Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

Clinical and psychological characteristics of propofol abusers in Korea: a survey of propofol abuse in 38, non-healthcare professionals / 대한마취과학회지

BACKGROUND: The aim of this study is to investigate the characteristics of propofol abuse based on the results of a survey analysis of abusers among non-healthcare professionals in Korea. METHODS: Thirty-eight propofol abusers were questioned between October and December 2010, and were enrolled and voluntarily participated in a structured survey consisting of an interview and completing a previously prepared questionnaire. The questionnaire was divided into three distinct parts: part 1 dealt with the history of propofol abuse; part 2 highlighted the problems caused by propofol abuse; and part 3 enquired regarding demographics of abusers. RESULTS: Thirty-one (81.6%) of the 38 interviewees abused propofol for more than one year. During the last 12 months, 34 (89.0%) received propofol at two or three times a week. The minimum and maximum amounts of propofol (median, range) administered each time were 500 (100, 1000) and 2000 (500, 4000) mg, respectively. Stress relief and the maintenance of a sense of well-being were quoted the most important reasons for the first-time administration of propofol and its subsequent abuse, respectively. The majority of abusers (36.0, 97.3%) reported a sense of pleasure or euphoria at the time of their propofol injection. Withdrawal symptoms occurred in five abusers (13.2%). Thirteen (36.1%) reported disruptions in their work life. None of the respondents had previously admitted to and or reported abuse of any other controlled substances. CONCLUSIONS: These results provided reference data for the regulation of propofol in Korea as a controlled substance and may also be of interest to international agencies in other countries.

Programas de monitoreo de medicamentos de prescripción en los Estados Unidos de América / Prescription drug monitoring programs in the United States of America

Desde finales de la década de los años noventa, el número de muertes por sobredosis que involucran analgésicos opioides se ha cuadriplicado en los Estados Unidos de América (de 4 030 muertes en 1999 a 16 651 en 2010). Los objetivos de este artículo son proporcionar una visión general del problema de sobredosis de medicamentos de prescripción en los Estados Unidos y discutir las acciones que podrían ayudar a reducir el problema, abordando en forma directa las características de los Programas de monitoreo de medicamentos de prescripción (PDMP). Estos programas están compuestos de bases de datos a nivel estatal que vigilan las sustancias controladas. La información recopilada en las bases de datos está a disposición de las personas autorizadas por el Estado (por ejemplo, los médicos, los farmacéuticos y otros proveedores de cuidado médico) y debe ser utilizada solo con propósitos profesionales. Los proveedores pueden utilizar dicha información para evitar la interacción con otros medicamentos, la duplicación terapéutica o la identificación de conductas de búsqueda de drogas. Las agencias del orden público pueden utilizar estos programas para identificar patrones de prescripción inadecuada, dispensación o desviación.

Since the late 1990s, the number of opioid analgesic overdose deaths has quadrupled in the United States of America (from 4 030 deaths in 1999 to 16 651 in 2010). The objectives of this article are to provide an overview of the problem of prescription drug overdose in the United States and to discuss actions that could help reduce the problem, with particular attention to the characteristics of prescription drug monitoring programs (PDMPs). These programs consist of state-level databases that monitor controlled substances. The information compiled in the databases is at the disposal of authorized persons (e.g., physicians, pharmacists, and other health-care providers) and may be used only for professional purposes. Suppliers can use such information to prevent interaction with other drugs or therapeutic duplication, or to identify drug-search behavior. Law enforcement agencies can use these programs to identify improper drug prescription or dispensing patterns, or drug diversion.

Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches

Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Delta9-tetrahydrocannabinol (Delta9-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Delta9-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.

Prescripción de Drogas Controladas por Médicos Residentes del Hospital Central del Instituto de Previsión Social / Prescription of controlled substances by Internal Medicine Residents from the Instituto de Prevision Social

Los objetivos de este trabajo son: Determinar la prevalencia y tipo de psicofármacos recetados por los médicos residentes del Hospital Central del Instituto de Previsión Social (HCIPS), establecer la frecuencia con que se prescribe el psicofármaco, comprobar la correlación de familiares y profesionales consumidores de fármacos controlados y conocer la preparación académica legal sobre la prescripción de fármacos controlados por los médicos residentes del HCIPS. Se realizó un estudio prospectivo, descriptivo de corte transversal. Se estudiaron 100 médicos residentes del H.C.I.P.S seleccionados aleatoriamente. Los datos fueron obtenidos de una encuesta anónima. Se encontró que: 48% era de sexo masculino y 52% femenino, el 79% refirió recetar fármacos controlados y el 21% negó haber recetado fármacos controlados. De las respuestas afirmativas refirieron recetar benzodiacepinas 99%, antidepresivos 32%, opiáceos 10%, hipnóticos y antipsicóticos 61%. De los que negaron recetar psicofármacos sólo el 19% afirmó estar al tanto de la Ley del Control de Drogas en el país, a diferencia del 81% que no la conoce. De los que si recetan fármacos controlados sólo el 40 % conoce la existencia de la ley y el 60% la desconocen. De los que recetan, el 45% refirió tener al menos un familiar que consume regularmente psicofármacos a diferencia del 55% que negó tenerlo. El 9% de los médicos afirmaron consumir psicofármacos y el 91% niega su consumo. De los que recetan el 32% lo hace más de cinco veces al mes, 39% al menos una vez a la semana, 20% al menos una vez cada tres meses, 8% cada seis meses y 1% al menos una vez al año. Se concluye que los médicos egresados de las diferentes universidades omiten en porcentaje alto la observancia de las leyes y consecuentemente se encuentran expuestos a penalizaciones ante las transgresiones de las normativas vigentes. Palabras claves: Psicofarmacos, Prescripción, Fármacos controlados

The aims of this study are: determine the prevalence and type of psychopharmaceutical drugs prescribed by the residents at the Hospital Central of the Instituto de Prevision Social (HCIPS), establish the frequency of these prescriptions, look at the correlation between patients and health care providers regarding the consumption of controlled substances and to study the legal and academic preparation regarding this type of drug prescription by the medical residents of the HCIPS. This is a prospective, observational and cross sectional study. We randomly selected 100 medical residents from the HCIPS. Data was obtained from anonymous survey: 48% males, 52% females; 79% prescribed controlled substances and 21% did not. From the cohort that prescribed controlled substances: 99% prescribed benzodiazepines, 32% antidepressants, 10% opiods, and 61% hypnotics and antipsychotics medications. From the ones who refused to prescribe pshycopharmaceuticals, only 19% have knowledge about the "Controlled Substance Law" in Paraguay; 81% did not know about this law. From the ones who did prescribe these drugs, only 40% knew about this law and 60% did not know about it. Within the group that prescribed these drugs, 45% admitted that they have at least one relative that was using these drugs; 55% denies have any relatives using them. 9% of the physicians admitted to take these drugs and 91% denied their use. From the prescription group, 32% prescribe these drugs more than 5 times per month, 39% at least once a week, 20% once every three months, 8% every six months and 1% at least once a year. We concluded that physicians who graduate from different universities in Paraguay do not know about the laws related to controlled substances and they find themselves expose to be punish by breaking them. Keywords: psychotropic drugs, prescription, controlled drugs

Designation of a new drug as a controlled substance

Opioids are widely used as painkillers and anesthetics. Though we use opioids to relieve pain, these drugs can induce mood elevation, dependency, and withdrawal symptoms. This is why opioids are controlled-substances. Most physicians think that some substances should be controlled if they have opioid-like pharmacological properties, especially a long duration, preservation of respiration, and dependency. It is noteworthy that short-acting substances, such as midazolam and thiopental, are included in controlled substances. Their abuse is very dangerous because they frequently induce severe respiratory depression due to a narrow therapeutic window. Teaching point of this article is that designation of a new drug as a controlled substance requires scientific evidence of its link to dependency and/or withdrawal symptoms. However, this does not require abusers' convenience (long duration) or safety (maintenance of respiration). The authors present the addiction and abuse patterns of propofol as an reasons for the Korean Food and Drug Administration to designate propofol as a controlled substance. As a future study, an animal and/or a clinical model for dependency is needed to identify addictive substances. Though several neurotransmitters and their loci in the central nervous system have been studied, the precise mechanism for addiction is unknown. Also, it should be recognized that the potential for drug addiction and abuse could be masked in the early marketing period of a new drug. Physicians should monitor patients' responses carefully when they deal with the drug.