Designer drugs: mechanism of action and adverse effects.

Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at µ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

Designers Drugs-A New Challenge to Emergency Departments-An Observational Study in Poland.

Background and Objective: In the last decade, the phenomenon of using new psychoactive substances (NPS), called designer drugs, has been on rise. Though their production and marketing in Poland is prohibited, reports of the Supreme Audit Office noted that young people are increasingly reaching for new intoxication agents in the form of designer drugs. There is a significant increase in the number of patients with NPS abuse admitted to the emergency departments. As NPS cannot be detected by standard tests for the presence of psychoactive substances, it is difficult to choose the appropriate therapeutic intervention. Therefore, the aim of the present study was to evaluate the patient characteristics in the population of adults and children suspected of using NPS and formulate the protocol for diagnosis and treatment. Materials and Method: The paper is based on a retrospective analysis of medical records of hospitalized patients in the Clinical Emergency Department of The Regional Specialist Hospital in Olsztyn (SKOR WSS, emergency department (ED)) and the Pediatric Emergency Department of the Provincial Specialist Children's Hospital in Olsztyn (SORD WSSD, pediatric emergency department (PED)) between years 2013 to 2018. The patient records related to their general symptoms at admission, mental state and laboratory diagnostic tests were evaluated. Results: The majority of patients hospitalized due to the suspected use of NPS were adolescents in 2013-2016 and a reversal of this trend was observed in 2017-2018 when number of adults admitted to the emergency department (ED) due to NPS use was higher. The NPS abuse was significantly higher among male patients, alcoholics, people using other psychoactive substances, patients suffering from mental disorders and teenagers in difficult socio-economic family situations. Whereas, the most common symptoms among pediatric patients were co-ordination disorder and aggression, in adults mainly tachycardia and aggression was observed. The laboratory tests in significant number of adult patients showed leukocytosis and ketonuria. Conclusions: In the present study, no unambiguous toxidrome or biochemical pattern characteristic for using NPS was observed. However, evaluation of blood morphology, coagulation parameters, liver and kidney function can be helpful in the diagnostic and therapeutic process. Symptomatic treatment of patients, fluid therapy and sedation was sufficient in most cases to resolve the patient symptoms in 48 h.

Coagulopathic hemorrhage with use of synthetic cannabinoids.

Synthetic cannabinoids contain many different chemicals and compounds, which pose new health risks to the population using these drugs. In May of 2018 the Center for Disease Control issued a health alert providing information on a multistate outbreak of coagulopathy from exposure to synthetic cannabinoid products containing a Vitamin K-dependent antagonistic agent such as brodifacoum. Recognizing signs, symptoms and imaging findings related to this outbreak is essential for clinicians caring for patients with a history or suspicion of using synthetic cannabinoids. To our knowledge, there are no studies that report the imaging findings demonstrating the coagulopathic complications associated with these synthetic compounds.

Novel complication of Flakka: Stevens-Johnson syndrome/Toxic epidermal necrolysis overlap.

Flakka, as the newest member of the synthetic cathinone group, is a substance with serious cardiovascular, neurological, psychiatric, infectious effects and addictive potential. There are only a few case reports and laboratory studies in the literature and there is no dermatological side effects reported yet. We present the first Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN) overlap case after Flakka use.

Stimulant and Designer Drug Use: Primary Care Management.

Approximately 10% of the U.S. population 12 years and older reported using illicit substances in 2015. This article reviews the clinical effects and treatment of persons who use cocaine, methamphetamines, 3,4-methylenedioxymethamphetamine (MDMA), synthetic cannabinoids, and synthetic cathinones ("bath salts"). Cocaine blocks the reuptake of the monoamine transporters dopamine, norepinephrine, and serotonin. Immediate clinical effects include increased energy and euphoria, as well as hypertension and arrhythmias. Acute myocardial infarction, seizures, hallucinations, hyperthermia, and movement disorders are among the possible adverse effects. Like cocaine, methamphetamine blocks reuptake of monoamine transporters, but also stimulates dopamine release and has a longer duration of action. Methamphetamine misuse is associated with severe dental problems. MDMA is a stimulant and psychedelic with a chemical structure similar to serotonin. Adverse effects include serotonin syndrome, hyponatremia, long-term memory impairment, and mood disorders. Synthetic cannabinoids can have a more intense and long-lasting effect than natural cannabis. Acute intoxication may cause severe cardiac and respiratory complications and seizures. Synthetic cathinones are marketed as cheap substitutes for other stimulants. Their effects are similar to those of other stimulants, and they are addictive. Psychosocial intervention is the main form of treatment for addiction to these substances. Promising therapies include disulfiram and substitution therapy for cocaine misuse disorders, and mirtazapine for methamphetamine use disorder.

Seizures, Systemic Inflammatory Response, and Rhabdomyolysis Associated With Laboratory-Confirmed 2C-I and 25-I Exposure.

The 2C drugs are hallucinogenic phenethylamines. They and their n-benzyloxymethyl analogs have become popular as "legal highs," and significant toxicity has been attributed to their use. We report on a case of seizures, systemic inflammatory response, and rhabdomyolysis associated with laboratory-confirmed 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine exposure. A 17-year-old male teenager developed seizures after taking "2 strips of acid." The seizures resolved with midazolam, but he became apneic and was intubated. His head computed tomography was unremarkable. Initial creatinine level was 1.5 mg/dL, with a creatine kinase of 112 U/L. His urine immunoassay drug screen was negative. He was extubated within 12 hours but had elevated temperatures for 48 hours. He was treated with antibiotics, but no source of infection was identified. His creatinine level peaked at 2.46 mg/dL. His creatine kinase peaked 72 hours later at 14579 U/L. He was treated with intravenous fluids and did not require renal replacement therapy. He recovered fully and was discharged after 5 days. Serum and urine samples were tested using liquid chromatography time-of-flight mass spectrometry. We detected 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine in both serum and urine. No other substances were detected. The 2C drugs and their n-benzyloxymethyl analogs are potent serotonergic agents. Their use has been associated with multiple adverse effects including seizures, rhabdomyolysis, and death. They should be considered in differential diagnosis for drug-induced seizures and as a cause for systemic inflammatory response. This case highlights the significant toxicity seen with these compounds.

Alterations of the hematologic cells in synthetic cannabinoid users.

BACKGROUND: Functions, morphology, distributions, and index of the circulating cells are the most useful parameters that indicate various inflammatory and toxic conditions. The aim of this study was to investigate the clinical significance of these parameters in patients diagnosed with (synthetic) cannabis use disorder. METHODS: This study included a total of 40 patients in the study group (SG) with synthetic cannabis use; and 40 healthy individuals as the control group (CG). Participants, who had hematological disorders and other chronic diseases, were excluded from the study. All hematological parameters of SG were compared with CG. Neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) values were calculated and compared between groups. RESULTS: There were statistically significant differences between the groups in terms of WBC, MCH, RDW, MCV, MPV, and NEU, LYM%, MONO% parameters (P<.05). MPW and LYM% were significantly lower in SG compared to CG. WBC, MCH, RDW, MCV, MPV, MONO, and NEU parameters were significantly higher in SG compared to CG (P<.05). UIBC and TIBC levels were significantly higher in SG compared to CG (P<.001). Although there was statistically significant difference between groups in terms of NLR, there was no significant difference for PLR values. CONCLUSION: Our data suggested that chronic use of cannabinoids can lead to deterioration of hematopoietic cells. Chronic use of cannabinoids was consistent with subthreshold/subclinical megaloblastic anemia with iron deficiency. Inflammatory cells, especially neutrophil and monocyte counts were higher in SG compared to CG. Thus, recovery of subclinical hematological parameters should be considered in cannabis use disorder patients.

A case of fatal idiosyncratic reaction to the designer drug 3,4-methylenedioxypyrovalerone (MDPV) and review of the literature.

The stimulant designer drug 3,4-methylenedioxypyrovalerone (MDPV) was first synthesized by Boehringer Ingelheim in 1969 and introduced on the black market in 2006. Only a small number of fatal intoxication cases have been reported in the literature, all with significant blood MDPV concentrations. In this report, we describe one fatality attributed to an idiosyncratic reaction to MDPV. The victim displayed agitation, violent behavior and delirium followed by cardiac arrest. Hyperthermia was observed at the hospital. The MDPV cardiac and femoral blood concentrations were 6 ng/mL. The presence of excited delirium syndrome and MDPV, a drug with a pharmacology similar to cocaine, leads to the conclusion that the victim suffered a fatal adverse reaction to MDPV. This is the first published case of idiosyncratic reaction to MDPV.

Increase in Adverse Reactions Associated with Use of Synthetic Cannabinoids - Anchorage, Alaska, 2015-2016.

In July 2015, personnel in the Alaska Division of Public Health's Section of Epidemiology became aware of an increase in the number of patients being treated in Anchorage hospital emergency departments for adverse reactions associated with use of synthetic cannabinoids (SCs). SCs are a chemically diverse class of designer drugs that bind to the same cannabinoid receptors as tetrahydrocannabinol, the main psychoactive component of cannabis. A public health investigation was initiated to describe clinical outcomes, characterize the outbreak, and identify SC chemicals circulating in Anchorage. During July 15, 2015-March 15, 2016, a total of 1,351 ambulance transports to Anchorage emergency departments for adverse SC reactions were identified. A review of charts obtained from two Anchorage hospitals determined that among 167 emergency department visits for adverse SC reactions during July 15-September 30, 2015, 11 (6.6%) involved a patient who required endotracheal intubation, 17 (10.2%) involved a patient who was admitted to the intensive care unit, and 66 (39.5%) involved a patient classified as being homeless. Testing of 25 product and paraphernalia samples collected from patients at one hospital identified 11 different SC chemicals. Educational outreach campaigns focused on the considerable health risks of using SCs need to complement judicial and law enforcement actions to reduce SC use.

Staphylococcus aureus bacteraemia associated with injected new psychoactive substances.

Injecting drug use is often associated with deep-seated infection. In Lothian in Scotland there has been a recent increase in the use of injected new psychoactive substances (NPS). Patients who have injected NPS have presented with Staphylococcus aureus bacteraemia (SAB) with life-threatening complications. We describe a unique case-series of 14 episodes of SAB in ten patients. Users of injected NPS had a significantly higher incidence of endocarditis and cavitating pulmonary lesions (P < 0·05) compared to those who inject only opiates. Cases of SAB in people who inject NPS have contributed to a significant rise in the overall incidence of SAB in people who inject drugs (P < 0·05) which has in turn impacted on the ability of Lothian to meet national targets for reducing the incidence of SAB.

Designer Drugs and the Impact on the Adolescent User.

There are serious concerns regarding adolescent use of designer drugs. Designer drug usage is often undetected and can result in life-threatening physical and psychiatric reactions. This article explores the history of designer drugs, identifies some of the more recent designer drugs available, distinguishes the symptoms of designer drugs usage, and identifies reasons the designer drugs are popular with our young population. Lastly, this paper addresses what nurses can do to facilitate early and proper treatment to reduce serious physiological damage and death that can result from not detecting the use of designer drugs.

[Synthetic Drugs - An Overview of Important and Newly Emerging Substances]. / Synthetische Drogen ­ wichtige und neue Substanzen im Überblick.

Background: Synthetic drug use and abuse are on the rise. Governmental institutions report a shift in consumption from natural drugs to synthetic drugs, and show an increase in confiscation, particularly of methamphetamine and newly identified psychoactive substances. In addition, the media report an alarming increase in the rate of consumption and casualties resulting from the use of drugs such as "crystal meth" and warn against a flood of this and other designer drugs from eastern European countries. Objectives: The present article gives an overview of current popular and widely used synthetic drugs, both classical substances (amphetamine, methamphetamine, MDMA) and new psychoactive substances ("designer drugs", "legal highs"). It addresses their pharmacology, effects, side effects, and risks. It furthermore explores newly emerging problems for the health system and clinical practice regarding the treatment of intoxication as well as withdrawal. Methods: The current scientific literature concerning synthetic drugs is summarized and official statistics and reports provided by the government are reviewed. Results: Different derivatives of amphetamine vary in their risk of harm and addictive potential. Methamphetamine, one of the most dangerous derivatives, is increasingly being consumed in certain regions of Germany. New psychoactive substances represent a heterogeneous group of substances. Since the substances are often unknown to the user, they are unpredictable in their effects and side effects.

The Spice of Life...and Death: A Case Presentation and Review of Synthetic Marijuana Use in Mississippi.

Like cocaine and heroin before, SCs represent a major health risk to individuals. The ever-changing formulations ofSCs make them potentially more toxic, as manufactures attempt to skirt current drug laws. Catastrophic neurologic, cardiovascular and renal disease may result from SCs and other impurities packaged with these "herbal products". Ongoing education to the public about these hazardous drugs is needed to 'Combat the fact that they are sometimes promoted as safe and natural. The epidemic of SC use must be emphasized to Mississippi physicians to improve recognition of SC symptoms until a rapid detection assay is available.

[Cannabinoid and cathinone designer drugs - the workings and selected methods of analysis]. / Dopalacze z grupy kannabinoidów i katynonów ­ dzialanie oraz wybrane metody analizy.

Recently, there has been an increase in the consumption of designer drugs, substances aimed at producing psychoactive, energizing, euphoric or anesthetic effects. Designer drugs are substitutes of actual narcotics, whose possession is banned under Polish law according to the Act of 29 July 2005. The latest reports suggest that the number of synthetic psychoactive substances is increasing. In the span of 2012, a total of 28 new synthetic cannabinoids were discovered in member states of the European Union. Synthetic psychoactive substances appear in different forms on the market: tablets (often very colourful and interestingly-shaped), seeds, dried product (sprayed with synthetic substance and redried), crystals or powder. The way of application is greatly diverse, and depends on the form in which a drug is produced and dispensed. The methods of intoxication include smoke inhalation (oftentimes blends are smoked), intranasal or oral application, placing crystals on the eye, or injection. Said methods correspond, with varying degrees, to invoking different psychotic effects, such as agitation, panic attacks, paranoia, hallucinations, overall irritation, and aggression. Various cardiovascular effects, such as tachycardia or increase in blood pressure, may follow as well. However, the primary influence is on the nervous system, inhibiting the reuptake of neurotransmitters such as serotonin, noradrenalin and dopamine, and leading to their increased concentration at the presynaptic cleft, which in turn causes feelings of agitation and pleasure. The knowledge regarding the strength, toxicity, and metabolism of designer drugs is yet sparse. The same pertains to the knowledge regarding the handling of overdose cases.

[Knowledge to the subject of legal highs and popularity of their use amongst secondary-school students from the Silesian Voivodeship].

Aim of work: Evaluation of knowledge to the subject of legal highs and popularity of their use amongst secondary-school students from the Silesian Voivodeship. Material and Methods: Studies were conducted in spring of 2016 in two randomly selected secondary schools in Katowice and Dabrowa Górnicza. The survey was carried out amongst students of these schools and concerned question about the knowledge of legal highs effect on the body and their use by young people. The study consisted of 336 questionnaire forms, 159 filled by secondaryschool students from Katowice and 177 by secondary-school students from Dabrowa Górnicza. Results: Legal highs for 78.3% of young people are as dangerous as drugs. Almost 70% of respondents believe that legal highs strongly affected the physical health, psyche, may cause a loss of life or health, as well as cause addiction. As the main effects of legal highs, young people point to strong agitation and aggression, as well as visions and hallucinations. 12.5% of respondents answered "Yes" to the question, whether they ever took legal highs. Most of students (69.7%) think that legal highs should be forbidden. Conclusions: The use of legal highs declared 12.5% of secondaryschool students. Most of respondents are aware of threats to health associated with use of legal highs.

Baths salts, spice, and related designer drugs: the science behind the headlines.

The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e., "spice") are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.

Myocardial Ischemia Secondary to Synthetic Cannabinoid (K2) Use in Pediatric Patients.

K2 is a synthetic cannabinoid that has potential cardiovascular side effects, including myocardial ischemia, myocardial infarction, and arrhythmias. Cardiac testing of pediatric patients is often not performed owing to a lack of symptomatology. We report a series of pediatric patients with concern for myocardial ischemia temporally associated with K2 exposure.

Driving under the influence of synthetic phenethylamines: a case series.

New psychoactive drugs, so-called legal highs, have gained more and more popularity during the last years. One of the most important groups of these legal high substances are the synthetic phenethylamines that share a common phenethylamine moiety. Based on certain structural characteristics, these synthetic phenethylamines can be divided into further subclasses, among which the synthetic cathinones ('bath salts') are particularly noteworthy. Synthetic cathinones are characterized by an additional carbonyl group attached at the beta position on the amino alkyl chain. Consumption of synthetic phenethylamines can lead to impairments similar to those observed after the use of, for instance, amphetamine or 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy'). These impairments include diverse neurological and psychological symptoms which can affect a safe driving behaviour. Although several reports on clinical symptoms and poisonings due to these substances have been published, most of these publications do not contain any analytical data. Additionally, there is still a lack of information concerning pharmacological and toxicological effects of these rather new psychoactive substances. In particular, the knowledge of the impact on the ability to drive following consumption of synthetic phenethylamines is relevant for the police as well as for forensic toxicologists. In this publication, several cases of individuals driving under the influence (DUI) of synthetic phenethylamines (4-fluoroamphetamine, mephedrone (4-methylmethcathinone, 4-MMC), 2-DPMP (desoxypipradol), methylenedioxypyrovalerone (MDPV), benzedrone, N-ethylamphetamine (etilamfetamine), 3-methylmethcathinone (3-MMC)) are presented, focusing on analytical results and signs of impairment.

The effect of banning MDPV on the incidence of MDPV-positive findings among users of illegal drugs and on court decisions in traffic cases in Finland.

In this study, we sought to determine what impact the banning of 3, 4- methylenedioxypyrovalerone (MDPV) had on the incidence of MDPV-positive findings and on user profiles in driving under the influence of drugs (DUID) and postmortem (PM) investigations in Finland. All MDPV-positive cases and a selection of corresponding court cases between 2009 and 2012 were examined. The median serum concentration of MDPV in DUID cases was 0.030 mg/L and in PM blood 0.12 mg/L. The number of MDPV-positive cases decreased both in DUID and PM investigations after the drug was banned. The decrease in the mean monthly numbers of MDPV-positive DUID cases was 51.1%. In court cases, MDPV was rarely mentioned until banned and frequently mentioned thereafter. Of the convicted, 37% were without a fixed abode, 98% had other charges besides that of DUID, and 13% appeared in the study material more than once. In MDPV-positive PM cases, the proportion of suicides was very high (24%). Research on new psychoactive substances is required not only to support banning decisions but more importantly to be able to provide a scientific assessment of the risks of these new substances to the public and potential users.

Psyclones: a roller coaster of life? Hidden synthetic cannabinoids and stimulants in apparently harmless products.

OBJECTIVE: The urge to gain information on a new drug marketed online as 'Psyclone' has emerged after the death of a 38-year-old man in Bolton (UK). The fatality appeared to be a consequence of smoking this psychoactive product. METHODS: From October to December 2013, qualitative searches of the Web have been carried out in English and Italian, using the keywords 'Psyclone', 'Psyclone legal high', 'Psyclone incense' and 'Psyclone research chemical' on the Google search engine and on the database provided by the Global Public Health Intelligence Network. RESULTS: Our research highlighted the existence of two psychoactive products labelled as Psyclone but with different contents and packaging: a herbal blend containing two synthetic cannabinoids (AKB-48 and 5f-PB-22) and a research chemical containing 50% ethylphenidate, 30% caffeine and 20% lidocaine. Desired and side effects of both compounds are explored in the paper. CONCLUSIONS: Being sold as a legal product, Psyclone may appeal to recreational users, who remain unaware of its real content. This is a serious public health threat, which may lead to acute intoxications and fatalities. Further studies in the field, including Internet monitoring, are therefore required.