Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Neuropharmacology of Synthetic Cathinones.

Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the ß-keto analog of amphetamine, and all synthetic cathinones display a ß-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin®), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users.

A scoping review of home-produced heroin and amphetamine-type stimulant substitutes: implications for prevention, treatment, and policy.

Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies.

An Internet Study of User's Experiences of the Synthetic Cathinone 4-Methylethcathinone (4-MEC).

Abstract A synthetic cathinone called 4-methylethcathinone (4-MEC) emerged online in 2010, and was cyber-marketed to be a replacement for mephedrone. The study aimed to present user experiences of 4-MEC as reported on the Internet, with a focus on user profiles, sourcing and product characteristics, routes of administration, dosage, positive and undesirable effects, and comparisons to mephedrone. Twenty-three individual, anonymous trip reports of the sole use of 4-MEC, and 112 screenshots of general 4-MEC user discussion boards, were taken from a purposeful sample of public drug-related sites. A content textual analysis was conducted on extracted qualitative information and produced 41 categories compiled into five general themes: "Type of 4-MEC user"; "Sourcing, informed decision making, product characteristics, and quality assurance"; "Routes of administration, gauging of dosage, and consumption of other drugs"; "Time course effects and outcomes"; and "Comparisons with mephedrone." 4-MEC is sold as white beads, crystalline shards, or green balls. User motives centered on curiosity, pricing, and ease of web sourcing. Oral, nasal, injecting, eyeball, and rectal routes of administration were described. Testing for purity, "allergy testing," and gauging of dosage were common. Users described euphoric but short-lived effects, with little comedown. Continued research is vital to inform harm reduction.

Not-so-clean fun: a profile of bath salt users among a college sample in the United States.

This research examines the characteristics of users of synthetic stimulants marketed as "bath salts." Synthetic stimulants such as MDPV (3,4-Methylenedioxypyrovalerone), Mephedrone (4-Methylmethcathinone), and Methylone (3,4-Methylenedioxymethcathinone) are often contained in products sold at convenience stores and over the Internet in the United States. Despite the recent legal action banning these types of synthetic stimulants, little is known about the characteristics of the users of these substances. This research provides a profile of bath salt users in the United States among an emerging adult population. A self-report survey instrument was administered to 2,349 students at a large university in the southeastern United States. Respondents indicated whether they had used synthetic stimulants and reported demographic characteristics. Results indicated that users of bath salts were more likely to be male, Hispanic or Native American, student athletes, employed, identify as a members of the LGBT community, and users of other substances.

Synthesis, crystal structure and anti-fatigue effects of some benzamide derivatives.

A series of benzamide derivatives such as 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) were synthesized by the reaction of substituted benzoic acids with piperidine, morpholine or pyrrolidine using a novel method. The crystals of these benzamide derivatives were obtained by recrystallization. Structures of target and intermediate compounds were determined via FT-IR, 1H-NMR and elemental analysis and X-ray crystallography of select examples. The crystal structures of these compounds have potential applications to identify the binding site for allosteric modulators of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. The anti-fatigue effects of the benzamide derivatives in weight-loaded forced swimming mice were investigated in a swimming endurance capacity test used as an indicator of fatigue. The swimming times to exhaustion were longer in the b3, d3, and e3 groups than in the caffeine group (p<0.05). In conclusion, b3, d3 and e3 enhanced the forced swimming capacity of mice. The mechanism of the anti-fatigue effects will be studied in the future.

Influence of precursor solvent extraction on stable isotope signatures of methylamphetamine prepared from over-the-counter medicines using the Moscow and Hypophosphorous routes.

A number of methods of clandestine manufacture of methylamphetamine involve the extraction and subsequent reaction of pseudoephedrine hydrochloride with other essential chemicals. The precursor can be easily extracted from over-the-counter medication widely available in the UK and elsewhere. Essential chemicals such as iodine and red phosphorous are also readily available and can be extracted from iodine tinctures and matchboxes, respectively. This work reports the repetitive preparation of methylamphetamine using two popular routes (the Moscow and Hypophosphorous synthesis). The focus was on the extraction solvent used for isolation of the precursor chemical and any consequential isotopic variation which may arise in the final product. Six batches of methylamphetamine were prepared under precisely controlled conditions for each synthetic route and for each of three different precursor extraction solvents. Synthesis of the final product from laboratory grade precursor using the synthetic methods described was used as a template for comparison. The resultant IRMS data from all 48 prepared samples suggests some underlying trends in the identification of the synthetic route which may aid in the interpretation of IRMS data derived from clandestine samples.

[Beta-cathinone derivatives--a new generation of dangerous psychostimulant "designer drugs"]. / Pochodne beta-katynonu--nowa generacja niebezpiecznych zwiazków psychostymulujacych z grupy "dopalaczy".

Synthetic beta-cathinone derivatives belong to the novel group of psychostimulant "designer drugs". They show significant structural similarity to catecholamines and exogenous central nervous system (CNS) stimulating agents such as amphetamine, methamphetamine, ephedrine, 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy), and act as dopamine, noradrenaline and serotonin reuptake inhibitors. Popular synthetic beta-cathinones include e.g. mephedrone (4-methylmethcathinone, 4-MMC), naphyrone (naphthylpyrovalerone) and MDPV (3,4-methylenedioxypyrovalerone). Ingestion of synthetic cathinones produces effects of CNS stimulation, often comparable to those evoked by cocaine, amphetamine and MDMA. Chronic abuse of beta-cathinone derivatives leads to the development of tolerance, psychic and physical dependence. This paper discusses pharmacological properties of the most commonly used beta-cathinone derivatives as well as risks associated with their abuse. Special emphasis is given to neurological, psychiatric, cardiovascular and hematologic disturbances. Authors also present cases of fatalities caused by acute beta-cathinone intoxication or resulting from the drug-related accidents and crimes.

Chiral analysis of chloro intermediates of methylamphetamine by one-dimensional and multidimentional NMR and GC/MS.

Impurity profiling and classification of abused drugs using chiral analytical techniques is of particular interest and importance because of the additional information obtained from this approach. When these methods are applied to the synthesis of illicitly used substances, they can supply valuable information about the conditions/chemicals used in the synthesis. We have applied GC and NMR methods to the study of intermediates found in methylamphetamine manufacture with the aim of linking the intermediates to the ephedrine/pseudoephedrine starting materials. Therefore, determination of the stereochemical makeup within samples of forensic interest is important giving further specific information to the analyst. This study investigates the stereochemical course of the Emde synthesis of methylamphetamine with particular focus on intermediate formation via the chlorination of ephedrine and pseudoephedrine enantiomers. The configurations of these chloro-phenethylamines were determined by 1D and 2D NMR analysis, and thereafter, the GC/MS analysis was carried out. We have shown here that chlorination of the ephedrine/pseudoephedrine compounds occurs via inversion (S(N)2) and retention (S(N)i) of configuration around the α carbon and mixture of diastereoisomers (chloroephedrine and chloropseudoephedrine) were formed, with the ratio of the resulting compounds dependent on the precursors used. The preparation and analytical properties of these intermediate standards provide data for laboratories interested in the stereochemical analysis of methylamphetamine intermediates such as forensic/law enforcement, and illustrate the value of using a combination of analytical methodology.

Investigation of the reaction impurities associated with methylamphetamine synthesized using the Nagai method.

The synthesis of methylamphetamine hydrochloride from l-ephedrine or d-pseudoephedrine hydrochloride via reduction with hydriodic acid and red phosphorus was investigated. Eighteen batches of methylamphetamine hydrochloride were synthesized in six replicate batches using three different reaction times. This allowed the investigation of the variation of impurities in the final product with reaction time. The results obtained have resolved previously conflicting impurity profile data reported in the literature for this synthesis route. The impurity profile was shown to change with reaction time, and all previously reported impurity components were identified but not in all batches. Additionally, 20 batches of methylamphetamine hydrochloride were synthesized from either from l-ephedrine or d-pseudoephedrine hydrochloride in reactions which were allowed to proceed for 24 h. The impurities present in the resulting batches were investigated, and route-specific impurities present in all batches were identified. Batch-to-batch fluctuations in the resultant chromatographic impurity profile, despite careful synthetic monitoring and control, were also noted.

Wake-promoting agents: search for next generation modafinil: part II.

In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.

Wake-promoting agents: search for next generation modafinil: part I.

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.

Impurity profiling of methamphetamine synthesised from α-phenylacetoacetonitrile (APAAN).

The rise in popularity of 'designer' precursor compounds for the synthesis of amphetamine-type stimulants poses a significant challenge to law enforcement agencies. One such precursor is α-phenylacetoacetonitrile (APAAN). APAAN emerged in Europe in 2010 and quickly became one of the most popular precursors for amphetamine synthesis in that region. Previous literature has identified four APAAN-specific impurities formed in the synthesis of amphetamine; however, there is currently no research on the use of APAAN in the synthesis of methamphetamine, which is more likely to be employed in a non-European market. In this study methamphetamine was synthesised via three common clandestine methods: the Leuckart method and two reductive amination methods. We report the identification of five new impurities and two previously identified impurities characteristic for the use of APAAN in the synthesis of methamphetamine. The newly identified impurities were characterised by MS and NMR and determined to be (E)-3-(methylamino)-2-phenylbut-2-enenitrile, 3-(methylamino)-2-phenylbutanenitrile, 3-methyl-2,4-diphenylpentanedinitrile, 2-phenylbutyronitrile and 3-hydroxy-2-phenylbutanenitrile.

Ocular injuries from shake and bake methamphetamine labs.

PURPOSE: To review ocular injuries resulting from "shake and bake" methamphetamine labs. METHOD: Retrospective case series of 4 patients with ocular injuries sustained from "shake and bake" lab explosions. RESULTS: Four men ages 20-39 underwent complete ophthalmologic examination after an injury from a "shake and bake" methamphetamine lab explosion.The mechanism of injury was initially misrepresented in each case; the physical findings were suggestive of thermal and alkali injury. Visual acuity ranged widely from 20/20 to light perception only. Treatment in the acute setting included irrigation, pH monitoring, and intraocular pressure lowering. CONCLUSION: Methamphetamine production by means of the"shake and bake" method can result in combined thermal and alkali ocular injury. Patients who sustain this type of injury may not accurately report the mechanism of exposure. Increased awareness of this type of ocular injury may increase the rapidity of diagnosis, avoid early misdiagnosis, and ultimately improve outcomes.

Syntheses and analytical characterizations of novel (2-aminopropyl)benzo[b]thiophene (APBT) based stimulants.

Two groups of amphetamine-like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzo[b]thiophene structure (resulting in (2-aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT-type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.

Identification of specific markers for amphetamines synthesized from glycidic acid pre-precursors and retrospective search in German profiling database.

The pre-precursor market and the clandestine production of amphetamine-type stimulants (ATS) has become more diverse in recent years. Besides α-phenylacetoacetonitrile (APAAN) and α-phenylacetoacetamide (APAA), glycidic acid derivatives and methyl α-phenylacetoacetate (MAPA) are gaining importance. This conclusion is based on seizure data of police and customs. However, analytical data are needed to confirm and quantify the actual prevalence of new pre-precursors by elucidating the percentage of seized ATS that have been produced from them. A recent study showed that APAAN use is currently declining, which supports the view that new pre-precursors are being used. In this study, several conversion procedures using different batches of glycidic acid derivatives and a complete Leuckart reaction to produce amphetamine were carried out. The resulting organic phases were analyzed using gas chromatography - mass spectrometry to identify possible marker compounds. Three marker compounds were discovered and characterized using mass spectra and nuclear magnetic resonance spectroscopy. They were identified as phenyl-1-propanone, N-(1-phenylpropyl)formamide and 1-phenylpropan-1-amine. Their prevalence was investigated by searching the markers in an amphetamine impurity profiling database to determine to what extent they occurred in amphetamine samples from recent years. Data from the central German amphetamine profiling database of more than 250 cases were used for this purpose. The yearly occurrence of the three glycidate marker compounds was determined going back as far as 2009, revealing an increasing trend from 2016 on. This article presents experimental proof that APAAN is currently being replaced by other pre-precursors, such as glycidic acid derivatives.

Synthetic cathinones - From natural plant stimulant to new drug of abuse.

As recreational substances, synthetic cathinones started to be used at the beginning of the 21st century. There is still limited data on these compounds, introduced to the illicit drug market for the most part after 2009. Considering that synthetic cathinones are currently the second largest group of new psychoactive and dangerous substances among over 670 new psychoactive substances identified in Europe and monitored by the EMCDDA, research on them should be regarded as extremely important. This review focuses on the availability of synthetic cathinones on the illicit drug market, presentation of current trends in the use of these substances, and their mechanisms of action and toxicity. The authors discuss cases of intoxication with synthetic cathinones and post-mortem diagnostics as well as the problem of combined used of synthetic cathinones with other psychoactive substances. Literature as well as clinical and forensic data indicate the need for further research on the metabolism, toxicokinetics, toxicodynamics, clinical effects, and addictive potential of synthetic cathinones, especially in the context of potential threats caused by increased consumption of this group of drugs in future.

Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability.

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT Ki = 50.6 nM), 21b (DAT Ki = 77.2 nM) and 33 (DAT Ki = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.

Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods.

Impurity profiling of seized methamphetamine can provide very useful information in criminal investigations and, specifically, on drug trafficking routes, sources of supply, and relationships between seizures. Particularly important is the identification of "route specific" impurities or those which indicate the synthetic method used for manufacture in illicit laboratories. Previous researchers have suggested impurities which are characteristic of the Leuckart and reductive amination (Al/Hg) methods of preparation. However, to date and importantly, these two synthetic methods have not been compared in a single study utilizing methamphetamine hydrochloride synthesized in-house and, therefore, of known synthetic origin. Using the same starting material, 1-phenyl-2-propanone (P2P), 40 batches of methamphetamine hydrochloride were synthesized by the Leuckart and reductive amination methods (20 batches per method). Both basic and acidic impurities were extracted separately and analyzed by GC/MS. From this controlled study, two route specific impurities for the Leuckart method and one route specific impurity for the reductive amination method are reported. The intra- and inter-batch variation of these route specific impurities was assessed. Also, the variation of the "target impurities" recently recommended for methamphetamine profiling is discussed in relation to their variation within and between production batches synthesized using the Leuckart and reductive amination routes.

Methamphetamine production is hazardous to your health.

BACKGROUND: To describe the thermal injuries related to methamphetamine (METH) production, characterize patients' courses, and compare patients with matched controls and to the previously published series. METHODS: Trauma registry data from January 2001 to November 2005 was retrospectively reviewed. METH patients were compared with other burn patients of similar age and total body surface area burn size for toxicology, injury extent, therapies, hospital course, outcomes, and hospital charges. The METH group was compared with the other published series of METH-related burn patients. RESULTS: Twenty-nine patients (86.2% male) had METH-related burns. METH and control groups were similar in age, gender, predicted resuscitation fluid volume, and total body surface area. Mortality, mean length of stay, surgical procedures, and mean hospital charges did not differ significantly between the groups. Endotracheal intubation was required more frequently in METH patients (55.2% vs. 24.1%, p = 0.020). METH patients mean resuscitation volume was greater than controls (9,638 mL vs. 6,633 mL, p = 0.011), but neither group exceeded the volume predicted by the Parkland formula. More METH patients had inhalation injury (41.4% vs. 13.8%, p = 0.019). A METH patient was more likely to have a complication than his matched control (p = 0.049), and pneumonia was more frequent in the METH group (p = 0.005). Private insurance was less common in METH patients (10.3% vs. 58.6%, p < 0.001). CONCLUSIONS: METH patients suffer more frequent inhalation injuries, need greater initial fluid resuscitation volume, require endotracheal intubation more frequently, and are more likely to have complications than matched controls. This does not translate to greater mortality, longer length of stay, more surgical procedures, or significantly greater hospital charges. Few METH patients hold private insurance.