I’m skeptical about … cannabis (part 1).

“Marijuana, the Devil’s flower; if you use it, you’ll be enslaved.

Marijuana, it brings you sorrow; and may send you to your grave.”

                                                                                                  —Mr. Sunshine and his Guitar Pickers, 1951.

Attitudes have changed a lot in the decades since those lyrics first echoed across the AM radio dial. According to a 2018 Pew Research Center poll, 62% of Americans support marijuana legalization; among Millennials that number jumps to 74%. This marks a huge increase in acceptance. In 1988, fewer than one-quarter of Americans favored legalization. Marijuana has gone from underground to main street, and nobody reflects that shift better than lifelong conservative and former Speaker of the House, John Boehner, whose opinion regarding marijuana legalization has gone from “unalterably opposed” to full speed ahead. Of course, some things haven’t changed, and Boehner’s about-face likely has little to do with marijuana’s medicinal effects and everything to do with the $20 million he stands to gain should Canopy Growth move ahead with the purchase of Acreage Holdings, a cannabis company where Boehner sits on the board in addition to owning 625,000 shares. The pending sale to Canopy, the world’s largest cannabis corporation based out of Ontario, hinges on a softening up of marijuana laws here in the States, and who better than Boehner to serve as pitch man? Although denying that he’s ever tried it himself, Boehner professes that his “thinking on cannabis has evolved.” Pigs at the trough. Same as it ever was.

The public’s growing acceptance of cannabis required a massive PR campaign, re-framing it from that of a dirty, addictive weed to an easily-grown, flowering plant offering a safe, mellow high while also possessing a host of health benefits. This change of heart certainly didn’t happen because a bunch of Deadheads, skateboard-stoners, and High Times readers finally convinced their state legislatures that dope was okay; it happened via the efforts of deep-pocket, establishment players. It happened because people like John Boehner woke up to the profit potential of marijuana.

 

 

The only real surprise is what took so long? In this country we have legalized gambling, legalized cigarettes, legalized alcohol, and legalized opioids—why not weed? In 1973, Oregon became the first state to decriminalize marijuana possession. It then took another 23 years before California legalized it for medicinal use, and 16 more before the states of Washington and Colorado finally legalized it for recreational use. The pace of legalization has followed a trajectory similar to Hemingway’s description of how bankruptcy proceeds in The Sun Also Rises: “Gradually, and then suddenly.” In the last few years, 33 states and the District of Columbia have enacted some form of legalized cannabis. Federal laws have been slow to follow. It remains a federal crime for physicians to prescribe marijuana, and illegal for people to transport it across state lines. Recognizing the conundrum, Congress passed the Rohrabacher-Farr Amendment in 2014 protecting state-legal medicinal prescribing from federal enforcement. Along the same lines, the Cole memorandum issued in 2013 urged federal prosecutors to refrain form targeting state-legal marijuana enterprises (a memo later rescinded by then-acting, Attorney General, Jeff Sessions in 2018).

 

 

Marijuana remains a schedule 1 drug under the Controlled Substance Act of 1970, meaning that, in the eyes of the Fed, marijuana carries a ”high potential for abuse,” has “no currently accepted medical use,” and is a drug where “there is a lack of accepted safety for use” even under medical supervision. Other schedule 1 drugs include heroin, LSD, MDMA (i.e. ecstasy), mescaline (peyote), and psilocybin (mushrooms). Thus far, attempts to reclassify marijuana as a schedule 2 drug, (those with high abuse potential but medically accepted indications, e.g. methamphetamine, methadone, oxycodone, and fentanyl etc.), have failed. It’s interesting to note that the primary intoxicating ingredient found in marijuana is THC (tetrahydrocannabinol), and that the FDA has approved two oral, synthetic forms of it [dronabinol (Marinol, Sundros) and nabilone (Cesamet)]. Both are classified as schedule 3 drugs (those with accepted medical uses possessing a low to moderate potential for abuse). How is it that marijuana containing less than 10% THC is a schedule 1 drug, but the concentrated, purified, pill form of the stuff is classified as a schedule 3 drug? Do you think it might have something to do with the lobbying power of Big Pharma and hired cronies like Boehner? Hmm, I wonder …

 

(JAMA 2015; 313(24); 2474.)

 

There also remains confusion regarding the differences between cannabis, marijuana, and hemp. Cannabis refers to any plant within the Cannabis genus, a subset of the larger Cannabaceae family. Marijuana and hemp are both strains of Cannabis sativa, a member of the Cannabis genus. The legal difference has to do with the THC concentration of the plants. Under H.R. 5485 – Hemp Farm Act of 2018, hemp is legal in all 50 states, provided the dry-weight THC content of the parent plant is 0.3% or less. Plants with higher concentrations of THC are referred to as marijuana. This legal definition raises another interesting conundrum: the latest fad to hit the market—CBD oil—can be derived equally well from both hemp and marijuana, but only hemp-derived CBD oil is legal for sale in the US under federal law. The exact same CBD oil, if derived from marijuana, is illegal. It’s a mess.

 

(https://medium.com/cbd-origin)

Granted, the laws are contradictory and confusing, in part, because marijuana is such a complex plant containing more than 100 different cannabinoids, the most potent of which is THC. Today’s marijuana isn’t your dad’s crappy stems and seeds either; the THC concentration of today’s weed runs between 10-12%, or roughly 3-times the potency of marijuana from 1995. Humans have two primary cannabinoid receptors, CB1 and CB2, with the highest concentration of CB1 receptors located within the brain’s hippocampus (memory), amygdala (emotion), hypothalamus (appetite), limbic forebrain (motivation), cortex (cognition), and cerebellum (coordination), providing a biological basis for the drug’s observed effects. There are CB2 receptors in the spleen, white blood cells, and to a lesser extent in the brain and GI tract. Cannabinoids exert their physiologic effects through interactions with these receptors. Note that the receptors are part of the body’s independent endocannabinoid system, responding equally well to the inhaled or ingested cannabinoids found in marijuana as they do to our own naturally produced ones. It’s true—our body produces cannabinoids capable of binding to receptors, just as it is capable of producing endorphins and other chemicals that exert physiologic effects.

 

THC Potency of Marijuana Over Time (NEJM 2014; 370 (23): 2219).

 

When inhaled from a joint, marijuana’s effects peak within 30 minutes and last for 1 to 3.5 hours. Similar effects are seen with edibles although the onset is slower (0.5 to 2 hours) and the duration longer (5 to 8 hours). Colorado has defined a legal “dose” of THC as 5 mg, while California and Washington define it at 10 mg. A typical joint weighing in at 0.06 grams, with a THC concentration of 8%, delivers a dose of 8.25 mg., more than enough to provide an adequate “buzz.” The clinical features are well known to most: increased appetite (“munchies”), altered perception, dry mouth (“cottonmouth”), diminished short-term memory, and impaired motor skills. At higher levels paranoia, agitation, and hallucinations may occur. Death due to direct THC toxicity likely doesn’t exist (but that doesn’t mean the drug is “safe”). After alcohol, cannabis is the most popular mind-altering drug in America with 22.2 million users, followed distantly by prescription opioids (3.8 million), tranquilizers and cocaine (1.9 million apiece), stimulants (1.7 million), hallucinogens (1.2 million) and heroin (0.3 million). People who smoke seem to like it—a lot. There are currently 7.8 million daily users, up from 1 in 9 cannabis users in 1992 to 1 in 3 users today. Not surprisingly, in states where cannabis is legal, use is higher. Although there has been a good bit of press about medical marijuana, almost 90% of use remains recreational. Despite the $111 million spent on NIH-funded cannabis research in 2015, it’s not really about the medicinal effects.

 

DSM-5 Defining Criteria for Cannabis Intoxication.

 

In 2017, the National Academies of Sciences, Engineering, and Medicine (formerly the Institute of Medicine) released a massive, 487-page tome summarizing the scientific evidence on cannabis. Overall, the results were sobering, and this likely explains why the report was largely ignored. But it shouldn’t have been. The committee, comprised of 16 multidisciplinary experts, reviewed more than 24,000 medical abstracts and included 10,700 of them in its report. Evidence across a variety of cannabis-related topics was graded as conclusive, substantial, modest, limited, or insufficient. As I plodded through the report, it became increasingly clear that the media has oversold the benefits while deemphasizing the dangers.

Modest therapeutic effects were found for only 3 indications: chemotherapy induced nausea, MS (multiple sclerosis) spasticity, and chronic pain. Of these, chronic pain is, by far, the most common indication for use, but there are problems with the studies. Most were performed outside the US employing synthetic or purified THC delivered in pill or spray form, whereas most of the cannabis used to treat pain here in the States comes in the form of joints or edibles. A 2017 meta-analysis on cannabis for chronic pain found low-level evidence that cannabis improves outcomes relative to traditional management options only for neuropathy pain, but at the expense of a significant increase in psychiatric and cognitive side-effects. Another systematic review looking at neurological-specific indications for cannabis found that cannabinoids were effective in treating chronic pain and MS-related spasticity, but ineffective for Parkinson’s and tremor, and inconclusive when treating epilepsy, Huntington’s, and Tourette’s.

One of the arguments frequently put forth by cannabis proponents is that marijuana is safer than opioids, and that if we could just get everyone with chronic pain smoking pot rather than popping pills the world would be a better place. Maybe so, but the data doesn’t support this notion. A 2018 cohort study in patients with chronic, non-cancer pain found worse outcomes when cannabis was added to opioids for pain control, concluding: “We found no evidence that cannabis improved patient outcomes; those who used cannabis had greater pain and lower self-efficacy in managing pain. Furthermore, we found no evidence that cannabis use reduced pain interference or exerted an opioid-sparing effect.” In other words, cannabis didn’t relieve chronic pain very well and didn’t result in patients taking fewer opioids. Another study reviewing opioid deaths in Colorado over a 15-year period from 2000-2015 reported a slight drop in opioid deaths after marijuana was legalized for recreational use, providing indirect evidence that people might avoid opioids if alternative drugs for pain (and a safer high) were available. Unfortunately, those numbers did an abrupt about-face in the years following the study, with the highest number of opioid deaths ever recorded in Colorado in 2018. Using marijuana doesn’t lower the risk of subsequent opioid use—in fact, it does the opposite, increasing both prescription and non-prescription opioid use by a factor of more than 2-fold.

As regards to treating chemotherapy-related nausea and vomiting, cannabis works well, and probably slightly better than traditional anti-nausea drugs but, again, at the expense of more side-effects (after all, not everybody likes feeling high). A 2015 Cochrane review on the topic concluded that there is no evidence to support cannabinoids (marijuana and oral THC drugs) as first-line treatments for chemotherapy-induced vomiting, but they remain a useful adjunct in patients who fail traditional anti-nausea drugs.

 

Summary of Cannabis Therapeutic Effects for Various Medical Conditions (Nat’l Academy of Sciences, Engineering, and Medicine, 2017, “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.”)

 

Paradoxically, marijuana can cause severe nausea and vomiting in a small subset of patients who smoke frequently. Patients with cannabinoid hyperemesis syndrome (yes, it’s a real thing) frequently come to the ER with severe abdominal pain and intractable vomiting. Among stoners the word is out that a hot shower provides relief, and there is a scientific basis for this, as hot water activates specific receptors interacting within the endocannabinoid system. Capsaicin (derived from hot peppers) applied topically in cream form also seems to help. Standard anti-nausea drugs are largely ineffective. The only cure is a complete cessation of marijuana use. When I see patients with the disorder, they rarely believe that marijuana is the cause, and since they also typically distrust mainstream medical literature, I point them instead to a High Times article on the syndrome (because who doesn’t trust that paragon of impartial, scientific literature?).

 

High Times article on Cannabinoid Hyperemesis Syndrome.

 

Before the days of effective antiretroviral drugs for HIV, AIDS-related wasting syndrome was a real concern and marijuana helped, but with better HIV treatment this indication has largely gone by the wayside. What about cancer-related anorexia and weight loss? Here, marijuana doesn’t seem to work very well. In one trial, THC worked no better than a placebo in treating cancer-related anorexia, nausea, and mood disorders, while in another, marijuana worked less well to promote appetite and weight gain in cancer patients than traditional therapy (Megace).

Marijuana has been touted to help a host of other conditions, but the data is almost entirely anecdotal. Randomized controlled trials are few and far between, and most have failed to demonstrate benefit over currently existing treatments. Irritable bowel syndrome, ALS, dementia, Parkinson’s, depression, and glaucoma, are examples of conditions where trials have not shown a consistent benefit with cannabinoids.

The data for PTSD, traumatic brain injury, epilepsy, addiction, and sleep disorders is equivocal and, while there are likely selected patients who might benefit, the trials have been small, mostly unblinded, and non-placebo controlled. The trials for epilepsy are especially noteworthy for having failed to account for the waxing-waning nature of the disease. The majority of patients with epilepsy have a cyclical pattern to their seizure frequency. If a cannabis product is started at the peak of a cycle that subsequently follows its natural decline (i.e. regression to the mean), patients will falsely attribute that decline to cannabis. Without placebo-controlled trials, the evidence is, at best, speculative. Solid data—either for or against—cannabinoid use for the above conditions simply doesn’t exist.

 

(JAMA 2015; 313(24): 2474.)

 

Marijuana has long been touted as a “mellow” drug, so it follows that it should reduce anxiety, and hopefully do so with less abuse potential than traditional benzodiazepine drugs like Valium, Xanax, and Ativan. Unfortunately, the National Academy of Sciences report was unable to find “any good quality primary literature that reported on medical cannabis as an effective treatment for the improvement of anxiety symptoms.” This shouldn’t be taken to mean that cannabis doesn’t relieve anxiety, only that its effects haven’t been scientifically documented. While one trial reported that cannabidiol improved anxiety (as assessed by a public speaking test) in patients with social anxiety disorder, several others have found cannabis use to be an independent predictor for the development of the disorder. Nonetheless, the majority of users clearly perceive that the drug works, as anxiety relief remains the most common reason (after pain relief) cited by people using the drug medicinally. It’s also clear, however, that at high doses, cannabis can cause anxiety and paranoia. Furthermore, the data suggests that long-term daily use likely worsens anxiety symptoms. Perception is reality—except when it isn’t.

 

Bottom Line: Cannabis has few well-defined indications for medical use. It remains primarily a drug of recreation. Benefits have been over-stated, harms under-emphasized.

 

Next up: Cannabis: The evidence regarding harm.

 

 

Disclosure: Despite my skepticism regarding marijuana legalization, I acknowledge owning stock in several cannabis ventures including Canopy Growth, Aurora Cannabis, CannTrust Holdings, Alternative Harvest ETF, Khiron Life Sciences, and Innovative Industrial Properties.

References:

  1. Elizabeth Williamson, “John Boehner: From Speaker of the House to Cannabis Pitchman,” NY Times, April 3, 2019.
  2. National Academies of Sciences, Engineering, and Medicine, “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research (2017),” Washington DC: The National Academies Press, 2017.
  3. World Health Organization, “The Health and Social Effects of Nonmedical Cannabis Use,” Geneva, Switzerland: WHO Press, World Health Organization, 2016.
  4. Shannon Nugent et al., “The Effects of Cannabis Among Adults with Chronic Pain and an Overview of General Harms: A Systematic Review,” Ann Int Med 2017; 167: 319-31.
  5. Mark Olfson et al., “Cannabis Use and Risk of Prescription Opioid Use Disorder in the United States,” Am J Psych 2018; 175:47-53.
  6. Barbara Koppel et al., “Systematic Review: Efficacy and Safety of Medical Marijuana in Selected Neurologic Disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology,” Neurology 2014; 82: 1556-63.
  7. Gabrielle Campbell et al., “Effect of Cannabis Use in People with Chronic Non-Cancer Pain Prescribed Opioids: Findings From a 4-year Prospective Cohort Study,” Lancet Pub Health 2018; 3: e341-50.
  8. Melvin Livingston et al., “Recreational Cannabis Legalization and Opioid-Related Deaths in Colorado, 2000–2015,” Am J Pub Health 2017; 107: 1827-29.
  9. Lesley Smith et al., “Cannabinoids for Nausea and Vomiting in Adults with Cancer Receiving Chemotherapy,” Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD009464. DOI: 10.1002/14651858.CD009464.pub2.
  10. Jeff Lapoint et al., “Cannabinoid Hyperemesis Syndrome: Public Health Implications and a Novel Model Treatment Guideline,” West J Em Med 2017; 19 (2): 380-86.
  11. Sirius J, “What is Cannabinoid Hyperemesis Syndrome?” High Times, Dec. 22, 2014.
  12. Karina Kedzior and Lisa Laebar, “A Positive Association Between Anxiety Disorders and Cannabis Use or Cannabis Use Disorders in the General Population: A Meta-Analysis of 31 Studies,” BMC Psychiatry 2014; 14: 136.
  13. Penny Whiting et al., “Cannabinoids for Medical Use: A Systematic Review and Meta-Analysis,” JAMA 2015; 313(24): 2456-73.

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