Acute skin and hair symptoms followed by severe, delayed eye complications in subjects using the synthetic opioid MT-45.

BACKGROUND: The introduction of unclassified new psychoactive substances (NPS) on the recreational drugs market through open online sale ('legal highs' or 'Internet drugs') continues unabated and represents a growing health hazard. The use of NPS has resulted in numerous, severe, adverse events and fatalities, due to unintended overdose or unknown toxic side-effects. OBJECTIVES: To try to find a possible common underlying cause for the skin-hair-eye symptoms complex observed in three men. METHODS: From late 2013 to mid-2014, three Swedish men aged 23-34 years with a history of recreational drug use independently presented with similar and very remarkable clinical signs, requiring extensive examination and prolonged treatment. RESULTS: Common clinical signs included hair depigmentation, hair loss, widespread folliculitis and dermatitis, painful intertriginous dermatitis, dry eyes, and elevated liver enzymes. Two of them also showed transverse white Mees' lines (leukonychia striata) on the fingernails and toenails, suggesting a temporary, drug-induced, disorganized keratinization. The clinical signs gradually disappeared over time. However, later on, two developed severe bilateral secondary cataracts requiring surgery. Because drug tests within the Swedish STRIDA project had demonstrated intake of the NPS opioid MT-45 in all patients, this was suspected to be the common causative agent. CONCLUSIONS: These cases highlight the importance for physicians and health professionals to consider the increasing number of novel, untested recreational drugs, as a potential cause of unusual and otherwise unrecognized clinical signs and symptoms.

MT-45, a new psychoactive substance associated with hearing loss and unconsciousness.

BACKGROUND: MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) is an opioid analgesic drug candidate developed in the 1970s that has recently been introduced as a new psychoactive substance (NPS) on the "recreational" drug market. We describe a case series of non-fatal intoxications associated with MT-45 within the Swedish STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden from November 2013 to February 2014. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. NPS analysis was performed by an LC-MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. CASE SERIES. Among nine intoxications where MT-45 was detected in the biological samples, four cases were indicated to only involve MT-45, while one or several psychoactive substances were found along with MT-45 in the others. All patients were men aged 17-32 years and they commonly presented with opioid-like adverse symptoms, such as unconsciousness and respiratory depression. Naloxone appeared to have utility in the treatment of MT-45 intoxication in several cases. Three patients complained of bilateral hearing loss that in one case persisted after two weeks. CONCLUSION: MT-45 should be added to the growing list of harmful NPS causing life-threatening poisonings, and rapid actions taken to make it a controlled substance.

Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): a case series from the Swedish STRIDA project.

CONTEXT: 5-(2-aminopropyl)indole (5-IT) is a new psychoactive substance (NPS; "legal high" or "research chemical") structurally related to indoleamines and substituted phenethylamines and implicated in several fatalities. We describe the clinical characteristics and results of laboratory investigations of 14 analytically confirmed nonfatal cases of 5-IT intoxication within the Swedish STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden in 2012. PATIENTS AND METHODS: Blood and/or urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. Analysis of NPS was performed using an LC-MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the Poisoning Severity Score (PSS). RESULTS: Eleven male and three female patients (age: 21-53 years, median: 27) tested positive for 5-IT in 2012, all cases appearing in April-July. The 5-IT concentration in serum ranged between 0.015 and 0.59 µg/mL (median: 0.22; n = 8) and in urine between 0.005 and 24.7 µg/mL (median: 5.95; n = 12). Five intoxications were indicated to be caused by 5-IT alone, whereas additional psychoactive substances were detected in the other nine cases. Six (43%) of fourteen cases were graded as severe (PSS 3), five (36%) as moderate (PSS 2), and three (21%) as minor (PSS 1) poisonings. In the severe cases, agitation, hallucinations, dilated pupils without light reaction, tachycardia, hypertension, hyperthermia, myoclonus, muscle rigidity, arrhythmias, seizures, rhabdomyolysis, and/or renal failure were noted. CONCLUSIONS: The results demonstrated that severe clinical toxicity was commonly present in patients with analytically confirmed 5-IT exposure. The clinical features are consistent with a sympathomimetic toxidrome, and some patients also displayed symptoms associated with serotonin toxicity.

Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice.

A mutation in the mouse tub gene causes a phenotype characterized by maturity-onset obesity, blindness and deafness. The role of the intact tubby protein and the pathogenesis resulting in the phenotype of tub/tub mice remain largely unknown. In this study, we have investigated whether obese tub/tub mice exhibit altered expression levels for agouti-related protein (AGRP) or glutamic acid decarboxylase-65 (GAD65) in body weight-regulating neurons of the hypothalamic arcuate nucleus. In situ hybridization revealed that AGRP, but not GAD65 mRNA levels, were significantly lower in obese tub/tub mice as compared to tub/+ mice. The lower levels of AGRP mRNA in the arcuate nucleus of tub/tub mice were paralleled by lower fluorescence intensity and numbers of AGRP- and neuropeptide Y (NPY)-immunoreactive (ir) nerve fibers and terminals in the arcuate, ventromedial, dorsomedial hypothalamic nuclei and perifornical and lateral hypothalamic areas. No obvious differences in GAD65-ir nerve fibers and terminals could be detected. Measurements of daily food intake revealed that tub/tub mice displayed progressively higher food consumption as compared to lean tub/+ littermates over a 15-day observation period. When moved to an unfamiliar environment, e.g. a novel cage, daily food intake was initially lower in tub/tub mice than in tub/+ mice suggesting that tub/tub mice may be more sensitive to psychogenic stress. The results together show that tub/tub mice are hyperphagic and exhibit, within the hypothalamic arcuate nucleus, a depressed expression of neuropeptides involved in the regulation of feeding behavior.

Cellular localization of GABA receptor alpha subunit immunoreactivity in the rat hypothalamus: relationship with neurones containing orexigenic or anorexigenic peptides.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, acts via two different type of GABA receptors. GABA(A) receptors are composed of five subunits that belong to eight different classes. Depending on their subunit composition, distinct pharmacological and electrophysiological properties are obtained. GABA is produced in certain hypothalamic neurones known to be involved in control of feeding behaviour. We report the detailed immunohistochemical localization of four GABA(A)R alpha subunits in hypothalamic regions associated with the regulation of feeding behaviour. Immunoreactive structures for all studied GABA(A)R alpha subunits were observed in the hypothalamus, but with subunit-specific staining patterns. GABA(A)R alpha(1) immunoreactivity was most prominent in the dorsomedial hypothalamic nucleus and in the lateral hypothalamic area (LHA), whereas GABA(A)R alpha(2), alpha(3) and alpha(5) subunits exhibited particularly strong immunoreactivity in the ventromedial hypothalamic nucleus. In comparison, GABA(A)R alpha subunit immunoreactivities were generally weak in the arcuate nucleus. In the ventromedial part of the arcuate nucleus, neuropeptide Y- and agouti-related peptide-containing cell bodies, which also are known to be GABAergic, were immunoreactive for only the GABA(A)R alpha(3) subunit, whereas pro-opiomelanocortin- and cocaine- and amphetamine-regulated transcript- containing cell bodies located in the ventrolateral subdivision of the arcuate nucleus, showed GABA(A)R alpha(1), alpha(2) and alpha(3) subunit immunoreactivity. In the LHA, GABA(A)R alpha(3) subunit immunoreactivity was demonstrated in both melanin-concentrating hormone (MCH) and orexin-containing neurones. In addition, MCH neurones contained GABA(A)R alpha(2) immunoreactivity. In neurones of the tuberomammillary nucleus, GABA(A)R alpha(2) and alpha(5) subunits were colocalized with histidine decarboxylase, a marker for histamine-containing neurones.

Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight.

Gamma-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABA(A) and metabotropic GABA(B) receptors. The functional form of the GABA(B) receptor is a heterodimer consisting of GABA(B) receptor-1 (GABA(B)R1) and GABA(B) receptor-2 (GABA(B)R2) proteins. Within the heterodimer, the GABA-binding site is localized to GABA(B)R1. In the present study, we used an antiserum to the GABA(B)R1 protein in order to investigate the cellular localization of GABA(B)R1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABA(B)R1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABA(B)R1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABA(B)R1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABA(B)R1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABA(B)R1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABA(B)R1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABA(B) receptors.