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Official websites use. Share sensitive information only on official, secure websites. Correspondence should be addressed to Eugene A. Psychomotor stimulants are frequently used by humans to intensify subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of psychophysiological activation and often in warm, humid environments that prevent normal heat loss could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV and methylone, three structurally-similar recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how the hyperthermic effects of these drugs are modulated in rats under conditions of social interaction and at warm ambient temperature. We will also discuss the mechanisms underlying hyperthermic effects of these drugs, particularly the roles of intra-brain heat production due to metabolic brain activation and peripheral vasoconstriction. Finally, we will present our recent data, which compared the efficacy of different pharmacological strategies for reversing MDMA-induced brain and body hyperthermia. These data could be important not only for understanding the potential dangers of each drug, but also the development of a pharmacotherapy to alleviate drug-induced hyperthermia and potentially save the lives of highly-intoxicated individuals. In contrast to therapeutic psychoactive drugs, which are taken voluntarily or given by medical professionals to alleviate specific pathological symptoms, individuals take drugs recreationally to induce pleasurable, novel, or unusual psycho-emotional effects. At low doses, the physiological effects of such drugs may mimic physiological responses induced by naturally arousing stimuli. However, at higher doses, these drug-induced responses may reach pathological levels, resulting in acute drug-induced intoxication and posing a significant risk to human health. Drug dose is an obvious critical parameter in predicting acute intoxication; however, many other factors play important roles in determining the severity of drug-induced responses, including individual responsiveness, previous drug experience, simultaneous multi-drug use, silent pre-existing pathologies, as well as the specific conditions under which the drug is taken. As such, our focus here will be on drug-induced perturbations in temperature homeostasis, with a special emphasis on brain temperature as an important parameter that not only reflects the metabolic aspects of brain activity, but also affects neural activity and neural functioning Kiyatkin While the direct monitoring of brain temperature in rats is a relatively simple procedure, human data are limited and often restricted to neurological patients Mariak et al. Therefore, it has not been definitely proven that similar, relatively large brain temperature fluctuations could occur in healthy humans. However, several observations suggest that this could be the case. First, monkeys show robust physiological changes in brain temperature within a range comparable to that observed in rats Baker et al. Finally, direct measurements of venous outflow from healthy human volunteers wearing water-impermeable clothing which impaired normal heat dissipation to the external environment revealed that brain temperatures could reach Importantly, even at such high brain temperatures, the physical and mental states of these volunteers remained normal, suggesting that the brain can tolerate relatively large, but transient temperature increases. Brain temperature is determined by the balance of two opposing forces: metabolism-related intra-brain heat production and heat loss via cerebral blood outflow to the rest of the body and then to the external environment. This heat is removed from brain tissue by the cerebral circulation due to arrival from the lings of cooler arterial blood Feitelberg et al. Although mechanistic, the cooling of an internal combustion engine is a good analogy when considering brain temperature exchange. Similar to circulating coolant that continuously removes heat from a working engine, cool, oxygenated arterial blood removes heat from the brain via heat exchange. The now warmed venous blood then returns to the heart to be cooled and re-oxygenated in the lungs. Such an arrangement determines the critical role of cerebral blood flow in brain temperature homeostasis and the essential inter-dependence between temperature in the brain and the rest of the body. While brain temperature tends to increase due to metabolism-related intra-brain heat production, it also rises when brain-generated heat cannot be properly dissipated to the body and then to the external environment. Similarly, a decrease in cerebral metabolism tends to lower brain temperature; however this effect could be strongly enhanced by a peripheral vasodilatation that promotes heat loss to a cooler environment Kiyatkin and Brown Since most psychoactive drugs affect metabolism as well as the state of peripheral and cerebral blood vessels, drug-induced brain temperature responses should depend significantly upon the ongoing state of the organism and the environmental conditions of drug-use. A drug at a certain dose could induce minimal temperature effects in an environment where the adaptive mechanisms of heat loss are fully effective, but the same drug at the exact same dose could induce very powerful hyperthermic effects in an environment where heat dissipation mechanisms are significantly impaired. Since peripheral vasodilatation and perspiration are powerful means for heat loss in humans, drug-induced impairment of these adaptive mechanisms may be a very important determinant of drug-induced increases in brain and body temperatures. Similar to other psychostimulants, MDMA increases metabolism and induces hyperactivity coupled with hyperthermia Gordon ; Alberts and Sonsalla ; Mechan et al. The influence of environmental conditions and specific activity states could be especially important for MDMA because, in addition to metabolic activation, it also induces peripheral vasoconstriction Gordon ; Pederson and Blessing , thus diminishing heat dissipation from body surfaces and enhancing heat accumulation in the brain and body. Such products were designed to circumvent regulations controlling the sale and use of psychoactive substances. Two very popular synthetic cathinones are 3,4-methylenedioxymethcathinone methylone and 3,4-methylenedioxypyrovalerone MDPV Spiller et al. While low recreational doses of synthetic cathinones enhance mood and increase energy, high doses or chronic use can cause serious medical complications, including agitation, psychosis, tachycardia, hyperthermia, and even death Prosser and Nelson ; Ross et al. Methylone is a non-selective transporter substrate that evokes the release of dopamine, norepinephrine and serotonin, analogous to the effects of MDMA Baumann et al. By contrast, MDPV is a potent transporter blocker that inhibits the uptake of dopamine and norepinephrine, with minimal effects on serotonin uptake Baumann et al. Although robust increases in body temperature have been reported in humans as the result of acute intoxication with both methylone Pearson et al. In rats, MDPV 1. Since these drugs are structurally similar to MDMA, we compared the thermogenic effects of MDPV and methylone with those induced by MDMA and assessed whether and how these thermogenic effects are modulated by social interaction and moderately warm environments. By using this three-point recording procedure we were able to assess how these drugs affect intra-brain heat production NAc-muscle differential and skin vascular tone i. Figure 1 shows that MDMA, MDPV and methylone each increased brain and muscle temperatures, rapidly decreased skin temperature, and induced locomotor activation. These changes differed from a transient temperature increase induced by the saline injection, which did not result in an evident motor response a-c. While brain temperature increases induced by all three drugs were approximately equal in its magnitude 1. Injections of each drug induced rapid increases in NAc-Muscle differentials, but this effect, suggesting metabolic brain activation and enhanced intra-brain heat production, was clearly larger vs. Each drug also rapidly decreased Skin-Muscle differential, suggesting cutaneous vasoconstriction; this effect was about the same for each drug. Finally, all three drugs induced locomotor activation; this effect was clearly the greatest for MDPV. Filled symbols mark values significantly different from pre-injection baselines. Bold arrows mark the moment of injection. Original data shown in this graph were reported in Kiyatkin et al. To examine how the temperature effects of drugs are affected by associated physiological activation, we examined temperature dynamics during social interaction between two rats. While the changes in NAc and muscle temperatures were generally parallel, the rise was stronger and more rapid in the brain. This resulted in a significant increase in NAc-Muscle differentials that indicated metabolic brain activation. Social interaction was also accompanied by a strong decrease in Skin-Muscle temperature differentials, indicating stimulus-induced cutaneous vasoconstriction. While NAc-Muscle differentials rapidly returned to baseline after the end of the social interaction period, Skin-Muscle differentials increased above baseline, suggesting a rebound vasodilation. These physiological parameters and locomotion showed consistent changes at the start and end of the social interaction. Filled symbols mark values significantly different from the pre-injection baseline. The first and third vertical hatched lines in each graph show onset and offset of social interaction 60 min and black arrows at the second hatched lines mark the moment of drug administration. When rats received methylene instead of saline, temperature differences were minimal, but the decreases in NAcc and muscle temperatures and Skin-Muscle differentials after the end of social interaction were more prolonged Fig. Mean values of all parameters did not differ statistically vs. The mean increase in NAc temperature calculated for the entire 5-hour post-drug interval as the area under the curve was maximal with methylone used under quiet resting conditions 1. Similar to methylone, injection of MDPV delayed brain and muscle temperature decreases after social interaction Fig. MDPV, quiet-resting conditions 0. When taken in an activated physiological state, MDPV also enhanced both increases in NAc-Muscle differentials and decreases in skin-muscle differentials, suggesting a weak potentiation of MDPV-induced metabolic and vasoconstrictive effects. The most robust potentiation of hyperthermic effects was found with MDMA used during social interaction Fig. These changes, however, were highly variable in individual rats, with peak brain temperatures ranging from The mean temperature elevations were maximal in this case 2. The pure effects of MDMA on brain temperature were also significantly stronger during social interaction than in quiet resting conditions 1. Social interaction likewise potentiated metabolic brain activation as well as vasoconstriction, two major physiological mechanisms underlying MDMA-induced hyperthermia. Rats exposed to a warm ambient temperatures maintained stable but slightly higher internal temperatures mean: Saline injections under these conditions induced weak, transient injection-related temperature responses similar to that seen with saline injection at standard room temperature Fig. Black arrows at the hatched lines mark the moment of drug administration. Since all rats exposed to MDMA died within 6 hrs post-injection, MDMA data are shown as individual changes j and mean values of NAc-Muscle, Skin-Muscle differentials and locomotion k and l for the first 80 min post-injection when all rats were still alive. The potentiation of these hyperthermic effects was coupled with stronger and more prolonged increases in NAc-Muscle differentials and stronger decreases in Skin-Muscle differentials. However, these changes were not significant vs. When calculated as the pre-lethality temperature peak, the mean increase in NAc temperature was 2. Drug-specific differences in the pattern of modulation are especially evident when we compare the brain hyperthermic effects of each drug administered under different experimental conditions Fig. As can be seen, each of the three drugs induced an approximately equal brain hyperthermic effect when tested at standard laboratory conditions. However, the effects of these drugs showed distinct differences when they were administered during social interaction and at warm ambient temperatures. This pattern of interaction suggests that methylone and social interaction share common effector mechanisms e. When these mechanisms are naturally activated during social interaction i. Horizontal hatched line in A show values in control saline group. Horizontal hatched lines in B show values induced by each drug under quiet resting conditions. While the mechanisms underlying this potentiation remain unclear, it is likely that MDPV, in addition to its central action, acts directly on the vessels potentiating skin vasoconstriction and increasing intra-brain heat accumulation. A powerful enhancement of the hyperthermic effects of MDMA by environmental conditions seen in rats may help to explain the exceptionally strong, sometimes fatal, responses of some individuals induced by this drug under rave party conditions. However, some caution should be taken in extrapolating these findings to human conditions because humans have much more sophisticated mechanisms of heat loss from the body than do rats Gordon , thus making them more resistant to high environmental temperatures and thermogenic effects of psychomotor stimulants. In contrast to rats, humans have a well-developed ability to sweat and have a very high dynamic range of flow rates in the skin, thus allowing them to lose more metabolic heat 1 kW than could be maximally produced in the body Rowell These differences in the effector mechanisms of heat loss could explain weaker MDMA-induced body temperature increases and their lesser dependence on ambient temperatures found in monkeys Taffe et al. Despite their high efficiency, the compensatory mechanisms of heat loss in humans could be greatly impaired under specific conditions, resulting in progressive heat accumulation in the organism. Therefore, pathological brain hyperthermia induced by overdose of psychomotor stimulants under rave conditions results not only from excessive heat production due to drug-induced and associated psycho-physiological activation, but also from the powerful drug-induced peripheral vasoconstriction and impaired ability to dissipate metabolic heat due to warm, humid environment. Since our previous work established a critical role of peripheral vasoconstriction in potentiating brain and body hyperthermic effects of MDMA, we explored two alternative pharmacological strategies for possible reversal of this effect in order to decrease brain and body temperature Kiyatkin et al. We assessed the effects of clozapine, an atypical neuroleptic, and carvedilol and labetalol, mixed alpha and beta adrenoceptor blockers. These medications are routinely used to treat chronic health problems in humans, and were chosen because of their preclinical success in attenuating MDMA-induced body hyperthermia Blessing et al. Clozapine acts on multiple neural receptors and glial cells in the brain, presumably inhibiting MDMA-induced metabolic neural activation, sympathetic tone, and centrally-mediated vasoconstriction Baldessarini and Frankenburg ; Breier et al. Carvedilol and labetalol act peripherally to dilate skin vessels by blocking alpha and beta adrenoceptors Sponer et al. Similar to our previous studies, brain temperature was our primary focus, but we also simultaneously recorded temperatures from the temporal muscle and facial skin to determine the basic physiological mechanisms underlying brain temperature responses. This three-point recording technique allowed us to evaluate the effects of the drugs on intra-brain heat production due to metabolic neural activation and heat loss due to changes in peripheral vascular tone Kiyatkin Our experimental protocol has three important features. This protocol is more relevant for human conditions because MDMA is recreationally used in social settings associated with high arousal e. Third, in contrast to most studies, where a treatment drug was administered before or at the same time as MDMA Yeh ; Sprague et al. This dosing regimen closely mimics the clinical situation, in which MDMA-intoxicated patients are treated for pathological hyperthermia in hospital emergency rooms. Although we strived for a fully factorial, within-subjects design, the variability associated with MDMA temperature response made this difficult. In rats from the first two groups, we injected MDMA 10 min after the onset of the 1-h social interaction followed by a counterbalanced injection of either a treatment drug clozapine, carvedilol, and labetalol or saline. In rats from two other groups, we injected either a treatment drugs clozapine, carvedilol, and labetalol or saline under quiet resting conditions. Each rat received only two MDMA injections, either alone or with a treatment drug. As shown in Figure 5e-f , after clozapine injection, NAc temperature rapidly decreased, resulting in a large difference vs. The clozapine-induced temperature decrease was rapid and profound; the final temperature values in the clozapine treatment group were lower than the initial baseline and significantly lower than in the control group that received MDMA with saline. These post-treatment temperature values, however, remain within the physiological range; similarly low or even lower values occur in well-habituated rats during day-time recording Kiyatkin Muscle and skin temperatures also decreased after clozapine injection, and the difference vs. The effects of clozapine, carvedilol and labetalol on MDMA-induced temperature and locomotor responses. The graphs show changes in different parameters before and after administration of each testing drug and saline 0 min. Filled symbols show values significantly different from the last pre-treatment value; the absence of filled symbols indicates the absence of a significant effect on a specified parameter evaluated with one-way ANOVA, n: number of rats original data of this study were published in Kiyatkin et al. In contrast to the stable increase in NAc-Muscle differentials present in the control group Fig. However, the most rapid and strong effects of clozapine were found for the Skin-Muscle differentials, which reflect the vasomotor tone of skin vessels. While this parameter further decreased after saline injection Fig. The difference between clozapine and saline appeared from the second data point 3—6 min and this difference continued to increase throughout the entire post-treatment interval. Carvedilol also had a strong attenuating effect on MDMA-induced increases in NAc, temporal muscle, and skin temperatures, returning these parameters to near-baseline levels by the end of the session Fig. Carvedilol minimally affected NAc-Muscle differential Fig. Lastly, carvedilol inhibited MDMA-induced locomotor activation, although locomotor activity was maintained at normal levels throughout the recording session Fig. Labetalol had no evident effects on any of the temperature responses caused by MDMA plus social interaction Fig. Additionally, we approximated temperature change, as analyzed by the integral of the difference between saline and drug treatment groups i. Comparative effectiveness of different drugs in reversing MDMA-induced temperature responses. Left panel shows the time-course of the effects of each drug difference vs. Right panel shows the mean effects area under curve for 80 min post-injection for each testing drug E-H. As can be seen in Fig. Clozapine also has the greatest attenuating effects on MDMA-induced intra-brain heat production and skin vasoconstriction, showing the largest decrease in NAc-Muscle differential and a strong, sustained increase in Skin-Muscle differential, respectively. In contrast, carvedilol had a much weaker effect on NAc-Muscle differentials and a less pronounced, short-lived effect on Skin-Muscle differentials. Finally, labetalol had minimal effects on MDMA-induced changes in all temperature measures. The downstream pharmacological and biochemical mechanisms underlying MDMA-induced hyperthermia are complex and involve multiple factors, including excessive sympathetic activation, dopamine hyperactivity, decoupling of mitochondrial ATP and heat production in both the brain and periphery are currently being explored see Dao et al. As such, rather than focusing on the specific downstream neurotransmitter, receptor, or signaling mechanisms, we chose to focus on the basic physiological mechanisms underlying MDMA-induced hyperthermia and its reversal by the treatment drugs. Consistent with its central, antipsychotic action, clozapine strongly reduced MDMA-induced increases in NAc-Muscle temperature differentials, suggesting a gradual decrease in intra-brain heat production due to blockade of drug-induced metabolic brain activation. Within the first 3 min post-treatment, clozapine also reversed the decreases in Skin-Muscle temperature differentials, suggesting a rapid blockade of skin vasoconstriction. In addition, clozapine decreased MDMA-induced locomotor activation while maintaining normal activity levels and showing no evident signs of sedation. Carvedilol and labetalol are mixed alpha-beta adrenoceptor blockers that directly dilate blood vessels Sponer et al. In contrast to the strong effects of clozapine on MDMA-induced increases in NAc-Muscle differentials, peripherally acting carvedilol had virtually no effects on this metabolism-related parameter. Surprisingly, the effects of carvedilol on MDMA-induced changes in Skin-Muscle differentials, an index of cutaneous vascular tone, were weaker and incomplete compared to the effects of clozapine. Although human reports suggest that labetalol taken before MDMA exposure decrease MDMA-induced hyperthermia Liechti , in our hands this drug was ineffective and had minimal, if any, effects on all temperature parameters. The reasons for the differences between carvedilol and labetalol are unclear and may be due to their different affinities for the various subgroups of alpha- and beta-adrenoceptors Ruffolo et al. As a vasodilator, labetalol also appears to be less potent than carvedilol Tomlinson et al. Current emergency therapeutic options to counteract MDMA-induced pathological hyperthermia mainly focus on whole body cooling, water substitution, and sedative therapy. Indeed, body cooling should have a hypothermic effect, but the effectiveness of this treatment is limited due to strong, sustained MDMA-induced vasoconstriction and the natural vasoconstrictive effect of skin cooling. To the best of our knowledge, our study is the first to compare the effectiveness of clozapine and carvedilol in alleviating MDMA-induced hyperthermia under conditions that mimic recreational drug use. Using our three-point thermorecording procedure, we were able to clarify the basic physiological mechanisms underlying the therapeutic actions of these drugs. In conclusion, the data indicate that carvedilol, by acting directly on blood vessels, is modestly effective in attenuating MDMA-induced brain and body hyperthermia. In contrast, clozapine induces much more rapid and powerful hypothermic effects by both decreasing MDMA-induced brain activation and diminishing the sympathetic outflow to peripheral vessels. A therapeutic agent such as clozapine that not only mitigates, but reverses, MDMA-induced hyperthermia could be indispensable for emergency situations and could save the lives of highly-intoxicated individuals. As a library, NLM provides access to scientific literature. Curr Top Behav Neurosci. Published in final edited form as: Curr Top Behav Neurosci. Find articles by Eugene A Kiyatkin. Find articles by Suelynn E Ren. PMC Copyright notice. The publisher's version of this article is available at Curr Top Behav Neurosci. Open in a new tab. Disclosure of Potential Conflicts of Interest No potential conflicts of interest are disclosed. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. 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Illicit Non-Pharmaceutical Fentanyl and Its Analogs: A Short Review of Literature

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Official websites use. Share sensitive information only on official, secure websites. Keywords: fentanyl, analogs and derivatives, buprenorphine, opioid, opioid use disorder. According to the U. Fentanyl, an analgesic compound, is 50 times more potent than heroin and times more potent than morphine. The illicit drug industry is plagued with widespread fentanyl adulteration, which increases overdose risk for persons who use non-prescribed opioids. Search terms were fentanyl, buprenorphine, opioid use disorder, opioid dependence, pharmacokinetics, and non-pharmaceutical fentanyl. Studies were selected based on novel information related to NPF, its pertinent analogs, and differences in pharmacokinetics. Surveys were included because NPF is not used clinically and population sizes for trials were limited. Fentanyl was synthesized initially by Paul Jensen in in Belgium for pain management. By , many people who previously used pharmaceutical opioids had transitioned to drugs such as heroin later fentanyl , which had become cheaper and easier to obtain. Government organizations such as the DEA and CDC have attempted to introduce legislation to regulate these compounds but have been unable to keep up with the readily available analogs produced abroad. There are key differences between NPF and alternatives such as heroin or pharmaceutical grade fentanyl. Additionally, NPF is significantly easier to manufacture and distribute, leading to reduced prices in comparison to heroin and pharmaceutical opioids. Authentic oxycodone M30 tablets top vs. The most common form of heroin is black tar, which when available, had an increasing frequency of contamination with NPF. NPF pills allowed users to transition from the injection route of opioid administration to smoking. Others felt the smoking route of NPF could limit the overdose risk, however, objective data on this could not be obtained. Abstinence from NPF also has proved to be more difficult, thought to be due to greater potency and more severe withdrawal symptoms. Fentanyl and its analogues have varying potencies and side effects, aggravated by a short elimination half-life minutes when compared to other opioids. When analyzing chronic users, a recent study indicated that renal clearance for fentanyl in opioid use disorder was highly variable, but consistently longer than the two to four day clearance of other short-acting opioids. Although pharmaceutical fentanyl is well characterized, little is known about the metabolic pathways of new fentanyl analogs. This disparity prompted a study in which analyzed the various pathways and potencies of new analogs Table 1. A profile of fentanyl and its analogs was analyzed in Washington, D. Nine major compounds were identified; the four most common being fentanyl The data illuminated a rising presence of furanyl fentanyl which was proposed to be seven times as strong as fentanyl and can be used in tandem with other isotopes. It is becoming evident that proper identification of these analogs is crucial to guide further treatment. Data on metabolism and potency along with chemical structures of fentanyl and its analogs. Buprenorphine is a partial mu-agonist with high binding affinity and slow dissociation from the receptor. Fentanyl, though, has a higher binding affinity compared to other mu-opioid agonists, which may limit the opioid blockade benefit of buprenorphine. It is possible that long-term buprenorphine outcomes could be affected, as those testing positive for fentanyl had lower opioid abstinence and marginally lower retention after six months of buprenorphine treatment compared to those with negative toxicology. This subtle interaction has potential to alter the overall management of opioid cessation. A total of , drug overdose deaths occurred in the U. Over the past decade, there was emerging unpredictability and accessibility of NPF and its analogs. Fentanyl testing strips have grown in popularity to help individuals with safer drug use practices, but they are considered illegal to use in outpatient clinics per the DEA; advanced and legal technology to detect NPF and analogs more easily and accurately is required. This will facilitate and guide proper treatment protocols. As a library, NLM provides access to scientific literature. Kans J Med. Find articles by Vivek Velagapudi. Roopa Sethi , M. Find articles by Roopa Sethi. Received Sep 29; Accepted Jan 5; Collection date Open in a new tab. Compound Metabolites Relative Potency fentanyl Structure Fentanyl hydroxyfentanyl, hydroxynorfentanyl, despropionylfentanyl 1 Alfentanil Noralfentanil 0. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Norsufentanil, N-phenylpropanamide, demethylsufentanil.

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