More and more data, both from real world analyses and clinical trials, are shedding light on the effective uses of cannabis, as well as the contraindications for its use in patients.
Like opioids, cannabis has a very long history of use dating back thousands of years, explained Leah Sera, PharmD, MA, BCPS, during her presentation at the APhA 2023 Annual Meeting & Exposition. However, cannabis wasn't introduced to Western medicine until the 19th century by the Irish physician Sir William Brooke O'Shaughnessy, MD, FRS, while he was working in India. After O'Shaughnessy brought cannabis to Western medicine in the 19th century, it was then included in the US Pharmacopoeia (USP) in 1851.
However, in the early decades of the 20th century, concern about recreational cannabis use obscured the medical and industrial uses, and cannabis was essentially prohibited in 1937 and then removed from the USP in 1942. Then in 1964, tetrahydrocannabinol (THC), the psychoactive phytochemical in cannabis, was isolated, and a subsequent search for its receptor led to the identification of what became known as the CB1 receptor, which is the first cannabinoid receptor identified in 1990. In 1970, in between the isolation of THC and the discovery of the CB1 receptor, cannabis was classified as a Schedule 1 drug by the DEA, which is a classification that identifies cannabis as having a high potential for abuse with no accepted medical use.
In 1986, California became the first state to legalize medical cannabis and, since that time, there has been a snowball effect of decriminalization or legalization of cannabis use over the past 25 years, according to Sera. However, cannabis remains federally classified as a Schedule 1 drug.
Cannabis, which is the scientific name of the plant, has classic varieties that include Cannabis sativa and Cannabis indica. At one point, there were certain morphological characteristics that distinguished these 2 varieties, according to Sera. Today, there are still some claims that sativa is stimulating and energizing, and indica is relaxing and calming. However, over the past several decades there has been so much crossbreeding that nearly every kind of cannabis grown today is some form of a hybrid, rendering these classifications irrelevant to today's cannabis.
Further, “marijuana” is a term for cannabis that originated in Mexico and was popularized in the United States in the early 20th century as a way to distance cannabis from its medicinal and industrial uses and create negative associations. Introducing this term was intended to create public support for anti-cannabis legislation because there was also a lot of simultaneous concern about large scale immigration from Mexico.
Additionally, there are cannabinoids, which are any of the several molecules that interact with cannabinoid receptors, and there are endocannabinoids, which are endogenous cannabinoids that we make ourselves. There are also more than 100 phytocannabinoids known today, but the main cannabinoids of interest are Delta-9 THC and cannabidiol (CBD).
“As an aside, I think it's interesting to consider why a plant would make compounds that affect human or animal physiology because the cannabinoids are not critical to the survival of the cannabis plant. Since the plant doesn't need them to survive, it's got to be made for defense,” Sera said. “So maybe an animal falls asleep and stops eating it or the cannabis plant gets propagated because maybe an animal likes it and spreads the seeds. We really don't know why this occurs. But I think it's something interesting to consider.”
THC is a partial agonist at the cannabinoid receptors CB1 and CB2, and it has a very high binding affinity, Sera explained. THC is by far the most studied phytocannabinoid in terms of both the therapeutic value and the potential harm of cannabis. Further, it is a psychoactive and it may have other anti-inflammatory, neuro-protective, antiemetic, or analgesic effects.
CBD, on the other hand, may interact indirectly with the CB1 and CB2 receptors, but with a much lower binding affinity than THC. However, CBD also interacts with other receptors, such as dopamine receptors, serotonin receptors, and it may interact with multiple other receptors as well. Notably, THC really doesn't have this same breadth of interaction and only interacts by CB1 and CB2 receptors.
“Another interesting point is that there's actually only a teeny tiny amount of THC, CBD, or these other cannabinoids in the plant itself. So where are we getting all of this THC and CBD? The answer is it comes from us; it comes from what we do to the plant,” Sera said.
THC, CBD, and other cannabinoids exist in the plant as their respective acids, Sera explained. THCA is what exists in the plant THC, but THCA is not psychoactive. However, when THCA is heated, it undergoes decarboxylation, and as it falls off, we have THC, which is a psychoactive compound. This same process occurs with CBD, CBC, and CBG.
Additionally, Sera also noted that patients who are pregnant or breastfeeding should not use cannabis. According to Sera, there's preclinical evidence that suggests exposure to cannabinoids is associated with short- and long-term harms to developing offspring in utero.
“Evidence from human observational studies is complex,” Sera said. “There are a lot of compounding factors in the studies that may account for associations, but heavy cannabis use during pregnancy may be associated with low birth weight, and cannabinoids are detectable in breast milk for up to 6 days.”
Because the effects of cannabis on pregnant and breastfeeding patients is not entirely understood yet, Sera explained that it is recommended that pregnant and breastfeeding patients not use cannabis until there are further data. Additional contraindications are for patients younger than 25 years of age, as THC in large doses can have negative effects and increase the risk of cannabis use disorder in this population.
Further, patients with cannabis use disorder should not use THC products and patients with a history of substance use disorder should not use THC products. However, Sera noted that if cannabinoids are indicated, then these patients should be carefully screened for problematic use and with more stringent follow up.
Some other precautions to consider are for patients with severe liver disease. Since cannabinoids are metabolized in the liver, these patients have a higher risk of adverse effects. Additionally, patients who are immunocompromised may have a higher infection risk when exposed to contaminated cannabis, and cannabis can be contaminated because it's a plant and it's often grown outside, Sera explained.
“Many patients with immunocompromising conditions take a lot of medications that may interact with cannabinoids,” Sera said. “Older patients may also have physiological changes that increase the risk or magnitude of adverse effects, but there are limited studies of populations with comorbidities and those patients are more likely to use multiple medications increasing the risk of drug interactions.”
For patients in whom there is an indication for cannabis or in whom cannabis is a safe therapeutic option, there's very little data to guide the selection of a specific strain of cannabis. Further, there are lots of choices.
“But the names mean very little with regard to the components of the actual cannabis product,” Sera said.
There was an analysis of cannabis samples in Canada that found that 35% of comparisons were more genetically similar to strains with a different name than 2 strains with the same name. For example, OG Kush in California doesn't have the same components as OG Kush in Arizona. For this reason, instead of focusing on the names, providers should look at the relative concentrations of cannabinoids, the chemical makeup of the cannabis product, and that is the chemovar, which is the plant's chemotaxonomy makeup.
“As an aside, I know that there are a lot of clinicians who think that the convention of naming strains like this is a barrier to cannabis being recognized as a medicine, because many providers are going to be hesitant to recommend something that's called granddaddy purple, but I've talked to other providers who just kind of shrug it off and laugh about it with the patient. So it really depends on the kind of patient and the kind of provider that you have, but this is what patients are going to see walking into a dispensary.”
Sera L. The Blunt Basics about Cannabis and Cannabinoids. Presented at: APhA 2023 Annual Meeting & Exposition in Phoenix, AZ; March 26, 2023.