative effects might be avoided by taking a lower dose. This is just one example.
(You can learn more about dose-dependent adverse effect of cannabinoids here)
In medicine, understanding the effects of a given dose of a drug begins with safety and tolerability. Specifically, it begins with toxicology studies in animals. Once the safety profile of a certain drug is characterized in laboratory animals, it is introduced in minuscule doses to small groups of healthy human volunteers in controlled settings. These are known as Phase I studies. This process winds thru various phases of experimental designs until it reaches clinical efficacy, which is substantiated by Phase III studies. These are randomized, double-blinded, placebo-controlled studies. The final hurdle is typically a ruling by the U.S. Food and Drug Administration (FDA).
The FDA approves drugs for certain indications. When a drug is used for a purpose other than its approved use, it is considered off-label. Off-label use is not illegal, or unethical, assuming the patient has been informed of the potential risks.
When doctors prescribe a new drug to their patients, they often consult a medical reference in order to determine the appropriate dose. There are many medical resources which contain this information.
Wouldn’t it be nice if we could look up the appropriate dose of cannabinoids in one of these resources?
Well, we can…
FDA-approved cannabinoids
Currently, there are two (Dronabinol and Nabilone) FDA-approved synthetic, or semi-synthetic, analogs of tetrahydrocannabinol (THC), the primary intoxicating compound in marijuana (drug).
Dronabinol was first approved in 1985 to treat nausea and vomiting induced by cancer chemotherapy. It was later approved to treat anorexia and cachexia in patients with HIV and AIDS. It is used off-label to treat obstructive sleep apnea and chronic pain. Clinical trials have explored off-label use of dronabinol as an analgesic (i.e. Pain reliever) in patients taking opioids for chronic pain. ![endif]--
Dronabinol is a schedule III controlled substance, which means the DEA has concluded it has an accepted medical use, but a potential for abuse.
Nabilone was approved in 2006 for the same indication as dronabinol’s initial approval, chemotherapy-induced nausea and vomiting. Nabilone is a schedule II controlled substance. This means the DEA has concluded that nabilone has a higher potential for abuse than dronabinol. This is due to nabilone’s activity at cannabinoid receptors (CBR). Nabilone is used off-label to treat fibromyalgia.
Both of these drugs are isolated compounds and manufactured according to pharmaceutical grade Good Manufacturing Practices (GMPs). Isolated means that a capsule of dronabinol contains dronabinol and very little else. This is in contrast to whole plant extracts of botanical products and drugs which may contain a variety of natural compounds, in addition to the “active ingredient”.
There are other cannabinoid drugs in the FDA drug approval pipeline.
Epidiolex is isolated CBD extracted from marijuana. This drug is manufactured by a UK-based pharmaceutical company called GW Pharmaceuticals. Their US-based subsidiary is called Greenwich Biosciences and their New Drug Application (NDA) for Epidiolex was submitted to the FDA in October of 2017. Epidiolex is being evaluated as a treatment for intractable seizure disorders in pediatric patients. Namely, Lennox-Gastaut syndrome (LGS) and Dravet syndrome. Most experts think this drug will be approved by the FDA in 2018.
Nabiximols, or Sativex, is also manufactured by GW Pharma. Sativex is THC and CBD extracted from marijuana in a 1:1 ratio with terpenes and other cannabinoids. Nabiximols is approved in over 30 countries to treat symptoms of multiple sclerosis (MS). GW Pharma declined to submit the NDA for nabiximols to the FDA because the drug did not meet the primary endpoint in its phase III clinical trials (i.e. A 30% reduction in pain among patients with intractable cancer pain).
In summary, there is actually some decent guidance for oral dosing of some cannabinoids for a broad range of medical conditions or symptoms, including:
1. Nausea and vomiting 2. Anorexia/Cachexia 3. Obstructive sleep apnea 4. Intractable seizure disorders 5. Multiple sclerosis 6. Neuropathic pain 7. Chronic pain
That’s not a bad start!
This information would be pretty useful if there were Cannabis products that could be administered orally and were available at licensed Cannabis dispensaries in States with medical and recreational Cannabis laws.
There are!
Caution is warranted Unfortunately, there are a few problems with simply substituting these products for the FDA-approved versions. First, many of them are “here today and gone tomorrow”. Secondly, virtually all of them are manufactured using manufacturing practices that would not be acceptable for a “drug”. Some do not contain what they claim to contain, and worse, they are sold in states that do not require adequate lab testing and labeling.2 Finally, guidance on dosing of many of these products is provided by individuals (e.g. Dispensary and product manufacturer sales reps) with no clinical education and training, and no experience managing patients. To be fair, many of these individuals know a lot more about Cannabis than doctors do! But, they are often practicing medicine without the proper training and experience and this can be dangerous.3
(You can learn more about factors that influence dosing and administration of cannabinoids here)
The dose-response relationship
Briefly, a dose-response curve describes the relationship between a given dose of a drug and its effects in the body. Ideally, there is a linear relationship between the dose and the response. The greater the dose, the greater the response. This is not always the case however. Most dose-response curves are not completely linear, they are often sigmoidal (i.e. S-shaped). This simply means that the relationship is roughly linear until it reaches a single plateau. At that point, incremental increases in the dose of the drug no longer result in an incremental change in the response.
(You can learn more about the dose-response relationship for cannabinoids here)
For example, in the study mentioned above, in which dronabinol was used as an adjunctive therapy in patients suffering from chronic pain and using opioids, 20mg of dronabinol (Semi-synthetic THC) provided no more pain relief than 10mg, yet those taking 20mg experienced more adverse effects. Where does the curve plateau? Finding the correct dose is not only about clinical efficacy, it is also about reducing the risk of adverse effects.
(You can learn more about dosing of cannabinoids for tolerability here)
There’s another issue. Studies in animals have demonstrated that the dose-response relationship for isolated cannabinoids is different than for cannabinoids administered as a whole plant extract.4
This means that while you may need 10mg of dronabinol to reduce chronic pain, you may need a different dose of THC in a whole plant extract. Whole plant extracts contain other plant compounds, like CBD, secondary cannabinoids, terpenes and flavonoids. In other words, taking 10mg of THC in a whole plant extract is not the same as taking 10mg of synthetic, isolated THC. Nor is it the same as taking 10mg of natural, isolated THC.
The bottom line
To some extent, we can use FDA-approved drugs to guide oral dosing of cannabinoids for a range of medical conditions. For the most part however, these compounds are synthetic analogs of the compounds found in nature. And, they are isolated, which means they are not administered with associated compounds that appear to modulate their biological activity. At best, these FDA-approved drugs are a starting point.
In health,
Despite the favorable safety profile, dosing and administration of cannabinoids is complicated. The process should be highly individualized and is best supervised by a trained health care professional. For more information, please consider booking a consultation (telephone or in-person) with Dr. Jamie Corroon, ND, MPH.
References
1. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The journal of pain : official journal of the American Pain Society. 2008;9(3):254-264.
2. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. Jama. 2017;318(17):1708-1709.
3. Haug NA, Kieschnick D, Sottile JE, Babson KA, Vandrey R, Bonn-Miller MO. Training and Practices of Cannabis Dispensary Staff. Cannabis and cannabinoid research. 2016;1(1):244-251.
4. Gallily R, Yekhtin Z, Hanus L. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by using Cannabis extract enriched in Cannabidiol. Pharmacology & Pharmacy,. 2015;6:75-85.
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