piperidines and 2-diphenylmethylpiperidine

2-DPMP (desoxypipradrol, 2-benzhydrylpiperidine, 2-phenylmethylpiperidine) and D2PM (diphenyl-2-pyrrolidin-2-yl-methanol, diphenylprolinol) are psychoactive substances, sold primarily over the Internet and in 'head' shops as 'legal highs', 'research chemicals' or 'plant food'. Originally developed in the 1950s for the treatment of narcolepsy and ADHD, 2-DPMP's use soon became very limited. Recreational use of 2-DPMP and D2PM appears to have started in March 2007, but only developed slowly. However, in the UK their popularity grew in 2009, increasing rapidly during summer 2010. At this time, there were many presentations to UK Emergency Departments by patients complaining of undesirable physical and psychiatric effects after taking 2-DPMP. In spring 2011 there were similar presentations for D2PM. Recreational use of these drugs has been reported only occasionally in on-line user fora. There is little scientifically-based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of these drugs. Here we describe what is known about them, especially on their toxicity, including what we believe to be the first three deaths involving the use of 2-DPMP in August 2010. There are no international controls imposed on 2-DPMP or D2PM. However, a ban on their UK importation was imposed in November 2011 and they became Class C drugs on 13 June 2012. It is critical that any other cases, including non-fatal overdoses, are documented so that a scientific evidence-base can be established for them.

Topics: Drug Administration Routes; Drug and Narcotic Control; Humans; Illicit Drugs; Molecular Structure; Piperidines; Pyrrolidines

Over the last decade there has been greater use of novel psychoactive substances ('legal highs') across Europe and the United States, including increasing reports of use of diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP). This review will discuss the pharmacology and mechanisms of action of these two compounds, available data on their sources and prevalence of use and reports of acute toxicity and fatalities associated with their use.. PubMed was searched using the search terms 'D2PM', '2-DPMP', 'diphenyl-2-pyrrolidinyl-methanol', 'diphenylprolinol', '2-diphenylmethylpiperidine' and 'desoxypipradrol'. These searches identified 70 articles, only five of which were relevant. PHARMACOLOGY AND MECHANISMS OF ACTION: D2PM is a pyrrolidine analogue and 2-DPMP is a desoxy analogue of pipradrol. Animal studies have shown that 2-DPMP increases the release of dopamine and decreases dopamine re-uptake comparable to the effects of cocaine. The binding and activity of D2PM at the dopamine re-uptake transporter, based on currently published data, is also similar to cocaine, although it appears that D2PM has less biological activity. SOURCES AND PREVALENCE OF USE: D2PM and 2-DPMP is available from internet-based suppliers and street level drug dealers; there is currently no systematic data to be able to determine the relative importance of these routes of supply. There is no population level, and limited subpopulation level, data on the prevalence of use of D2PM/2-DPMP. In one 2011 study, 1.6% of 315 individuals in 'gay friendly' nightclubs in South London reported that they had used a pipradrol: 1.0% had used within the last year and 0.6% had used or were planning to use a pipradrol on the night of the survey. ACUTE TOXICITY: Reports on internet discussion fora describe prolonged euphoria and stimulant effects including euphoria, sweating and bruxism with use of D2PM and 2-DPMP. The first report of analytically confirmed acute D2PM toxicity described chest pain and sympathomimetic features (hypertension and tachycardia). Five individuals with analytically confirmed acute D2PM toxicity developed agitation/anxiety and/or insomnia lasting 24-96 h in addition to sympathomimetic features (palpitations, anxiety and agitation). Reports of 49 enquiries relating to a 'legal high' product called 'Whack' (which on analysis was found to contain 2-DPMP and fluorotropacocaine) commonly described unwanted cardiovascular (hypertension in 10/49 and tachycardia in 12/49) and neuropsychiatric (agitation in 14/49 and psychosis in 13/49) effects; the neuropsychiatric effects were prolonged, and persisted for up to 5 days. No analysis of biological samples was undertaken so it is not possible to determine which of these agents if any was responsible for the clinical features. In a series of 26 cases related to the use of 'Ivory Wave' (analysis of a similar 'Ivory Wave' product showed that it contained 2-DPMP), 96% had neur. There is emerging evidence of the use of D2PM and 2-DPMP in Europe. D2PM and 2-DPMP have sympathomimetic properties similar to cocaine and, in addition, prolonged and clinically significant neuropsychiatric symptoms have been reported.

Topics: Animals; Europe; Humans; Illicit Drugs; Piperidines; Psychotropic Drugs; Pyrrolidines; Time Factors; United States

Desoxypipradrol (2-DPMP), a new psychoactive substance (NPS), acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). NDRIs can be addictive due to their action mechanisms similar to cocaine and methamphetamine. However, there is a lack of scientific information regarding the exact dependency of 2-DPMP. Thus, the purpose of this study was to evaluate rewarding and reinforcing effects of 2-DPMP in rodents. The effective dose range of 2-DPMP was determined by climbing behavior test. To evaluate rewarding effects of 2-DPMP, conditioned place preference (CPP) test was performed at selected doses in mice. Self-administration (SA) test was then undertaken at two doses that caused the highest effects in the CPP test. Dopamine level changes were analyzed using synaptosomes in order to investigate effects of 2-DPMP on the central nervous system (CNS). Significant responses were observed in the climbing behavior test at doses of 0.1, 0.5, and 1 mg/kg by intraperitoneal injection (i.p.). In the CPP test, mice i.p. administered 2-DPMP at 1 mg/kg showed a significant preference in drug-paired compartment. In the SA test, mice intravenously given 0.1 mg/kg/infusion showed significantly higher active lever responses. Further, dopamine was increased in a dose-dependent manner. Taken together, these results suggest that 2-DPMP may act on the CNS and induce rewarding and reinforcing effects, indicating its dependence liability.

Topics: Animals; Behavior, Animal; Conditioning, Psychological; Dopamine; Dose-Response Relationship, Drug; Male; Mice; Piperidines; Reward; Self Administration; Synaptosomes

Novel psychoactive substances (NPS) are easily accessible and the consumption has increased in recent years. New compounds as well as compounds derived from pharmaceutical research or the patent literature are provided, mostly without any declaration. As a consequence, severe adverse reactions may occur after consumption of unknown doses of these drugs, in particular after mixed intake of different psychoactive substances or co-medication. The toxic effects in such cases are not predictable. We report cases of rhabdomyolysis in patients after consumption of desoxipipradrol in combination with other NPS. Particularly in case of synergistic serotonergic effects a distinct stimulation of 5-HT2A-receptors (or 5-HT1A-receptors) should be considered which may lead to serotonergic syndrome.

Topics: Adolescent; Adult; Designer Drugs; Diagnosis, Differential; Female; Humans; Illicit Drugs; Male; Piperidines; Psychotropic Drugs; Rhabdomyolysis; Serotonin Syndrome; Young Adult

The aim of this study was to assess the incidence of the use of desoxypipradrol (2-DPMP) among drivers apprehended on suspicion of driving under the influence of drugs (DUID) and the prevalence of the drug in post-mortem cases in Finland. Serum samples from drivers apprehended on suspicion of DUID and blood samples from post-mortem cases in Finland between October 2010 and May 2012 were analysed for the presence of desoxypipradrol. All samples were analysed for desoxypipradrol by mass spectrometric methods following comprehensive drug screening. Psychomotor performance of subjects was assessed by a clinician. There were 106 positive desoxypipradrol samples from apprehended drivers (1.7% of all confirmed DUID cases) in the study period. In most cases amphetamine and/or benzodiazepines were also present. The median (range) desoxypipradrol concentration was 0.073 mg/L (0.006-0.890 mg/L). The presence of other psychoactive drugs confounded assessment of the effect of desoxypipradrol on psychomotor performance except for one case in which it was the only drug present at pharmacologically active levels. Desoxypipradrol was found in 5 autopsy cases (0.05% of the investigated cases) and thought to contribute to death in two of these. Even though there are few data available on the pharmacology of desoxypipradrol, based on our findings, and the growing number of users, it is reasonable to assume that desoxypipradrol - a long-acting psychostimulant with dangerous side effects has an increasing detrimental impact on traffic safety in Finland. However, it was only rarely found to be the cause of death in post-mortem cases.

Topics: Adult; Automobile Driving; Chromatography, Liquid; Female; Finland; Forensic Toxicology; Humans; Limit of Detection; Male; Mass Spectrometry; Middle Aged; Molecular Structure; Piperidines; Psychomotor Performance; Psychotropic Drugs; Substance Abuse Detection; Substance-Related Disorders; Vitreous Body; Young Adult

The antihistaminic, antiserotonergic drug cyproheptadine (CPH) is known to inhibit insulin synthesis in vivo and in vitro. This inhibition of insulin synthesis occurs without a commensurate decrease in preproinsulin mRNA (PPImRNA) levels, suggesting a post-transcriptional mechanism of action. The goal of the present study was to investigate the direct effects of CPH on translation of PPImRNA in RINm5F cells. Results produced using a subcellular fractionation technique followed by real-time RT-PCR indicated that a 2-h 10 microM CPH treatment resulted in a decrease in the percentage of cellular PPImRNA associated with endoplasmic reticulum (ER) bound polysomes and increases in the percentages of translationally uninitiated and monoribosome-associated PPImRNA. These alterations in PPImRNA distribution were found to be concentration-dependent, chemical structure-specific, and reversible with a time course consistent with a previously reported CPH-induced inhibition of insulin synthesis. Further investigations to examine the possible effect of CPH on translation initiation were then undertaken by examining the phosphorylation state of the translation initiation factors eIF2alpha, eIF4E, and 4E-BP1 after CPH treatment. CPH (10 microM) treatment resulted in increased phosphorylation of eIF2alpha, and decreased phosphorylation of both eIF4E and 4E-BP1. These changes are all consistent with decreased initiation of translation. Taken together, these results suggest that the inhibition of insulin synthesis known to be elicited by CPH treatment of RINm5F cells and intact animals involves alterations of initiation factor phosphorylation leading to a decrease in insulin synthesis and of stored insulin in insulin-producing cells.

Topics: Animals; Cell Fractionation; Cell Line, Tumor; Cyproheptadine; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Insulin; Insulin Antagonists; Phosphorylation; Piperidines; Proinsulin; Protein Biosynthesis; Protein Precursors; Rats; RNA, Messenger; Time Factors

The clonal insulin producing cell line RINm5F was evaluated as a model for the action of cyproheptadine (CPH)-like diabetogenic compounds in the rat pancreas. Treatment with 10 microM CPH and selected structural analogs under culture conditions produced a progressive loss of cellular insulin which reached 30% of control within 24 hours. Comparison of the activities of the analogs 4-diphenylmethylpiperidine (4-DPMP) and 2-diphenylmethylpiperidine (2-DPMP) to produce cellular insulin depletion showed that 4-DPMP was as active as CPH but 2-DPMP had no activity at the highest concentration employed (10 microM). The CPH metabolite desmethyl CPH-epoxide was five times more active than the parent compound in producing loss of insulin in RINm5F cells. These results are consistent with previously published results of CPH actions in vivo. An inhibition of insulin biosynthesis with no loss of preproinsulin mRNA occurred in RINm5F cells treated with CPH or DMCPH-epoxide. This suggests that an effect on transcription may not be the primary action by which CPH and its analogs inhibit insulin synthesis in vivo.

Topics: Animals; Blotting, Northern; Cyproheptadine; DNA; Indicators and Reagents; Insulin; Insulinoma; Pancreatic Neoplasms; Piperidines; Rats; RNA, Messenger; Tumor Cells, Cultured