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Official websites use. Share sensitive information only on official, secure websites. MLS and MMG made equal and extensive contributions to this work, including in the design of studies, the execution of experiments, the analysis and interpretation of results, and the writing of the manuscript. Use of drugs of abuse in combination is common among recreational users and addicts. Historically, the most popular speedball combination is that of cocaine and heroin. However, with the growing popularity of methamphetamine in recent years, there has been increased use of this drug in combination with other drugs of abuse, including opiates. Despite this, relatively little research has examined interactions between methamphetamine and opiates. In the current research, behavioral interactions between methamphetamine and the prototypical opiate, morphine, were examined across a variety of dose combinations in Sprague-Dawley rats. The combination of methamphetamine and morphine produced stimulation of behavior that was dramatically higher than either drug alone; however, the magnitude of the interaction was dependent on the dose of the drugs and the specific behaviors examined. The results demonstrate complex behavioral interactions between these drugs, but are consistent with the idea that this combination is used because it produces a greater effect than either drug alone. Polydrug use, in which individuals administer combinations of different drugs, is common among drug abusers. Speedball use and its dangers have been brought to the attention of the general public through the high profile deaths of celebrities from such drug combinations, including John Belushi in , River Phoenix in and Chris Farley in Burnett et al. Opiates and psychomotor stimulants produce their neural and behavioral effects through distinct actions on the brain. The behavioral and subjective effects of opiates are produced principally via actions at mu opioid receptors, while those of psychomotor stimulants are due to enhancement of synaptic levels of dopamine Leri et al. However, there is significant overlap between mu opioid receptors and dopamine, especially in the nucleus accumbens, a brain region that is critically involved in both the stimulant effects and the rewarding effects of opiates and psychomotor stimulants Trujillo et al. Three of the more likely are: 1 administration of the combination produces effects greater than either drug alone such as a greater high or greater rush ; 2 administration of one decreases the side-effects of another such as the opiate decreasing cocaine-induced agitation or anxiety, or conversely, cocaine tempering opiate-induced sedation ; or 3 the combination produces unique subjective effects desired by the user Ellinwood et al. Although a number of studies have examined these possibilities, there is still an incomplete understanding of the phenomenon, and of the behavioral consequences of coadministration of opiates and psychomotor stimulants. The most commonly abused and most widely researched speedball combination is that of heroin and cocaine Cornish et al. Considerably less is known about coadministration of other stimulants and other opiates. However, due to the current popularity and availability of stimulants other than cocaine especially methamphetamine , it is likely that drug combinations using other stimulants will increase in popularity. For example, the U. Six dose combinations were examined in laboratory rats, including three morphine doses 1. Although the specific neurochemical actions of cocaine and methamphetamine have been found to differ Izawa et al. Seventy-two adult male Sprague-Dawley rats weighing — g at time of purchase Harlan were used in these studies. Animals were housed three per cage, in standard plastic rat cages, with no restrictions on food and water. This work is in compliance with the Uniform Requirements for manuscripts submitted to Biomedical journals. Photocell arrays are interfaced with a personal computer for the collection of data, and the following measurements can be obtained: total photocell beam breaks, distance traveled, time at rest, ambulations interruptions of a successive photocell beams, characteristic of forward locomotion , fine movements interruptions of a single photocell beam, characteristic of stereotypic behavior and rearing. In the experimental room in which the enclosures reside continuous sound was provided by a white noise generator Lafayette Instruments, Lafayette, IN , and a ceiling incandescent light was set at a low level. Drugs were dissolved in 0. Three experiments were performed covering the six dose combinations, each with 24 animals. In each experiment, two doses of methamphetamine were tested 0. Each test consisted of four groups at a single dose combination: 1 saline control , 2 methamphetamine alone, 3 morphine alone, and 4 speedball. During the first week of each experiment, the lower dose of methamphetamine was tested with the selected dose of morphine; one week later, the higher dose of methamphetamine was tested with the same dose of morphine. This design using the same group of animals to test two dose combinations allowed for reduction in the number of animals. Additionally, three approaches were used to minimize the opportunity for crossover effects from one dose to the next: 1 at least one week separated injections, 2 testing of the lower dose of methamphetamine 0. For each test, animals were placed individually into an enclosure and allowed to habituate to the apparatus for 30 minutes prior to injection. The behavioral response to the injection was followed over the next minutes. Activity data was assessed at minute intervals for a total of minutes following injection. Three measures of activity were used to determine the response to the drug combinations: ambulations, rears and fine-movements, since these provided contrasting and enlightening information about the response to the drugs. Two distinct phases of activity were observed in the experiments: an early phase characterized by very high levels of activity during the first 90 minutes in the speedball groups, and a late phase characterized by a delayed increase in activity, peaking at lower levels, during the second 90 minutes. Methamphetamine 0. This was evident for both ambulations and fine movements, although relatively greater for the latter Figures 1 , 2 , 3 and 4. Morphine produced a more complex dose-dependent effect on activity: at 1. Locomotor activity, as expressed in ambulations, for the minute time course in rats treated with saline Sal , methamphetamine Ma; 0. Locomotor activity, as expressed in ambulations, in rats treated with saline Sal , methamphetamine Ma; 0. Locomotor activity, as expressed in fine movements, for the minute time course in rats treated with saline Sal , methamphetamine Ma; 0. Locomotor activity, as expressed in fine movements, in rats treated with saline Sal , methamphetamine Ma; 0. For ambulations, the speedball combination produced the greatest activity, which was dependent on the dose of morphine, with the greatest stimulation at 5. This was particularly evident in the examination of the first 90 minutes of the session, where the drug combination produced a nearly 4-fold increase in activity over either drug alone Figure 2. For fine movements, the combination produced effects that were not significantly different from methamphetamine alone Figure 3 and 4. The effects of the higher dose of methamphetamine 1. Methamphetamine alone produced a more potent stimulant effect than the lower dose, which peaked at approximately 40 minutes post-injection. As above, the stimulant effect of methamphetamine was greater for fine movements, when compared to ambulations Figures 5 , 6 , 7 and 8. The dose-dependent effects of morphine alone paralleled those described above. Locomotor activity, as expressed in ambulations, for the minute time course in rats treated with saline Sal , methamphetamine Ma; 1. Locomotor activity, as expressed in ambulations, in rats treated with saline Sal , methamphetamine Ma; 1. Locomotor activity, as expressed in fine movements, for the minute time course in rats treated with saline Sal , methamphetamine Ma; 1. Locomotor activity, as expressed in fine movements, in rats treated with saline Sal , methamphetamine Ma; 1. Similar to the lower dose of methamphetamine, a potent interaction was observed in ambulations for the drug combination, which was dependent on the dose of morphine, with the greatest stimulation at 5. This was particularly evident in the examination of the first 90 minutes of the session, where the drug combination produced a nearly 3-fold increase in activity over either drug alone Figure 6. For fine movements, the combination produced effects that were not significantly different from methamphetamine alone Figures 7 and 8. Interestingly, at the highest dose of morphine, the combination resulted in effects slightly lower than methamphetamine alone Figure 8. To further explore the magnitude of the speedball response, the first 90 minutes of activity were compared across doses for ambulations, fine movements and rears. Morphine by itself produced a modest inverted U-shaped dose-response, with the highest level of activity at 1. This inverted U-shaped dose-response was exaggerated in the speedball groups, with the 5. Dose-response summary. Total ambulations top panel , fine-movements middle panel and rears bottom panel for the first 90 minutes post-injection at each dose combination. Solid lines show the dose-response for morphine when combined with saline or methamphetamine 0. Dashed lines show theoretical additive response for each dose of methamphetamine in combination with each dose of morphine. The theoretical additive lines were calculated by adding the activity counts from methamphetamine Ma alone and morphine Mor alone at the respective doses. At the lowest dose of morphine 1. The response for rears and fine-movements at these doses of morphine was less-than additive — activity in the speedball group did not exceed the sum of morphine alone and methamphetamine alone Figure 9. Thus, for ambulations and rears the speedball combination produced effects greater than additive at 1—2 dose combinations, while fine movements did not. The key finding from this work is that methamphetamine and morphine, when administered together, produce a potent interaction in behavior. The interaction is dependent on the doses of the drugs used and the specific behavior examined, with ambulations horizontal activity and rearing vertical activity showing dramatic interactions, and fine movements stereotypy showing less evidence of interaction. Of particular note, the combination of 5. This finding indicates that the interaction between methamphetamine and morphine is synergistic — that is, the effect of the combination is significantly greater than the sum of each. Although isobolographic analysis would help strengthen the argument that a synergistic interaction occurred, the shallow, inverted U-shaped dose response for morphine prevented this approach. The differing results for ambulations and rears versus fine movements are of interest, suggesting that the speedball effect represents a complicated behavioral interaction -- rather than an increase in all behaviors equally, forward locomotion and vertical activity are dramatically enhanced, while stereotypy is not. The effects of the combination were clearly time-dependent, with the most potent interaction occurring during the first 90 minutes post-injection and less evidence of interaction in the later portion of the session. It is likely that a different time course for interactive effects would have been observed if the drugs had been administered sequentially with an interval between injections. The results demonstrate, that when administered together, there is a rapid onset for the interaction of morphine and methamphetamine, with the peak effects occurring by 30—60 minutes post-injection. The current results complement and extend previous work by others, which examined behavioral interactions between methamphetamine and morphine in different strains of mice: ddY Mori et al. In each of these studies synergistic locomotor interactions between morphine and methamphetamine were seen at lower dose combinations Ito et al. For example, Sprague-Dawley rats show a complex morphine dose-response, with modest locomotor stimulation at doses up to 5. Nevertheless, despite differences in response to individual drugs, studies in all three strains observed synergistic interactions between morphine and methamphetamine. The results illustrate that the interaction between methamphetamine and morphine is a robust phenomenon. Interestingly, the interaction between methamphetamine and morphine followed an inverted U-shaped dose-response, with the greatest effect at 5. This dose-response curve paralleled the dose-response for morphine alone. The inverted U-shaped dose-response was somewhat surprising, especially within the selected dose-range. One possibility is that the depressant effects of morphine in this dose range overwhelm the stimulant effects of methamphetamine. Yet another possibility is that the high dose combination caused the animals to shift from more ambulatory behavior to greater stereotypy. Indeed, such a shift has been reported for psychomotor stimulants at high doses -- as stereotypy increases, horizontal locomotion decreases due to behavioral competition Joyce and Iversen, ; Lyon and Robbins, ; Sharp et al. However, the latter alternative is contradicted by the decrease in fine movements seen at the high dose combination. If the higher dose combination caused the animals to shift from ambulations to stereotypy, then this should have been reflected in an increase in fine movements. Instead, both ambulations and fine movements decreased in a parallel manner. Together, these findings lead to the conclusion that at the higher dose of morphine the depressant effects of this drug overwhelm the stimulant effects of methamphetamine. Although we do not have evidence of toxicity in the current studies, it is important to comment on potentially toxic interactions between morphine and methamphetamine. Thus, at dose combinations higher than those used in the present studies, enhanced lethality would likely occur. This observation is consistent with the idea that individuals use such combinations to achieve enhanced effects from the drugs. In particular, the brain substrates of horizontal locomotion are closely related to those of drug reward Robinson and Berridge, ; Trujillo et al. Thus, the increase in locomotor behavior produced by the combination may be a reflection although indirect and nonspecific of increased reward. Indeed, enhanced rewarding effects have been reported from combinations of methamphetamine and heroin Ranaldi and Wise, Polydrug abuse is a complex issue, likely involving several potential interactions of drug combinations. However, the current results demonstrate that combinations of morphine and methamphetamine produce synergistic effects that likely contribute to the use and abuse of such combinations. These institutes had no involvement in study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The authors declare no conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. As a library, NLM provides access to scientific literature. Pharmacol Biochem Behav. Published in final edited form as: Pharmacol Biochem Behav. Find articles by Keith A Trujillo. Find articles by Monique L Smith. Find articles by Melissa M Guaderrama. Issue date Sep. All rights reserved. The publisher's version of this article is available at Pharmacol Biochem Behav. Open in a new tab. 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.

Powerful Behavioral Interactions Between Methamphetamine and Morphine

Trujillo buy Ecstasy

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors STBs. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts aOR range 0. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth. Suicide is the second leading cause of death among adolescents, and suicide rates in this population continue to rise despite years of research and medical advances 1 , 2. Even with a nearly exponential increase in the number of RCTs studying suicidal thoughts and behaviors STBs in the last decades, existing treatments have continued to have limited efficacy 3 , 4. Moreover, given that current research has not yielded improvements in treatment efficacy nor reductions in STBs among adolescents, there is a need for a wider range of research on factors that correlate with adolescent STBs. Classic psychedelics e. Conversely, these substances also can have negative consequences such as increased anxiety, paranoia, and significant distress associated with acute administration. Some of the most commonly used classic psychedelics are psilocybin the psychoactive agent in more than species of fungi , lysergic acid diethylamide LSD; derived from the hydrolysis of an ergot fungus , peyote a small cactus , and mescaline the main psychoactive compound in peyote. MDMA, on the other hand, is a synthetic amphetamine derivative that releases serotonin and is known to increase feelings of empathy and social connection; conversely, this substance can also give rise to adverse states of panic, anxiety, and fear as well. Researchers in the last decade have begun to explore the potential of classic psychedelics as a treatment for a multitude of mental disorders, many of which confer risk for STBs 7 , 8. Recent research has shown that classic psychedelics, most namely psilocybin and LSD, can alleviate anxiety and depression two of the main risk factors of suicide 9 , In a pilot experiment, researchers found that a single session of psilocybin-assisted psychotherapy led to sustained decreases in both anxiety and depression among subjects with advanced-stage cancer In , these findings were extended in a study that found that improvements in anxiety, depression, quality of life, and optimism due to psilocybin-assisted psychotherapy; furthermore, these improvements continued to be clinically significant at a 6-month follow-up Similarly, a pilot study in found that LSD can reduce anxiety when administered in a supervised psychotherapeutic environment Recent research has also found classic psychedelics to help treat substance use disorders, which are another significant risk factor for suicide 14 , 15 , MDMA-assisted psychotherapy in particular has been found to be not only safe, but also more effective than traditional therapy in patients with treatment-resistant PTSD 18 , 19 , 20 , 21 , It is important to note, however, that all of the aforementioned treatment studies on MDMA and classic psychedelics have been conducted using adult samples, underscoring the need for examining the link between these substances and suicidality in adolescents. Population-based survey studies, while not causal in nature, have helped further establish externally valid links between classic psychedelics and MDMA and STBs; these studies also invite further inquiry into the associations between psychedelics and suicidality in adolescents. A follow-up study by Hendricks et al. Additionally, Sexton et al. More recently, research by this team has extended previous work by analyzing data from the NSDUH spanning from to and found that lifetime MDMA use was associated with reduced odds of past-year suicidal thinking and planning while lifetime psilocybin use was associated with reduced odds of past month psychological distress and past year suicidal thinking in adults Importantly, this study also found that LSD was associated with increased odds of past-year suicidal thinking, indicating that in some cases classic psychedelics can confer increased risk for STBs. Although previous research has established an association between classic psychedelics and MDMA and STBs, few studies have examined the effects of these substances, let alone their link with STBs, among adolescents. Given that classic psychedelic use among adolescents has been rising 27 and MDMA is one of the most commonly used illicit substances by adolescents 28 , there is a need to assess the link between these substances and STBs in adolescents. This study used data from the National Survey on Drug Use and Health NSDUH; — , an annual survey that collects information on substance use and mental health outcomes in a nationally representative sample of the U. Furthermore, we carried out all methods in this project in accordance with the relevant guidelines and procedures. These independent variables were selected as this study aimed to extend findings from Jones and Nock a , which assessed the relationships of these substances to STBs in a sample of U. In line with Jones and Nock a , our study included the following demographic factors and substance use variables as a priori covariates in our analyses: sex, age, income, race, education, self-reported engagement in risky behavior, and lifetime use of the following substances cocaine, heroin, PCP, inhalants, pain relievers, tranquilizers, stimulants, sedatives, marijuana. Furthermore, these covariates also match those from numerous population-based psychedelic studies as well 23 , 25 , 29 , 30 , 31 , 32 , 33 , Our time horizons for the dependent variables in this study deviate from Jones and Nock a , which examined the associations between psychedelic use and past year STB outcomes for adults; however, all adolescent suicidality variables in the NSDUH assess lifetime STBs, thus explaining our approach for the current study. We used survey-weighted multivariable logistic regression to estimate the associations between our independent variables and our STB outcomes in this study. The demographics of our sample are presented in Table 1 , stratified by those who have versus have not tried classic psychedelics. Adolescents who have tried classic psychedelics were significantly more likely to fall into the following demographic categories: older, male, White, and more likely to engage in risky behavior. There were no significant differences in the income levels of those who had versus had not tried psychedelics. Psilocybin conferred significant lowered odds of all three outcome measures: lifetime suicidal thinking aOR 0. On the other hand, LSD conferred increased odds of all three outcomes: lifetime suicidal thinking aOR 1. In Supplemental Table 1 , we report the results from robustness analyses that assess whether our associations for psilocybin and LSD remain consistent while additionally controlling for a lifetime major depressive episode MDE , a major risk factor for suicide. We reconducted our original survey-weighted multivariable logistic regression models while including all of our original independent variables and covariates but also added a lifetime MDE in all models as a covariate as well. When we controlled for a lifetime MDE, psilocybin no longer shared a significant association with lifetime suicidal thinking aOR changed from 0. However, aside from this one difference, our pattern of results remained unchanged i. S adolescents. This study was an extension of Jones and Nock a , which tested the associations of the aforementioned substances to STBs in U. Importantly, this study yielded a similar pattern of results to Jones and Nock a , which found lifetime psilocybin use to be associated with reduced odds of past month psychological distress and past year suicidal thinking, and LSD to be associated with increased odds of past-year suicidal thinking in adults. The main limitation to this study is the findings cannot be used to establish a causal relationship between psychedelic use and STBs in adolescents. Future longitudinal research will be needed to more rigorously assess the associations that these substances share with STBs in adolescents. Additionally, because we used binary lifetime use outcomes to measure substance use, we cannot establish the recency nor the frequency of psychedelic use in the study. Relatedly, the operationalization of the variables in the NSDUH does not allow us to establish temporal precedence between psychedelic use and STBs as well. Follow-up work that employs more granular assessments of STBs can support a greater understanding of the impact of psychedelics on STBs in adolescents as well. Next, although we conducted robustness analyses to control for MDEs in our analyses, it nevertheless remains possible that psilocybin lowers odds of STBs by way of alleviating harmful and severe mental health conditions that give rise to STBs. Future studies that can control for a wider range of mental disorders and can assess the clinical severity of participants can overcome this limitation. Finally, multicollinearity—high levels of intercorrelation between independent variables in a given model—represents a possible limitation to our findings as well. However, the impact of multicollinearity on our results is likely minimal. The main effect of multicollinearity is to increase the standard errors within a given model, widening confidence intervals and making it less likely for statistical tests to reach significance; however, such an effect is mitigated in large sample sizes like the one included in this study Thus, although our independent variables may correlate with one another, one can remain confident in the observed findings, particularly given that they align with prior work in this research area Given the association between LSD use and increased odds of STBs in our study, LSD and other classic psychedelics may have caused harm at the individual or group level within our sample. Additionally, since these associations follow a pattern of results from other populations based research on classic psychedelics 26 , future research should be aimed at better understanding the link between naturalistic psychedelic use and adverse outcomes in both adolescents and adults. The need to study the potential harm of psychedelics is especially relevant as these substances are increasingly explored as potential treatments within clinical research. Although future research is needed, there are known risks associated with psychedelic use that may lead to increased odds of STBs. First, a risk associated with psychedelic use is that adolescent substance use is linked to the onset of substance use disorders, a key risk factor for suicide. For instance, epidemiological research has illustrated that individuals who start drinking at 11—12 years of age have nearly double the rate of problematic alcohol use than do individuals who begin drinking at age 21 Generally, young people have higher rates of substance abuse than those who are older as well Hence, adolescent psychedelic users may be at increased risk for problematic use of these substances and ultimately may be at higher risk for STBs. Future research should examine whether earlier psychedelic use is associated with increased risk of substance use disorders and STBs. Furthermore, adolescents might be less equipped to manage the distress engendered from bad trips, as research has demonstrated that younger individuals may be less successful at regulating their emotions Thus, adolescents may be at particular risk for STBs as a result of adverse psychedelic experiences. Psychedelic use is also reported to increase the risk of psychosis, although evidence on this link is equivocal Some historical studies have suggested that psychedelics engender an earlier onset of a psychotic break in individuals with premorbid mental illness Given that episodes of psychosis are a risk factor for STBs 42 , classic psychedelics could thereby also increase the odds of STBs in adolescents by increasing the risk of an early psychotic episode Our study also presents non-causal associations between psilocybin and lowered odds of STBs in adolescents that builds on previous work by Jones and Nock a linking psilocybin use with reduced odds of past year suicidal thinking in adults. Several mechanisms may underlie our findings linking psilocybin use to lowered odds of STBs in adolescents, although the below mechanisms remain speculative. For one, psilocybin use could have been associated with lowered odds of STBs in our sample because of demographic differences between adolescents who have versus have not used psilocybin. Future studies that examine the associations between demographics, LSD use, and STBs can shed light on these potential mechanisms. Additionally, there may be pre-drug differences between individuals who have versus have not used classic psychedelics, as previous work has found personality differences between psychedelic-using and psychedelic-naive adults that could extend to adolescent populations. Erritzoe et al. Thus, future work should further examine pre-drug differences associated with those who have versus have not used psychedelics, as investigations such as these may further explain our observed associations between psychedelics and STBs. Finally, there may be clinically-relevant third variable factors that also underlie these findings as well. For instance, there is robust evidence indicating that perceived social support from peers and school teachers is associated with STBs in adolescents, with greater support being linked to lowered odds of STBs 46 , If such differences exist within adolescent populations who have used psilocybin—such that adolescents who have used psilocybin spend more time with supportive peers or go to school in more supportive environments—these clinically relevant third variable factors may also underlie our observed findings. Better understanding the relationship between such factors and psilocybin use may further clarify the link between psilocybin and lowered odds of adolescent STBs. There are potential pharmacological explanations for our observed findings, although these mechanisms remain purely speculative. For instance, psilocybin may lower odds of STBs via interacting with and downregulating serotoninergic 5-HT2A receptors 48 , Suicidal behavior has been linked to alterations in the serotonergic system 50 , 51 and the activation of 5-HT2A receptors has been found to reduce markers of inflammation in adults that are linked to STBs and related mental health disorders Additionally, many mainline antidepressants and antipsychotics potentiate their effects through 5-HT2A receptors as well 53 , Thus, it is plausible that psilocybin could have lowered odds of STBs among our sample population through interactions with 5-HT2A receptors 50 , However, as none of the pharmacological mechanisms of psilocybin have been explored in adolescents, future pharmacological work is needed to better understand the link between psychedelic use and STBs in young people. These investigations can also further elucidate the mechanisms underlying any potential harm that may be associated with adolescent psychedelic use as well. Although classic psychedelic use among adolescents has been rising, and more attention has been given to the therapeutic and clinical potential of classic psychedelics in adults, we still know very little about how these drugs affect adolescent mental health. This study represents an important step forward to better understanding the relationship of psychedelic use to STBs in adolescents and highlights the importance of future cross-sectional, longitudinal, and clinical investigations within this research area. In: CDC. Accessed 5 Jan Hawton, K. Self-harm and suicide in adolescents. Lancet , — Article Google Scholar. Fox, K. Interventions for suicide and self-injury: A meta-analysis of randomized controlled trials across nearly 50 years of research. Kothgassner, O. Does treatment method matter? A meta-analysis of the past 20 years of research on therapeutic interventions for self-harm and suicidal ideation in adolescents. Griffiths, R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology , — Johnson, M. Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Editorial: Hallucinogens and entactogens: Establishing a new class of psychotherapeutic drugs?. Psychiatry 11 , Nutt, D. Effects of schedule I drug laws on neuroscience research and treatment innovation. Gaynes, B. Screening for suicide risk in adults: A summary of the evidence for the U. Hirschfeld, R. Assessment and treatment of suicidal patients. Grob, C. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Psychiatry 68 , 71—78 Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Gasser, P. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. Bohnert, K. Substance use disorders and the risk of suicide mortality among men and women in the U. Veterans health administration. Addiction , — Bogenschutz, M. Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Bentley, K. Anxiety and its disorders as risk factors for suicidal thoughts and behaviors: A meta-analytic review. Mitchell, J. Mithoefer, M. 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Age-related differences in emotional reactivity, regulation, and rejection sensitivity in adolescence. Emotion Washington DC 12 , — Strassman, R. Adverse reactions to psychedelic drugs. A review of the literature. Girgis, R. The neurobiology of suicide in psychosis: A systematic review. Pompili, M. Suicide risk in first episode psychosis: A selective review of the current literature. Erritzoe, D. Recreational use of psychedelics is associated with elevated personality trait openness: Exploration of associations with brain serotonin markers. Johnstad, P. The psychedelic personality: Personality structure and associations in a sample of psychedelics users. Drugs 53 , 97— Miller, A. Role of social support in adolescent suicidal ideation and suicide attempts. Health 56 , — Forster, M. The role of social support in the association between childhood adversity and adolescent self-injury and suicide: Findings from a statewide sample of high school students. Youth Adolesc. Ling, S. Molecular mechanisms of psilocybin and implications for the treatment of depression. CNS Drugs 36 , 17—30 Vollenweider, F. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Sudol, K. Biomarkers of suicide attempt behavior: Towards a biological model of risk. Psychiatry Rep. Underwood, M. Serotonin receptors and suicide, major depression, alcohol use disorder and reported early life adversity. Psychiatry 8 , 1—15 Flanagan, T. Psychedelics as anti-inflammatory agents. Psychiatry Abingdon Engl. Feighner, J. Mechanism of action of antidepressant medications. Psychiatry 60 Suppl 4 , 4—11 CAS Google Scholar. Schmidt, C. The role of 5-HT2A receptors in antipsychotic activity. Life Sci. Lengvenyte, A. Biological bases of suicidal behaviours: A narrative review. Download references. He has been a paid consultant in the past year for Microsoft Corporation, the Veterans Health Administration, Cerebral, and for legal cases regarding deaths by suicide. He is an unpaid scientific advisor for Empatica, Koko, and TalkLife. You can also search for this author in PubMed Google Scholar. Correspondence to Grant Jones. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Sci Rep 12 , Download citation. Received : 01 May Accepted : 02 December Published : 19 December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Human behaviour Psychology. Abstract Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. Race and ethnicity moderate the associations between lifetime psychedelic use MDMA and psilocybin and psychological distress and suicidality Article Open access 10 October Exploring protective associations between the use of classic psychedelics and cocaine use disorder: a population-based survey study Article Open access 16 February Introduction Suicide is the second leading cause of death among adolescents, and suicide rates in this population continue to rise despite years of research and medical advances 1 , 2. Method This study used data from the National Survey on Drug Use and Health NSDUH; — , an annual survey that collects information on substance use and mental health outcomes in a nationally representative sample of the U. Covariates In line with Jones and Nock a , our study included the following demographic factors and substance use variables as a priori covariates in our analyses: sex, age, income, race, education, self-reported engagement in risky behavior, and lifetime use of the following substances cocaine, heroin, PCP, inhalants, pain relievers, tranquilizers, stimulants, sedatives, marijuana. Analyses We used survey-weighted multivariable logistic regression to estimate the associations between our independent variables and our STB outcomes in this study. Results The demographics of our sample are presented in Table 1 , stratified by those who have versus have not tried classic psychedelics. Table 1 Demographic of those who have versus have not used classic psychedelics. Full size table. Limitations The main limitation to this study is the findings cannot be used to establish a causal relationship between psychedelic use and STBs in adolescents. Potential harm Given the association between LSD use and increased odds of STBs in our study, LSD and other classic psychedelics may have caused harm at the individual or group level within our sample. Potential mechanisms Our study also presents non-causal associations between psilocybin and lowered odds of STBs in adolescents that builds on previous work by Jones and Nock a linking psilocybin use with reduced odds of past year suicidal thinking in adults. Third variable factors For one, psilocybin use could have been associated with lowered odds of STBs in our sample because of demographic differences between adolescents who have versus have not used psilocybin. Pharmacological pathways There are potential pharmacological explanations for our observed findings, although these mechanisms remain purely speculative. Conclusion Although classic psychedelic use among adolescents has been rising, and more attention has been given to the therapeutic and clinical potential of classic psychedelics in adults, we still know very little about how these drugs affect adolescent mental health. Article Google Scholar Fox, K. Article Google Scholar Kothgassner, O. Article Google Scholar Griffiths, R. Article Google Scholar Nutt, D. Article Google Scholar Hirschfeld, R. Article Google Scholar Bohnert, K. Article Google Scholar Bogenschutz, M. Article Google Scholar Bentley, K. Article Google Scholar Mitchell, J. Article Google Scholar Mithoefer, M. Article Google Scholar Jones, G. Article Google Scholar Miech, R. Google Scholar Bates, M. Google Scholar Jones, G. Google Scholar Winters, K. Article Google Scholar Grant, B. Article Google Scholar Johnson, M. Google Scholar Silvers, J. Article Google Scholar Strassman, R. Article Google Scholar Pompili, M. Article Google Scholar Erritzoe, D. Article Google Scholar Miller, A. Article Google Scholar Forster, M. Article Google Scholar Ling, S. Article Google Scholar Underwood, M. Article Google Scholar Feighner, J. Article Google Scholar Download references. Funding Dr. View author publications. Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information. About this article. Cite this article Jones, G. Copy to clipboard. This article is cited by Novel mechanism-based treatments for pediatric anxiety and depressive disorders Chad M. Sylvester Joan L. Luby Daniel S. Pine Neuropsychopharmacology Optimizing real-world benefit and risk of new psychedelic medications: the need for innovative postmarket surveillance Joshua C. Black Andrew A. Monte Richard C. Publish with us For authors Language editing services Submit manuscript. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search. Close banner Close. Email address Sign up. Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing.

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