Good afternoon, everybody. And thanks for attending this talk. And thank you for the invitation to speak today about what's a pretty broad topic. I'll hit on the salient points of a number of drugs, but would recommend that you visit some of the references on the slides at your convenience. Here's my disclosures. I have no conflicts. So I just wanted to acknowledge up front that it's really possible to inhale most all of the substances that I'll talk about today. And the reason that people use many of these illicit and some commercially available substances is really that quick onset of action to the CNS to get that mind-altering effect that is the main reason that people use recreational drugs. It also provides a more intense effect than some of the other routes that people can use these substances, such as ingestion. And it's maybe nicer to use in that there's no needles involved. Substances can be inhaled via a couple of major routes, the first being burning the product or combusting the product, followed by inhaling the smoke. And you think about that in the setting of the use of cannabinoids and other drugs. You can also vape substances where you heat but don't burn the substance, followed by inhaling the resultant vapor. And there's a variety of ways to consume vape products, including commercially available tabletop vaporizers, e-cigarettes or vape pens, illustrated there on the right at the bottom, and then dabbing using a very concentrated amount of product that's superheated with a blowtorch and then inhaled through a glass device. And so just to know, there's a lot of different ways to vape. Vaping is increasingly popular, not just for nicotine-containing products but for others as well. And here's just a couple of studies to give you examples of that. In Canada, about a quarter of cannabis users endorse using cannabis via vaporization. And another study from the UK looking at people who used recreational drugs, 2,500 or so individuals, about a third of them endorsed using a number of different kinds of drugs through electronic vaping devices. And about 9% of them endorsed active use of some sort of vape device for a number of different kinds of drugs, not just cannabis. But you'll see on the bottom there, cocaine, heroin, tryptamines, and ketamine as well. So just to briefly touch on cannabis, and I really just want to emphasize that it's a very complex product, and so it's been difficult for studies to move forward for that reason and others. But it contains a large percentage of what are non-cannabinoids that are compounds such as terpenes and flavonoids, fatty acids, et cetera. So it's the majority of what you find in cannabis. And then only about 20% of what's in cannabis, this is plant cannabis, are cannabinoids, the ones you've heard of, delta-9, delta-HTHC, and cannabidiol. Cannabis and other cannabinoids, including the body's endogenous cannabinoids or endocannabinoids as well as synthetic cannabinoids, interact with a number of different receptors. The best described are G-protein coupled receptors that include CB1 and CB2 receptors. However, it's important to note that cannabinoids can act through a number of other channels as well, including TRP channels and other incompletely described mechanisms that lead to the number of physiological effects that have been ascribed to cannabis, including mood-altering effects as well as effects on immunity and other end organ properties as well. Cannabis intersects with critical care in a number of ways. Probably the best described way that's come to light so far was shortly before the COVID-19 pandemic when the EVALI pandemic or epidemic was noted, primarily among younger male users of vaporized cannabis. And this involves presentation with acute hypoxic respiratory failure, bilateral pulmonary infiltrates without a clear infectious cause. Not really clear what this is mediated through, although there have been some associations with vitamin E acetate, which acts as a diluent to help to solubilize the cannabinoid to allow it to be used via vaporization. Some of you may have taken care of patients with cannabis hyperemesis syndrome, which is cyclic, almost sometimes intractable, vomiting relieved with hot showering, less effectively with antiemetics. And we can and have taken care of patients in our ICU who come in with profound volume depletion and acute kidney injury. It's also important to think about cannabis use and cannabis hyperemesis in the setting of DKA. Patients may present in clear DKA, but perhaps not as acidotic as you might expect them to be because of a concomitant metabolic alkalosis. Cannabis can also lead to the need for ICU care because of its relationship with severe psychosis, particularly among individuals using edible forms of cannabis who aren't used to the delayed effects of this type of ingestion route. And of course, cannabis can be seen in association with trauma. To touch on synthetic cannabinoids, which I think are becoming more problematic in those states that haven't legalized plant-based cannabis types. And over the years, these synthetic cannabinoids have evolved in their structure and become more potent as evidenced by the lower EC50 compared to agents that were developed earlier in the 20-teens. Pharmaceutical companies actually started to develop these substances much earlier than the 21st century. The substances, the SCs that are available now for purchase come in a variety of colorful packaging and go by a bunch of funny names such as Spicer, K2, et cetera. Most of these cannabinoids are related somewhat chemically in structure to THC. And as I mentioned, they act through some of the same receptors that delta-9-THC acts through. All have a similar functional group structure. And the reason that companies have tried to continue to develop these compounds is basically to evade detection and therefore regulation, but also to enhance the efficacy for end users at lower doses. So SCs can be consumed in a variety of different ways. One common way, as illustrated in the picture on top, is to take some inert plant-based material and spray it with an active synthetic cannabinoid. And then the end user can smoke this substance in joints or pipes. There's also forms that can be vaped. And these products can also be ingested in a tea-like formulation. Important to remember that SCs are in a tea-like formulation. Important to remember that these aren't pure compounds, and their metabolites are also active as well. So think about SCs in patients who are coming into your ICU with very excited delirium. Some studies note self-talk or inappropriate laughter as symptoms. These do not come up on your talk screen as THC positive to know. And oftentimes, case reports have reported on the mixing of SCs with other substances that can have really harmful effects. One was a rat poison, a long-acting warfarin, where end users came in not only psychotic, but also with hemorrhage issues. No reversal agent in supportive care is really the order of the day. So I'll touch briefly on fentanyl. I think we're all pretty familiar with the pharmacology of fentanyl in this room. But I just wanted people to be aware that fentanyl, compared to many other opioids, has a better transmucosal bioavailability and actually was studied late in the 1990s and early 2000s via an inhaled route for efficacy in acute pain management, which I thought was kind of interesting. Since fentanyl is commonly used with other medications, it's really difficult to get a handle on the scope of the fentanyl problem in particular. For recreational use, fentanyl can be inhaled, as I mentioned. Anything can be inhaled, but also can be ingested. So we had a patient come in fairly recently who had reported smoking fentanyl patches. And I'm like, how in the world do you smoke a patch? There's gel on the patch that you can remove, and you can inject it, smoke it, snort it. You can boil a patch and drink the liquid as a tea, or you can chew the patch. And here's just a picture in the top right-hand corner of how to smoke a fentanyl patch. You take part or all of a patch, put it on a piece of foil, heat the foil with a lighter, and then inhale the resultant vapor or smoke with a little glass pipe. So pretty straightforward, unfortunately. Anyway, I'm trying to keep this a little lighter in the afternoon. People are very, at the bottom line, people are very creative with how they can figure out how to inhale substances. That's really a take-home point from this talk. Fentanyl tablets, similarly, you can think of creative ways to use fentanyl tablets as well, or one can. Very commonly, we're seeing fentanyl combined with other substances nowadays, particularly xylosine. More on that in a minute. People come in with acute symptoms referable to fentanyl consumption, complaining of, not surprisingly, shortness of breath or lung pain in higher amounts. I'm sure most all of you in this room have cared for or been involved with the care of a patient with fentanyl overdoses, where patients come in with respiratory or even cardiac arrest. Fortunately for fentanyl, unlike any of the other substances I'll talk about, there is a reversal agent, naloxone. And there are fentanyl test strips that are becoming increasingly available across the country. On the bottom right is a picture of one that I found that you could buy on Amazon. Xylosine, also known as the zombie drug or Trank, has been implicated in a series of overdose deaths in the Philadelphia area and in some other parts of the country as well. This was initially developed as an antihypertensive back in the 60s, but was found to be too potent for human use since it was relegated to the veterinary world. And I like to think of xylosine as sort of a supercharged clonidine or dexmedetomidine that has activity via the alpha-2 receptor. And it has a real high affinity for presynaptic receptors to mediate its sympatholytic effects. It's been found increasingly as an adulterant in a number of recreational drug mixtures, including with fentanyl. These mixtures are known sometimes as Trank dope. And it's an inexpensive way to make the high from fentanyl last longer. But therefore, it also increases the likelihood of overdoses. In the bottom right-hand corner was just a series of decedents who came in through the Miami-Dade medical examiner's office. And the number of those individuals where xylosine was detected has really spiked in recent years. The DEA noted in some 2022 data that about a quarter of the fentanyl powder being seized was actually adulterated with xylosine, so a very high percentage of drugs that are contaminated. And in murine and other studies, there are synergistic effects on lethality when fentanyl and xylosine are used together, so a very potent and very deadly combination. Xylosine can be injected often with fentanyl. And this is what can lead to the chronic toxicity related to xylosine, that is some of the skin wounds that have been reported. Although interestingly, these wounds can be found at areas of the body that are distal to, or not related to, injection sites with this drug. Xylosine also can be inhaled, as other drugs I've talked about. Generally, effects are pretty quick and last around eight hours or so. So think about xylosine being present in your individual who comes into your ICU very altered, of course, but also in those individuals in particular who have shock or who have bradycardia because of those alpha 2 effects from the drug. Test strips are in development. This drug is not reversed with naloxone. That being said, you should have a low threshold to use naloxone because of the concomitant use with fentanyl that patients have. And this drug is not removed by dialysis. Ketamine has been more in the press and on social media recently due to the death of Matthew Perry. This, again, is another old drug that was developed initially as a PCP alternative, and we all know of it now as an injectable anesthetic. That at low or moderate doses has analgesic and anesthetic properties and some hypnotic properties as well. But at higher doses, end users can be associated with sort of out-of-body experiences that some describe as going down the K-hole. Ketamine acts through a number of different receptors to give it this kind of multiple types of effects, including NMDA and opioid receptors. And fortunately, therapeutically, there are a number of applications where it's very useful in the clinical setting that have been, that are increasing and will likely continue to expand over time. We know that ketamine has a rapid onset of action when given IV, so it's useful for things such as RSI. But this drug is also just, to be aware, it's also used in the community by an IV route for control of acute behavioral issues. It actually was implicated in the death of Elijah McClain in the city of Denver a couple of years ago. Because of some benefits in the use of esketamine for issues with psychiatric disorders and different neurologic disorders, there's been an emerging interest for ketamine's use in these areas as well. And although ketamine is not approved for any psychiatric disorder, as far as I'm aware, there have been the emergence of a number of ketamine infusion centers across the country, and I counted about 15 to 20 in Denver alone. These are unregulated centers. They're not affiliated with any sort of hospital system. I believe that over time we may see additional toxicities related to people attending these clinics and receiving therapy for different mental illnesses and neurologic illnesses with ketamine. And this is one report from the medical examiner with Matthew Perry who was found to have ketamine in his bloodstream in the range used for general anesthesia. So really not explainable without someone going back multiple times to get infusions in these centers. So ketamine can be administered intravenously in more controlled settings, but it can commonly be snorted or smoked as well. Effects via this route take a little bit longer than by the IV route, around 10 minutes or so, and the symptoms with ketamine can persist for many hours. There is some tolerance that's associated with consistent use, such as in the setting of Matthew Perry. And the diagnosis, again, you have to have a high index of suspicion for this being present, of course, but patients can present with psychosis, depersonalization, impaired consciousness, et cetera. Generally, airway tone and respiration are preserved unless someone is exposed to very high doses of this medication. But think about the scialorrhea that can sometimes be seen in the setting of ketamine use, even in controlled clinical settings, and that might be a tip that this is a ketamine toxicity picture. Generally, cardiovascular and GI features aren't very prominent with ketamine intoxication, and ketamine's usually not the sole cause of death if someone expires from a toxicity presentation. Ketamine not detected on your intox screen, so very difficult to identify at the point of care, and treatment, again, is largely supportive, low stimulus environment, judicious use of benzodiazepines, et cetera. So I'll just round out the afternoon with psilocybin, which is the least nefarious of the drugs that I mentioned today. This is the substance found in magic mushrooms, and it's now being touted as a panacea for better mental health. This is a tryptamine alkaloid that's found in a certain species of mushrooms, along with other compounds, including muscarine, things that I can't pronounce, and the active metabolite is psilocin. I can pronounce psilocin, I got that one. This psilocin, the active metabolite, interacts with five-hydroxy tryptophan receptors and contributes to effects that are akin to the use of LSD. This drug has been tested in clinical trials for major depressive disorder, however, it's not a mushroom-derived or natural product, it's a synthetic form of psilocin being used in these clinical studies. The drug works through the autonomic nervous system, or alters the autonomic nervous system, so that engenders most of the symptoms that we see from psilocin exposure. There's a theoretical risk to serotonin syndrome in patients as well, but the side effects are more psychological. And I just mentioned this drug because I think we're likely to see an increase in the use of this medication with changes in legislation across the country. In the top right-hand here, you can see that in Colorado and Oregon, we've fully decriminalized psilocybin use for home purposes, and some other states, the cities within those states have decriminalized psilocybin use as well, illustrated in blue. And based on my little bit of research, it's apparently very easy to grow mushrooms at home, and since people tend to get their medical information from online sources, friends or family, I think that mushroom poisoning might increase in the next short period of time, and this can be seen in individuals anywhere from a quarter of an hour to a couple hours after they eat, who present with a compatible history and prominent muscarinic effects, such as those I've listed here. Treatment, again, largely supportive. And you can see that among individuals who presented for an ingestion or toxicity, it had been reported to the National Poison Database System, the amount of psilocybin exposures has really increased since 2012, when these drugs started to be explored for different psychiatric benefits. So a few take-home points. I hope I've convinced you that it's possible to inhale or smoke pretty much anything with a little know-how and a little thought, which is unfortunate, but causes a great deal of toxicity to many people. So the mainstay of therapy for most of these drugs is really just supportive care, but please remember that co-ingestion of these substances is really the norm and not an exception. It's important to take a good history in phytoscole, obtain collateral to figure out what's causing symptoms, low threshold for clinical toxicology testing, low threshold for using naloxone, which is really our only reversal agent at this point in time. This is just one other study that I found. It was recently published looking at patients presenting to 20 or so EDs in Europe with drug toxicity and among individuals who needed immediate ICU attention. This was primarily, the risk was primarily found to be most elevated among individuals who were 35 years of age or older who had used drugs together, so polysubstance use, or had used recreational drugs in combination with ethanol. So perhaps not surprising, but keep those folks in mind because they generally are sicker. And thank you very much for your attention. Thank you.

vaping

synthetic cannabinoids

fentanyl

xylosine

psilocybin

polysubstance use