Cannabis can cause overdoses. Can these drugs reverse it?

The phrase "drug overdose" doesn't often conjure images of smoking too much weed, but it's true—you can overdose on cannabis, especially the more potent stuff. The distinction many stoners like to rightfully point out is such overdoses are very rarely, if ever, fatal. In terms of risk, it doesn't entirely make sense to compare marijuana to powerful opioids like fentanyl, but an overdose on THC, the drug in cannabis that gets people stoned, is still possible and still quite uncomfortable.

As cannabis becomes legal in more regions, it's important for the public to understand the risk of overdose in order to prevent harm, just like we do with other drugs like alcohol and prescription medications. People use marijuana for good reasons. There are medicinal benefits, but it also just feels good. Ingesting THC either through smoking, vaporizing or edibles can make people feel euphoric, relaxed, sleepy, giggly and otherwise intoxicated.

As cannabis becomes legal in more areas, some emergency rooms are seeing more visits related to THC overdose, especially in kids that accidentally eat cannabis edibles, who can sometimes eat so much they can become comatose. Taking too much THC can trigger rapid heart rate, dizziness, nausea, paranoia, anxiety and panic attacks. Very rarely are these effects life-threatening and generally wear off in a few hours. But in some cases, they can require a hospital visit, sometimes including an overnight stay.

Part of the reason for this increase in emergency room visits is relaxed laws around marijuana can make people feel more comfortable visiting hospitals in the first place. Not fearing arrest is a good motivator for seeking help. Regardless of the driving factors, cannabis overdose can be scary, but the standard protocol in such cases is to manage symptoms or prescribe a sedative like Xanax.

But what if there were a drug that could instantly pull someone out of a cannabis overdose? After all, such drugs exist for other intoxicants, including opioids. To wit: naloxone is a medication that can stop an opioid overdose in mere minutes, even reversing the effects of extremely potent painkillers like carfentanil, an opioid used to sedate elephants.

Several companies are working on just such a solution for THC, and they see their potential product as comparable to naloxone. If they can get their medications off the ground, it would give emergency room doctors additional tools to treat cannabis overdose.

But some experts warn that these overdose reversal drugs can also come with some serious side effects in their own right.

In fact, one of these companies, Opiant Pharmaceuticals, already markets naloxone under the brand name Narcan. But since late 2018, the California-based biotech has also been developing a cannabinoid called drinabant into a treatment for THC overdose but also cannabinoid hyperemesis syndrome, a mysterious condition in which marijuana users suddenly become violently ill. Given that naloxone is a proven, effective drug that has been used safely for decades, it makes sense a pharmaceutical company would see dollar signs in similar overdose situations. The U.K.-based biotech Indivior, which recently acquired Opiant for $145 million, did not respond to Salon's request for comment.

Another company on this pathway is Austin, Texas–based Anebulo Pharmaceuticals, a biotech startup founded by Dr. Joseph Lawler just two years ago around a patent of a drug very similar to drinabant. For now, it has the obfuscated name ANEB-001, but it's in the same category of drugs called cannabinoid receptor antagonists.

"Ever eaten too many edibles?" Anebulo's Instagram reads. "THC overdose is possible and real. We are developing a treatment for cannabinoid intoxication."

"It's like Narcan. Sometimes people call it the Narcan for marijuana," Simon Allen, Anebulo's CEO, told Salon in a video call, referring to ANEB-001. "Now that there's a little bit of a juxtaposition there, because obviously fentanyl can really kill you. And marijuana can't really kill you."

These drugs are often compared to naloxone, but these comparisons aren't entirely accurate, according to Dr. Ryan Marino, a medical toxicologist, emergency room physician and addiction medicine specialist at University Hospitals Cleveland Medical Center.

"Cannabinoid overdose is not comparable to opioid overdose," Marino told Salon in an email. "Cannabinoid overdose is not associated with mortality like opioids and is not a driver of overdose deaths. It is usually self-limiting, and most people do not even seek medical care. In the emergency department, while cannabinoid toxicity is not incredibly uncommon, it is not a significant driver of ED visits or hospitalizations, and can be well-managed with less extreme and less costly interventions that are already widely available."

However, with kids, the situation can be different, Marino noted. A child that gets into their parent's cannabis edibles might eat so many that they experience respiratory depression. This problem is "not seen in older kids or adults and remains poorly understood as cannabinoid receptors are not known to be associated with respiratory depression," Marino said. "So having a reversal agent in these rare, extreme scenarios could potentially be useful."

To fully understand how these anti-cannabinoids work, we have to get granular. Our cells, including neurons, have little gates surrounding their membranes called receptors. Throughout our body is a network called the endocannabinoid system (ECS), which is made up of receptors like CB-1 and CB-2. The ECS serves many important functions related to immunity and homeostasis, or keeping the body stable. When drugs like THC bind to ECS receptors, it's called agonism. But THC is kind of a sloppy agonist and this partial binding creates the fuzziness we call being stoned or high.

Similarly, if someone takes too much heroin or morphine, the drug will bind to and agonize the opioid receptors throughout the body, causing downstream effects that slow or stop breathing. Basically, an opioid overdose involves suffocation.

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Drugs that bind to receptors but don't activate them are called antagonists. Like the term in fiction, antagonists get in the way of biochemical processes in the body. One of the most popular antagonists is caffeine, which blocks the effect of chemicals our bodies produce to make us feel sleepy.

But it's easy to reverse an opioid overdose using naloxone. Even most children can do it. That's because naloxone is a competitive receptor antagonist — the opposite of an agonist. The competitive part means naloxone not only binds to these receptors, it will push out anything that's already there.

Drinabant and ANEB-001 are both antagonists at the CB-1 receptor, so in theory, if someone had too much THC — that is, too many THC molecules are agonizing their ECS receptors — it could replace the drug and stop the overdose. Theoretically, this may also work with other drugs like synthetic cannabinoids, which can be far more unpredictable and dangerous than naturally-occurring drugs like THC. Because they can be so toxic, synthetic cannabinoids can cause death far more frequently.

But we may soon have an antidote. In fact, according to Allen, these antagonists are so effective that someone could take one and ingest as much cannabis as they want and they couldn't get high. In clinical trial data, which Allen says will be made public soon, patients were first given Marinol, a synthetic version of THC that has been a prescribed medication in the U.S. since the '80s. After an hour or so, patients were given ANEB-001, which comes in an oral gel capsule.

"We started with a 10 milligram dose of THC. And we've gone as high as 40. And we knock it all out," Allen said. "We had one patient that said to us, 'Someone stole my high.' You gotta laugh at that one. Because, yeah, they were there, obviously, to get some government-grade marijuana and potentially got high for that first hour, took something, someone stole it. I thought that was funny."

While Allen said the reported side effects in patients were mild, some aren't convinced this class of drugs is safe. That's because they're related to a medication called rimonabant, which is sometimes called an "anti-cannabinoid." Think of it like the complete opposite of THC. It was originally marketed as an anti-obesity drug, which makes some sense, given what we know about other cannabinoids and their impacts on appetite. If THC gives some people the munchies, introducing a drug with an opposing mechanism would presumably help with appetite suppression and weight loss.

And the drug works. Rimonabant is a remarkable antiobesity drug. In trials, it reduced waist size, controlled blood sugar and promoted weight loss in adults with type 2 diabetes. The French pharmaceutical company Sanofi-Aventis brought it to market in the European Union under the brand name Acomplia in mid-2006. But it soon became evident this drug was too good to be true.

In some patients, rimonabant triggers severe mental health episodes, including trouble sleeping, depression and suicidality, which appeared in some patients with no previous history of psychiatric illness. It also increases the risk of seizures and some patients develop multiple sclerosis. One clinical trial was abruptly ended after half of the patients on rimonabant dropped out, with the authors reporting the drug "is associated with an unacceptably high risk of psychiatric side effects."

In 2008, the EU yanked rimonabant from shelves, Sanofi-Aventis discontinued all trials with the drug and related compounds that work similarly, like ibipinabant, taranabant and yes, drinabant, were also discarded. In fact, to investigate drinabant, Opiant had to acquire the licensing rights from Sanofi. Because of these side effects, the Food and Drug Administration (FDA) never approved rimonabant in the U.S. and research into CB-1 receptor antagonists for weight loss has shifted instead to drugs like Ozempic or semaglutide, which act on different receptors.

So the fact that a few major pharmaceutical companies are exploring using drinabant is pretty concerning to some cannabis experts. Dr. Ethan Russo, a neurologist and psychopharmacology researcher who has been studying cannabis for nearly three decades, told Salon, "I wouldn't take this kind of thing on a bet."

"I don't recommend that class of drugs for anyone, for anything," Russo continued. "I would seriously wonder about the toxicity of this drug. Chemically, it's a sulfonamide, which are antibiotics. But they also can be associated with really nasty side effects involving liver, kidneys and allergic reactions. For example, one of the allergic reactions is called Stevens-Johnson Syndrome, where you basically slough your skin off."

Russo reiterated Marino's point that very few people present to the emergency room for THC overdose in the first place and most patients just need "to be talked down" over a couple hours. "When necessary, they can be sedated with something we know more about like a benzodiazepine," Russo said.

Allen emphasized that Anebulo's chemical has been given safely to over 130 patients and stated that the side effects associated with cannabinoid receptor antagonists are linked to long-term use, rather than a single dose in a hospital setting. The company is preparing to release its Phase 2 data, which brings it closer to approval as a medication through the FDA. In a press release last year, Anebulo said "all adverse events were mild and transient, except one subject in the 50 mg cohort who experienced moderate nausea and vomiting."

"I firmly believe that all of the issues around rimonabant were chronic dosing," Allen said. "We don't know of any drug that would create the type of chronic suicidal tendency outcome that you just take one dose and it does that to you. These typically happen after three months or six months of daily therapy."

Allen said that if things proceed smoothly with ANEB-001, the company will try developing it for cannabinoid hyperemesis syndrome, synthetic cannabinoids and even reversing cannabis overdoses in dogs. But Allen sees their narrow focus as being the best path for approval. "As a small biotech, we focused on what we thought was going to be the fastest, cheapest way to get to market," Allen said.

However, Marino noted that there is not yet clinical data available to support these claims, compared to the well-supported data linking cannabinoid receptor antagonists to serious side effects.

"If the concern is differentiating between psychiatric symptoms and symptoms induced by a cannabinoid, I would be extremely reluctant to administer an agent that has been shown to cause adverse neuropsychiatric effects itself without extensive evidence of greater benefit than harm," Marino said. "At the end of the day this seems like a search for an indication for this existing molecule, and overall the proposed indications do not pass muster without far better — or any at all — supporting data."

It's a long way to get federal approval for a drug, so it's not clear if drinabant or ANEB-001 will ever reach the market and end up at an ER near you. All things considered, THC is a pretty safe drug, but that doesn't mean it can't cause problems. It's possible to overdose on vitamin C or calcium, while even drugs like Tylenol can be dangerous if not used correctly. It's also possible to fatally overdose on water. But given the increasing need for managing cannabinoid overdoses, developing tools to reverse them is a decent pursuit, assuming it doesn't make the situation worse.