In 2015, at a 60-bed hospital in Grand Junction, Colorado, the nurses began to notice something odd.

When patients came in for routine medical procedures, like endoscopies or colonoscopies, some of them needed a lot more of the drugs that kept them sedated, like propofol, fentanyl, and midazolam. Those same people also seemed to be the ones who reported that they used cannabis frequently.

Doctors always ask before invasive procedures and surgeries about illicit drug use. But when cannabis became legal in Colorado in 2012, the nurses realized that it was no longer “illicit” and they started to inquire if, and how often, patients used weed.

That’s when they started to see that people who used cannabis chronically were being given much higher doses of sedatives than non-users. “It seemed like even if people were alcohol users or on other chronic medicines, that weed seemed to have more of an effect than any of those other drugs,” Mark Twardowski, a doctor of osteopathic medicine at Community Hospital-Grand Junction, says.

After about a year of swapping word-of-mouth stories, Twardowski and his colleagues decided to research the phenomenon more closely. The resulting study was published today in the Journal of the American Osteopathic Association. “We didn't expect to see the numbers that we saw,” Twardowski tells me.

They looked back at the medical records of a small group—25 people—who had procedures with Twardowski like colonoscopies and endoscopies, who also said that they used cannabis on a daily or weekly basis—both by smoking and eating edibles. They compared them to 225 people who had the same kinds of procedures, but who did not report using cannabis.

They found that the people who said they used cannabis needed 14 percent more fentanyl, 19.6 percent more midazolam, and 220.5 percent more propofol during their procedures—higher doses of all three of the commonly used sedative drugs.

Effects of Cannabis Use on Sedation Requirements for Endoscopic Procedures. Twardowski et al. 2019. The Journal of the American Osteopathic Association

Cannabis’s active ingredient, THC, attaches to cannabinoid receptors in the brain, but those receptors are different than the ones sedative drugs interact with. This led to a befuddling question: why would cannabis use lead to such an increased need for those other drugs?

Twardowski says that it’s possible the cannabinoid receptors downregulate, or suppress the activity of other receptors in the brain that anesthetic drugs interact with. But honestly, he tells me, that’s just a guess. “I don't have any good scientific basis for that,” he says. “The basic science really needs to be done.”

What worries him, outside of their findings, is that no one seems to have done that basic science research—a problem he attributes to cannabis still being a Schedule I drug. When he and his co-authors surveyed existing research, they expected their study to be added to a pile of already completed work. Instead, it’s one of the first in the country.

“We did these huge literature searches and found nothing,” he says. “Really? We're going to do the first study on this and it's just us? That was cool to be the first, but it's pretty scary too.”

Kevin Hill, an addiction psychiatrist at Beth Israel Deaconess Medical Center and a clinical expert on cannabis hadn’t heard of this effect but agrees that more research is crucially needed—especially as more states move towards legalization. Weed is currently legal for recreational use in 10 states, and 33 states have legalized medical cannabis. And cannabis use has increased 43 percent between 2007 and 2015.

“This preliminary report highlights the kind of research that we desperately need as states race forward with medical and recreational cannabis policies,” Hill says. “Physicians of all types must try to understand the impact of regular cannabis use upon their specialties.”

But just because no one has studied it officially doesn’t mean other clinicians aren’t aware of the impact cannabis has on anesthesia. Ethan Bryson, a professor of anesthesia and psychiatry at the Icahn School of Medicine at Mount Sinai, who was not involved in the study, says that he is well aware of this, and has been for awhile. “Anybody who has practiced anesthesia for any amount of time recognizes that this is definitely something that affects their job,” he tells me.

When he plans an anesthetic, he says that he has to consider a person’s drug use, and its effect on their tolerance levels. This goes not just for weed, but for alcohol and other drugs as well.

Bryson started observing the effects of cannabis and anesthesia around 12 years ago, and noticing that his patients chronically using marijuana and other drugs had a much higher tolerance. He tells me about a recent healthy patient, who was in his late 40s, who came in for a minor procedure. Normally, Bryson would have given him one dose of anesthesia. But after interviewing him, he found out that he smoked weed on a regular basis, had smoked the day before, drank alcohol daily, and had used cocaine two weeks prior.

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“This is somebody who is perfectly healthy otherwise, but because they're chronically exposed to these drugs, my anesthetic plan changed from IV sedation to general anesthesia,” Bryson says. “I'm not going to be able to keep him still without general anesthesia.”

His theory is that the chronic exposure to cannabis changes something about metabolism—that the speed at which the body eliminates drugs from the body is ramped up and increases tolerance. That might help to explain why cannabis use would affect with anesthetic drugs that interact with different parts of the brain and different receptors, he says.

Twardowski thinks that while that may be a factor, he believes it’s more than just metabolism. He can see the need for higher doses from the very beginning of a procedure, when he’s trying to put people under. “It seems to take longer to even accomplish that,” he says. “If it was wearing off quicker during the case then that may be part of it, but these folks are talking to me when I've given doses that would put you and me out.”

A small number of case studies have had similar findings: A study from Australia in 2009 found that more propofol was needed in people who used cannabis compared to those who didn’t when inserting a laryngeal mask, which keeps a person’s airway open during surgery.

In a case study from 2015, a 37-year-old man in Germany had shoulder surgery, and told his doctors that he smoked weed every week. After being given a slew of anesthetic drugs, he said that he was dizzy, but “the patient was still speaking with the anesthesia staff,” the authors of the paper wrote. After two more doses of propofol “the patient did not show any reduction of his conscious state.” Confused, the medical team ended up checking if his IV was attached correctly. It was, and eventually they were able to put him under with more medication, and his surgery went forward with no complications.

In a 2002 correspondence letter in the journal, Iris Symons from Barnet General Hospital in England recounted the case of a 34-year-old man who she had to give propofol, midazolam, Ketorolac, and local anesthetic. “Despite the high concentration of volatile and intravenous anesthetic, the blood pressure and pulse rate remained high at the pre‐induction levels,” she wrote. When the man woke up later, he asked Symons, “How was it?”

“I said; ‘Actually you were very difficult to anesthetize,’” Symons wrote. He replied: ‘Well if I tell you something it might incriminate me.’ I said: ‘You may tell me anything in confidence.’ He replied: ‘I smoked cannabis last night.’

In these case studies and according to Bryson and Twardowski, it appears that if someone needs these high levels of anesthetic, they can’t tell afterwards. “Even though we've given them a high dose—and sometimes it's ridiculously high based on the patient's size—they're waking up just like everybody else a half hour later,” Twardowski says.

But there could still be potential harms: it is known that taking high amounts of these drugs can lead to breathing and blood flow problems, so the potential adverse effects need to be studied more closely. Twardowski says that since he uses conscious sedation, where a person isn’t assisted with their breathing while they’re unconscious, giving high doses of drugs like propofol is concerning– that’s what’s thought to have killed Michael Jackson after all.

Twardowski and his colleagues are now starting a second phase of their study. They’re going to look at all of anesthesia and sedation at their hospital to try and see where the effects of cannabis have the most effect. He’s hoping they’ll find an anesthetic that cannabis doesn’t increase the tolerance for.

Twardowski tells me they’ll also be looking into another troubling observation from the nurses: that people who use cannabis chronically have a harder time controlling their pain after surgery, which could mean higher amounts of painkillers prescribed. “Everybody's a little concerned about sending you home with way more pain medicine,” he says.

For now, Bryson and Twardowski say that if you can, try to abstain from smoking or eating edibles a month before your procedure— THC sticks around in the body for about 25 days after using.

And the best move is to be extremely upfront with your anesthesiologist about drugs and alcohol, whether you’re getting major surgery done or just getting your wisdom teeth out or an endoscopy. There’s no real point in lying, because your ability to be sedated will likely reveal your tolerance levels, and it’s best that your anesthesiologist know beforehand if you’ll need higher doses.

“The last thing you want to do is get your case canceled because the anesthesiologist is getting into doses of medicines that they're concerned with and don't feel comfortable with,” Twardowski says. “You have to be honest about that."