by Dan Rusyniak
Stimulant-Induced Hyperthermia, a (sort of) memoir.
I will admit my biases up front. This post is based primarily on my own research or the research of people I have collaborated with. There may be other viewpoints out there, but I will stick with what and who I know. If someone disagrees with me, then they can start their own blog (ouch, burn). OK, I will admit I really just wanted to use the word burn in this post.
Like many clinical toxicologists, my research interests started at the bedside. In the summer of 2001, my pager went off.
The ED was consulting on a 17-year-old who used ecstasy at a rave party and collapsed. When he arrived in the ED his rectal temperature was 108˚F (42.4˚C). He developed rhabdo and acute kidney injury. He was discharged neurologically intact after a week in the hospital. I was left with a burning (sorry) question – how? How do stimulants cause hyperthermia and knowing that, how can it help us treat these patients better?
From a simplistic standpoint, thermoregulation is the balance between heat generation and heat dissipation. There are, however, many different sources of heat generation (e.g., mitochondria and metabolism, brown fat, motor activity, vasoconstriction, behavioral, etc.) and heat dissipation (e.g., sweating, vasodilation, behavioral, etc.). Stimulants might cause alterations in any of these. Where to start? I went where any good card-carrying toxicologist would go – to the mitochondria.
Maybe stimulants act as an uncoupler? This would make them similar to overdoses of aspirin or dinitrophenol. You probably remember that electrons flow through the electron transport chain causing protons to be pumped across a membrane. This creates a proton gradient, which acts as a battery. The potential energy generated by this proton gradient is coupled to the synthesis of ATP (Figure 1)
Drugs like salicylate and dinitrophenol “short circuit” the proton gradient, producing heat instead of ATP. So, for the first few years of my research career, I spent my time in the lab playing around with mitochondria and adding doses of MDMA that would make Charlie Sheen gasp. What I found is that even at high doses, neither MDMA or cocaine (unpublished) directly uncoupled mitochondria.1,2 But this work was all in isolated mitochondria. Maybe uncoupling happened if you could somehow study it in the whole living animal. Fortunately, at that time I ran into a cancer researcher at my institution who, by using NMR, could measure chemical markers of uncoupling (i.e., ATP formation, temperature, lactate, pH) in the tissues of a whole animal. Using his lab, we gave anesthetized rats big doses of MDMA and put them in the NMR. What we found were the hallmarks of uncoupling: increased temperature, decreased ATP, decreased pH.2 This led me to think that MDMA caused uncoupling not directly, but by activating the sympathetic nervous system through a process called non-shivering thermogenesis.
Non-shivering thermogenesis occurs when a protein channel in the mitochondria opens and allows protons to travel down their concentration gradient. Same as with salicylates, this type of uncoupling results in decreases in ATP synthesis and increases in heat production. There are a variety of uncoupling proteins in the body. The two that play a role in stimulant-induced hyperthermia are uncoupling proteins 1 (UCP-1) and 3 (UCP-3).3 UCP-1 is located in brown fat (a blob of dark colored fat between the scapula and along the cervical chain) and UCP-3 in skeletal muscle. UCPs are activated by norepinephrine (NE), which binds to beta-3 receptors, leading to the liberation, uptake, and oxidation of fatty acids in mitochondria. The physiologic benefit of these proteins is heat generation.4 Compared to shivering, this is a more cost-efficient way to generate heat. This is how small mammals survive winter during hibernation. This is also one of the ways newborn humans generate heat; remember newborns can’t shiver. But does non-shivering thermogenesis occur in adult humans? When I started my research career the answer from the scientific community was NO! However, another example of the scientific power of serendipity would prove this to be wrong.
A common problem using PET imaging to detect cancer metastasis was a recurring artifact – dark areas of uptake around the neck, and scapula (sound familiar?). While radiologists did not know the cause, they knew it wasn’t cancer and therefore it was a nuisance. They focused not on figuring out what it was causing this but rather eliminating it. One way was by increasing the temperature of the room. Eventually a researcher who studied brown adipose tissue (BAT) had a fortunate conversation with a radiologist and they quickly realized that one person’s nuisance was another’s research grant. And thus, there was confirmation that brown adipose tissue existed and was active in adult humans.5 What is even more interesting is that there had been evidence that stimulants activated human brown adipose tissue as far back as the 70’s. In a great example of Who Goes First?, two researchers give themselves ephedrine and took pictures of their back using a thermal camera. They showed not only that brown adipose tissue was present in humans, but also that ephedrine seemed to activate it.6
To be fair, a study of two scientists going old school in a lab is far from conclusive. When you look at the animal literature, however, it’s clear. Stimulants (e.g., MDMA, amphetamine, cathinones, etc.) activate brown adipose tissue.7,8 The other source of UCP, skeletal muscle, also plays a role. Work done by my friend, John Sprague, showed that mice who did not express UCP3 in their skeletal muscle had less hyperthermia and lower mortality rates from huge doses of MDMA and methamphetamine.9,10 This seemed to settle it. Stimulants generate heat through non-shivering thermogenesis. But what about the other side of the coin, heat dissipation?
In normal thermoregulation when you, or a rat, are in a hot environment, brown adipose tissue is turned off. The environment itself provides enough heat for the animal to maintain a normal body temperature. In this setting, thermoregulation depends on heat dissipation. Humans are unique among all animals. We dissipate heat primarily through sweating (interesting fact, horses also sweat, but in a different way). Rats dissipate heat by dilating their tail artery; that is, in part, why they have the big naked tail. So how do stimulants affect tail blood flow? You already know the answer. Stimulants cause vasoconstriction of skin blood vessels. Work by another friend, Bill Blessing, has shown that MDMA causes vasoconstriction and that drugs that prevent and reverse hyperthermia from MDMA (e.g., olanzapine and 5-HT2A antagonists) also prevent vasoconstriction11,12; these drugs also prevent non-shivering thermogenesis in BAT. So right now, you are saying to yourself “OK, but this is rats”. There is, however, work to suggesting that constricting skin blood vessels in humans contributes to stimulant-induced hyperthermia. In a study with human volunteers wearing a specialized heatable bodysuit, cocaine (I’m guessing there was no problem getting enrollment in this study) caused inappropriate vasoconstriction; it also caused less sweating.13
Let’s summarize what we know so far. Stimulants cause hyperthermia by . . .
- increasing heat generation through non-shivering thermogenesis, and
- causing inappropriate vasoconstriction and impairing the onset of sweat
And that would have been the end of my looking into this question if I had not been simultaneously involved in a different line of research.
After working with mitochondria, I became interested in finding out which areas of the brain controlled non-shivering thermogenesis, and how these areas were affected by stimulants. Lots of brain areas, however, are involved in thermoregulation. I focused on one area deep deep in the hypothalamus – the dorsomedial hypothalamus (DMH). I chose it for two reasons. One, it was an important brain area regulating sympathetic responses in animals. Two, and more importantly, my research mentor Joe DiMicco had made a career studying this brain region. So, without getting too nerdy on the methods (although they are totally awesome), our initial experiments showed that if you inhibited neurons in the area of the DMH before you give rats a moderate dose of MDMA, they got less hyperthermic, less tachycardic, less hypertensive, and less hyperactive.14 Yay. We did it. Drop the mic.
Except something bothered me. Even at doses of MDMA (7.5 mg/kg i.v.) 5 times higher than people typically use to get high, the temperature responses we got in our rats were not exactly life threatening. These animals increased their body temperature to 100.4 – 103˚F (38 or 39°C). Hot, but nothing that we toxicologists would really worry about. One of the problems with studying stimulants in rats is that ambient temperature critically affects temperature responses.15 When the ambient temps get in the range of ~72˚F (22˚C) a transition occurs. Below this temperature MDMA causes hypothermia, and above it hyperthermia.
Ambient temperature is also relevant to complications from stimulant use in humans. In a now classic paper, Marzuk et al. showed that deaths from cocaine strongly correlated with ambient temperature.16 Takeaway, you do not want to be using cocaine when ambient temps are > 88˚F (31.1˚C). Yet another problem associated with climate change.
So, to study this problem in a clinically relevant manner, we needed to test animals at an elevated ambient temperature. In addition, I wanted to confirm that the way inhibiting the DMH affected body temperature was by preventing the effects on non-shivering thermogenesis (by measuring BAT) and heat dissipation (by measuring tail blood flow). I repeated my initial experiments, but now at very toasty 90˚F (32˚C). One thing I quickly learned doing this work was that at an ambient temperature this high, an animal given MDMA often died. So to prevent this we created a surrogate for death. We used a core body temperature of ~106˚F (41˚C). What did we find? Just like at room temp, inhibiting the DMH, even at this elevated ambient temperature, decreased hyperthermia and, more importantly, prevented death. This is what we expected to find. What was unexpected, however, was that these decreases in temperature and mortality had nothing to do with non-shivering thermogenesis or cutaneous blood flow.17 If inhibiting the DMH did not prevent MDMA-mediated hyperthermia and death by decreasing heat generation in BAT or by reversing heat conservation through tail vasoconstriction, then what was it doing? It was preventing hyperlocomotion. When a rat gets a stimulant, it runs around; hell, when a human gets a stimulant they run around. Inhibiting neurons in the region of the DMH prevents the increased locomotion seen with MDMA.14,17 Pretty cool actually. Inhibit these neurons and animals just don’t run as much. The opposite is also true. If you stimulate these neurons, rats run around alot.18
These experiments led me to an even more interesting question. If stimulants cause you to run around, and if running around contributes to life threatening hyperthermia, then why wouldn’t people just stop? This was seeded in my brain watching rats in our early experiments at elevated ambient temperature. They would run and run and run, all the while their temperature was climbing higher and higher and higher. And if you didn’t stop the experiment and cool them off, they would literally run themselves to death. The reason they don’t stop running is they never got the signal to stop. And what is that signal? Exhaustion.
When you are running on a 90˚ F day, it’s exhaustion that tells you to stop or you’re going to die. What causes us to feel exhausted? For one thing, body temperature. When you are exercising, as your temperature temperature approaches ~104 ̊ F (40 ̊ C) you develop the feeling of exhaustion. It doesn’t matter how long you have exercised either. If you start your run with a higher temperature, the time you can exercise till exhaustion occurs is shortened. The opposite is also true. If you start a race with a lower temperature you can go longer.19 Athletes take advantage of this by drinking cold liquids before running or use cooling suits or blankets to lower their temp before a race.20 Want to know why on a hot day it feels like it is harder to run? Exhaustion. Your muscles are just as capable of working on a hot day as on a cold day, but your brain is telling them to slow down. So maybe stimulants prevent or delay exhaustion? Afterall, what is one of the reasons people use stimulants – to prevent fatigue and exhaustion.
We decided to study this and found what we expected. Amphetamine delays the onset of fatigue and exhaustion in rats running on treadmills in a warm environment.21 Furthermore, this delay came at the expense of body temperature; i.e., the longer it takes to develop exhaustion the higher your body temperature is when you finally collapse. On a side note, we also showed that stimulating neurons in the DMH also decreases onset of fatigue and exhaustion.22
I feel like this is a good point to stop and summarize (thanks to those of you still with me). Stimulants cause hyperthermia by three main mechanisms:
- Increasing heat generation through non-shivering thermogenesis and motor activity
- Decreasing heat dissipation through vasoconstriction and delayed sweating, and
- Decreasing fatigue and exhaustion, allowing animals to exert themselves longer in a hot environment
What does all this mean for toxicologists? For one, it explains the circumstances in which we often see deaths from stimulants. What do rave parties and outdoor summer concerts have in common? They involve young adults using stimulants and exerting themselves in warm environments. They are also common venues for cases of life-threatening hyperthermia.23,24 What is commonly associated with death in police custody cases? You guessed it – warm days, stimulant use, and exertion (i.e., resisting arrest).25,26 Any setting in which someone might use a stimulant on a warm day is a setup for cases of life-threatening hyperthermia.
So, what does this mean for treatment? My advice is to stop the activity, turn off the sympathetic nervous system, and cool the patient. All the sciency blabber above about BAT and tail blood flow involves activation of the sympathetic nervous system. And while animal studies have shown that drugs that are alpha-127,28, beta-327,29, or serotonin-2a receptor antagonists7,30 are effective at reducing hyperthermia in animals given stimulants, they are often not readily available in your ED or are not easy to dose to effect. And what about drugs that would stop motor activity and make people feel exhausted? If only there was a drug class that decreases activation of the sympathetic nervous system and causes fatigue? There is! Benzodiazepines. This class of drug is available in every ER, has many routes of admission, is an effective anticonvulsant, anxiolytic, causes fatigue, can be dosed to effect, has a tolerable and predictable side effect profile, and has few drug-drug interactions. This is why benzos are my first drug of choice. In those cases, in which life-threatening hyperthermia has or is developing (core temperature >104˚F or 40˚C) I may go right to the sedative big gun – propofol.
Drugs are however just the first step of treating life-threatening hyperthermia. Another equally important step is active cooling. Here there is no controversy. Time at temperature is the single best predictor of survival. The longer a person’s core temperature is >104˚F (40˚C), the worse the outcomes.31,32 So in these cases, you need to cool people as fast as possible. And how do we do that? Cold water submersion.33 One question that comes up is how do you do this in an emergency department? One way is to use an old cholera bed – I’m looking at you Bellevue.34 For the rest of us, a body bag works great. Put the patient in a body bag and douse them with water and ice. If you are worried about the EKG leads and the difficulty moving a wet patient when you are done the treatment, you can use two body bags (what I call the modified Greller technique). One contains the ice and water and the other, which goes inside the first, your patient. It goes without saying that in these cases, you need a way to continually monitor temperature. I recommend either a bladder or rectal temperature probe. You take the patient out when core temperature is <102˚ F (39˚ C). This approach of using cold water submersion to treat heat stroke is the same approach taken by colleagues at my institution and by others at large outdoor sports events.31,35
Because I have already run on too long, I won’t go into treatment for rhabdomyolysis, renal failure, coagulopathy, or other issues associated with stimulant use. Suffice it to say good critical care treatment is warranted in all of these.
As we bask in one of the hottest summers on record, I implore you to be prepared for these cases. Remember, sedate with benzos and cool with ice and water. This approach is simple, effective, and life saving. How cool is that!Rave by Josh Gordon
- 1.Rusyniak D, Tandy S, Kamendulis L, Sprague J, Klaunig J. The effects of ecstasy (MDMA) on rat liver bioenergetics. Acad Emerg Med. 2004;11(7):723-729. https://www.ncbi.nlm.nih.gov/pubmed/15231458.
- 2.Rusyniak D, Tandy S, Hekmatyar S, et al. The role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine-mediated skeletal muscle hyperthermia and rhabdomyolysis. J Pharmacol Exp Ther. 2005;313(2):629-639. https://www.ncbi.nlm.nih.gov/pubmed/15644431.
- 3.Riley C, Dao C, Kenaston M, et al. The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation. J Physiol. 2016;594(24):7455-7464. https://www.ncbi.nlm.nih.gov/pubmed/27647490.
- 4.Enerbäck S, Jacobsson A, Simpson E, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997;387(6628):90-94. https://www.ncbi.nlm.nih.gov/pubmed/9139827.
- 5.Virtanen K, Lidell M, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518-1525. https://www.ncbi.nlm.nih.gov/pubmed/19357407.
- 6.Rothwell N, Stock M. A role for brown adipose tissue in diet-induced thermogenesis. Nature. 1979;281(5726):31-35. https://www.ncbi.nlm.nih.gov/pubmed/551265.
- 7.Blessing W, Zilm A, Ootsuka Y. Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats. Neuroscience. 2006;141(4):2067-2073. https://www.ncbi.nlm.nih.gov/pubmed/16814930.
- 8.Tariq M, Islam M, al-Meshal I, el-Feraly F, Ageel A. Comparative study of cathinone and amphetamine on brown adipose thermogenesis. Life Sci. 1989;44(14):951-955. https://www.ncbi.nlm.nih.gov/pubmed/2927251.
- 9.Mills E, Banks M, Sprague J, Finkel T. Pharmacology: uncoupling the agony from ecstasy. Nature. 2003;426(6965):403-404. https://www.ncbi.nlm.nih.gov/pubmed/14647371.
- 10.Sprague J, Mallett N, Rusyniak D, Mills E. UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia. Biochem Pharmacol. 2004;68(7):1339-1343. https://www.ncbi.nlm.nih.gov/pubmed/15345323.
- 11.Blessing W, Seaman B. 5-hydroxytryptamine(2A) receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats. Neuroscience. 2003;117(4):939-948. https://www.ncbi.nlm.nih.gov/pubmed/12654345.
- 12.Blessing W, Seaman B, Pedersen N, Ootsuka Y. Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats. J Neurosci. 2003;23(15):6385-6391. https://www.ncbi.nlm.nih.gov/pubmed/12867524.
- 13.Crandall C, Vongpatanasin W, Victor R. Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med. 2002;136(11):785-791. https://www.ncbi.nlm.nih.gov/pubmed/12044126.
- 14.Rusyniak D, Zaretskaia M, Zaretsky D, DiMicco J. Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses. Brain Res. 2008;1226:116-123. https://www.ncbi.nlm.nih.gov/pubmed/18586013.
- 15.Malberg J, Seiden L. Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci. 1998;18(13):5086-5094. https://www.ncbi.nlm.nih.gov/pubmed/9634574.
- 16.Marzuk P, Tardiff K, Leon A, et al. Ambient temperature and mortality from unintentional cocaine overdose. JAMA. 1998;279(22):1795-1800. https://www.ncbi.nlm.nih.gov/pubmed/9628710.
- 17.Zaretsky D, Zaretskaia M, Durant P, Rusyniak D. Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment. Pharmacol Res Perspect. 2014;2(2):e00031. https://www.ncbi.nlm.nih.gov/pubmed/24765530.
- 18.Zaretskaia M, Zaretsky D, Shekhar A, DiMicco J. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res. 2002;928(1-2):113-125. https://www.ncbi.nlm.nih.gov/pubmed/11844478.
- 19.González-Alonso J, Teller C, Andersen S, Jensen F, Hyldig T, Nielsen B. Influence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol (1985). 1999;86(3):1032-1039. https://www.ncbi.nlm.nih.gov/pubmed/10066720.
- 20.Tyler C, Sunderland C, Cheung S. The effect of cooling prior to and during exercise on exercise performance and capacity in the heat: a meta-analysis. Br J Sports Med. 2015;49(1):7-13. https://www.ncbi.nlm.nih.gov/pubmed/23945034.
- 21.Zaretsky D, Brown M, Zaretskaia M, Durant P, Rusyniak D. The Ergogenic Effect of Amphetamine. Temperature (Austin). 2014;1(3):242-247. https://www.ncbi.nlm.nih.gov/pubmed/27570800.
- 22.Zaretsky D, Kline H, Zaretskaia M, et al. Disinhibiting neurons in the dorsomedial hypothalamus delays the onset of exertional fatigue and exhaustion in rats exercising in a warm environment. Brain Res. 2018;1689:12-20. https://www.ncbi.nlm.nih.gov/pubmed/29577887.
- 23.Henry J. Ecstasy and the dance of death. BMJ. 1992;305(6844):5-6. https://www.ncbi.nlm.nih.gov/pubmed/1353390.
- 24.Ridpath A, Driver C, Nolan M, et al. Illnesses and deaths among persons attending an electronic dance-music festival – New York City, 2013. MMWR Morb Mortal Wkly Rep. 2014;63(50):1195-1198. https://www.ncbi.nlm.nih.gov/pubmed/25522087.
- 25.Ross D. Factors associated with excited delirium deaths in police custody. Mod Pathol. 1998;11(11):1127-1137. https://www.ncbi.nlm.nih.gov/pubmed/9831212.
- 26.Ruttenber A, Lawler-Heavner J, Yin M, Wetli C, Hearn W, Mash D. Fatal excited delirium following cocaine use: epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci. 1997;42(1):25-31. https://www.ncbi.nlm.nih.gov/pubmed/8988571.
- 27.Sprague J, Brutcher R, Mills E, Caden D, Rusyniak D. Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with alpha1- plus beta3-adrenoreceptor antagonists. Br J Pharmacol. 2004;142(4):667-670. https://www.ncbi.nlm.nih.gov/pubmed/15159279.
- 28.Sprague J, Banks M, Cook V, Mills E. Hypothalamic-pituitary-thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (Ecstasy). J Pharmacol Exp Ther. 2003;305(1):159-166. https://www.ncbi.nlm.nih.gov/pubmed/12649364.
- 29.Sprague J, Moze P, Caden D, et al. Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model. Crit Care Med. 2005;33(6):1311-1316. https://www.ncbi.nlm.nih.gov/pubmed/15942349.
- 30.Herin D, Liu S, Ullrich T, Rice K, Cunningham K. Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine. Psychopharmacology (Berl). 2005;178(4):505-513. https://www.ncbi.nlm.nih.gov/pubmed/15765263.
- 31.Demartini J, Casa D, Stearns R, et al. Effectiveness of cold water immersion in the treatment of exertional heat stroke at the Falmouth Road Race. Med Sci Sports Exerc. 2015;47(2):240-245. https://www.ncbi.nlm.nih.gov/pubmed/24983342.
- 32.Heled Y, Rav-Acha M, Shani Y, Epstein Y, Moran D. The “golden hour” for heatstroke treatment. Mil Med. 2004;169(3):184-186. https://www.ncbi.nlm.nih.gov/pubmed/15080235.
- 33.McDermott B, Casa D, Ganio M, et al. Acute whole-body cooling for exercise-induced hyperthermia: a systematic review. J Athl Train. 2009;44(1):84-93. https://www.ncbi.nlm.nih.gov/pubmed/19180223.
- 34.Laskowski L, Landry A, Vassallo S, Hoffman R. Ice water submersion for rapid cooling in severe drug-induced hyperthermia. Clin Toxicol (Phila). 2015;53(3):181-184. https://www.ncbi.nlm.nih.gov/pubmed/25695144.
- 35.Sloan B, Kraft E, Clark D, Schmeissing S, Byrne B, Rusyniak D. On-site treatment of exertional heat stroke. Am J Sports Med. 2015;43(4):823-829. https://www.ncbi.nlm.nih.gov/pubmed/25632055.
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