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1.
PLoS One ; 15(2): e0229067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084160

RESUMO

Psilocybin, a substance mainly found in mushrooms of the genus psilocybe, has been historically used for ritualistic, recreational and, more recently, medicinal purposes. The scientific literature suggests low toxicity, low risk of addiction, overdose, or other causes of injury commonly caused by substances of abuse, with growing interest in the use of this substance for conditions such as treatment-resistant depression. However, the presence of negative outcomes linked to psilocybin use is not clear yet. The objective of this study is to investigate the negative effects of psilocybin consumption, according to the users' own perception through self-reports extracted from an online platform. 346 reports were analyzed with the assistance of the IRAMUTEQ textual analysis software, adopting the procedures of Descending Hierarchical Classification, Correspondence Factor Analysis and Specificities Analysis. The text segments were grouped in 4 main clusters, describing thinking distortions, emergencies, perceptual alterations and the administration of the substance. Bad trips were more frequent in female users, being associated with thinking distortions. The use of multiple doses of psilocybin in the same session or its combination with other substances was linked to the occurrence of long-term negative outcomes, while the use of mushrooms in single high doses was linked to medical emergencies. These results can be useful for a better understanding of the effects of psilocybin use, guiding harm-reduction initiatives.


Assuntos
Psilocibina/química , Agaricales/química , Feminino , Alucinógenos/química , Humanos , Masculino , Autorrelato , Software
2.
Chemistry ; 26(13): 2813-2816, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31943443

RESUMO

This work reports the synthesis, characterization, and sensing behavior of a hybrid nanodevice for the detection of the potent abuse drug 25I-NBOMe. The system is based on mesoporous silica nanoparticles, loaded with a fluorescent dye, functionalized with a serotonin derivative and capped with the 5-HT2A receptor antibody. In the presence of 25I-NBOMe the capping antibody is displaced, leading to pore opening and rhodamine B release. This delivery was ascribed to 5-HT2A receptor antibody detachment from the surface due to its stronger coordination with 25I-NBOMe present in the solution. The prepared nanodevice allowed the sensitive (limit of detection of 0.6 µm) and selective recognition of the 25I-NBOMe drug (cocaine, heroin, mescaline, lysergic acid diethylamide, MDMA, and morphine were unable to induce pore opening and rhodamine B release). This nanodevice acts as a highly sensitive and selective fluorometric probe for the 25I-NBOMe illicit drug in artificial saliva and in sweets.


Assuntos
Dimetoxifeniletilamina/análogos & derivados , Alucinógenos/química , Serotonina/química , Dimetoxifeniletilamina/análise , Dimetoxifeniletilamina/química , Humanos
3.
Forensic Sci Int ; 304: 109972, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31604205

RESUMO

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT) is a designer hallucinogen that is a synthetic tryptamine derivative. It is highly abused and is involved in criminal activities because of its psychotropic properties. Herein, we presented an UHPLC-MS/MS method allowing for the qualitative and quantitative determination of 5-MeO-DiPT in human hair. The hair was first decontaminated and then cut into pieces. Thirty milligrams of hair samples was pulverized below 4°C in the presence of 0.5mL deionized water containing 0.1% formic acid. After centrifuging twice, 5µL of supernatant was injected into the LC-MS/MS system. A T3 column (100mm×2.1mm, 1.8µm) was used, and mobile phases consisted of 20mmol/L ammonium acetate, 5% acetonitrile and 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). The gradient elution was used at a flow rate of 0.3mL/min. The resulting calibration curve for 5-MeO-DiPT was y=281.50213x+0.00231 (R2=0.992), the limit of detection (LOD) was 0.05pg/mg, and the lower limit of quantification (LLOQ) was 0.1pg/mg. The accuracy was between 92.1% and 105.6%, and the intra- and interday precision, recovery and matrix effect were acceptable. The validated method was successfully used in 106 real cases, and the concentration of 5-MeO-DiPT in hair samples of these suspected users was 0.2-7532.5pg/mg. These cases present data to document illegal 5-MeO-DiPT use.


Assuntos
5-Metoxitriptamina/análogos & derivados , Drogas Desenhadas/análise , Cabelo/química , Alucinógenos/análise , Detecção do Abuso de Substâncias/métodos , 5-Metoxitriptamina/análise , 5-Metoxitriptamina/química , Adulto , Cromatografia Líquida de Alta Pressão , Drogas Desenhadas/química , Feminino , Toxicologia Forense , Alucinógenos/química , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Estrutura Molecular , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Adulto Jovem
4.
Drug Alcohol Depend ; 201: 49-57, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181437

RESUMO

BACKGROUND: Impurities in commonly used illicit drugs raise concerns for unwitting consumers when pharmacologically active adulterants, especially new psychoactive substances (NPS), are used. This study examines impurities detected in illicit drugs seized in one Australian jurisdiction. METHODS: Queensland Health Forensic and Scientific Services provided analytical data. Data described the chemical composition of 9346 samples of 11 illicit drugs seized by police during 2015-2016. Impurities present in primary drugs were summarized and tabulated. A systematic search for published evidence reporting similar analyses was conducted. RESULTS: Methamphetamine was the primary drug in 6608 samples, followed by MDMA (1232 samples) and cocaine (516 samples). Purity of primary drugs ranged from ∼30% for cocaine, 2-CB and GHB to >90% for THC, methamphetamine, heroin and MDMA. Methamphetamine and MDMA contained the largest variety of impurities: 22 and 18 variants, respectively. Drug adulteration patterns were broadly similar to those found elsewhere, including NPS, but in some primary drugs impurities were found which had not been reported elsewhere. Psychostimulants were adulterated with each other. Levamisole was a common impurity in cocaine. Psychedelics were adulterated with methamphetamine and NPS. Opioids were quite pure, but some samples contained methamphetamine and synthetic opioids. CONCLUSIONS: Impurities detected were mostly pharmacologically active adulterants probably added to enhance desired effects or for active bulking. Given the designer nature of these drug cocktails, the effects of the adulterated drugs on users from possible complex multi-drug interactions is unpredictable. Awareness-raising among users, research into complex multi-drug effects and ongoing monitoring is required.


Assuntos
Contaminação de Medicamentos/estatística & dados numéricos , Drogas Ilícitas/análise , Estimulantes do Sistema Nervoso Central/química , Cocaína/química , Alucinógenos/química , Heroína/química , Humanos , Metanfetamina/química , Polícia , Queensland
5.
Proc Natl Acad Sci U S A ; 116(23): 11207-11212, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31061128

RESUMO

Over several millennia, various native plant species in South America have been used for their healing and psychoactive properties. Chemical analysis of archaeological artifacts provides an opportunity to study the use of psychoactive plants in the past and to better understand ancient botanical knowledge systems. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to analyze organic residues from a ritual bundle, radiocarbon dated to approximately 1,000 C.E., recovered from archaeological excavations in a rock shelter located in the Lípez Altiplano of southwestern Bolivia. The site is located at an elevation of ∼3,900 m above sea level and contains evidence of intermittent human occupations during the last 4,000 years. Chemical traces of bufotenine, dimethyltryptamine, harmine, and cocaine, including its degradation product benzoylecgonine, were identified, suggesting that at least three plants containing these compounds were part of the shamanic paraphernalia dating back 1,000 years ago, the largest number of compounds recovered from a single artifact from this area of the world, to date. This is also a documented case of a ritual bundle containing both harmine and dimethyltryptamine, the two primary ingredients of ayahuasca. The presence of multiple plants that come from disparate and distant ecological areas in South America suggests that hallucinogenic plants moved across significant distances and that an intricate botanical knowledge was intrinsic to pre-Columbian ritual practices.


Assuntos
Plantas Medicinais/química , Psicotrópicos/química , Arqueologia/métodos , Banisteriopsis/química , Bolívia , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alucinógenos/química , Humanos , América do Sul , Espectrometria de Massas em Tandem/métodos
6.
Drug Test Anal ; 11(8): 1122-1133, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31083768

RESUMO

The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One recent addition to this series of LSD analogs is 1-butanoyl-LSD (1B-LSD), a constitutional isomer of 1-propanoyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B-LSD employing nuclear magnetic resonance spectroscopy (NMR), low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B-LSD from 1P-ETH-LAD was straightforward. LSD and other serotonergic hallucinogens induce the head-twitch response (HTR) in rats and mice, which is believed to be mediated largely by 5-HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B-LSD has LSD-like behavioral effects. 1B-LSD produced a dose-dependent increase in HTR counts, acting with ~14% (ED50  = 976.7 nmol/kg) of the potency of LSD (ED50  = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B-LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B-LSD serves as a pro-drug for LSD. Further investigations are warranted to confirm whether 1B-LSD produces LSD-like psychoactive effects in humans.


Assuntos
Drogas Desenhadas/química , Drogas Desenhadas/farmacologia , Alucinógenos/química , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Drogas Desenhadas/administração & dosagem , Relação Dose-Resposta a Droga , Alucinógenos/administração & dosagem , Dietilamida do Ácido Lisérgico/administração & dosagem , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Espectrometria de Massas por Ionização por Electrospray
8.
Drug Test Anal ; 11(8): 1172-1182, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009168

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) tablets are widely used recreationally, and not only vary in appearance, but also in MDMA content. Recently, the prevalence of high-content tablets is of concern to public health authorities. To compare UK data with other countries, we evaluated MDMA content of 412 tablets collected from the UK, 2001-2018, and investigated within-batch content variability for a sub-set of these samples. In addition, we investigated dissolution profiles of tablets using pharmaceutical industry-standard dissolution experiments on 247 tablets. All analyses were carried out using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data supported other studies, in that recent samples (2016-2018) tend to have higher MDMA content compared to earlier years. In 2018, the median MDMA content exceeded 100 mg free-base for the first time. Dramatic within-batch content variability (up to 136 mg difference) was also demonstrated. Statistical evaluation of dissolution profiles at 15-minutes allowed tablets to be categorized as fast-, intermediate-, or slow-releasing, but no tablet characteristics correlated with dissolution classification. Hence, there would be no way of users knowing a priori whether a tablet is more likely to be fast or slow-releasing. Further, within-batch variation in dissolution rate was observed. Rapid assessment of MDMA content alone provides important data for harm reduction, but does not account for variability in (a) the remainder of tablets in a batch, or (b) MDMA dissolution profiles. Clinical manifestations of MDMA toxicity, especially for high-content, slow-releasing tablets, may be delayed or prolonged, and there is a significant risk of users re-dosing if absorption is delayed.


Assuntos
Alucinógenos/química , Drogas Ilícitas/química , N-Metil-3,4-Metilenodioxianfetamina/química , Cromatografia Líquida , Humanos , Solubilidade , Comprimidos , Espectrometria de Massas em Tandem , Reino Unido
9.
Nature ; 569(7754): 141-145, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31019304

RESUMO

The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons1-3. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action2,4. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines2,3, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder2,5. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane1,6-12. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties13,14. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors15,16. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.


Assuntos
Microscopia Crioeletrônica , Ibogaína/química , Ibogaína/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/ultraestrutura , Inibidores de Captação de Serotonina/farmacologia , Serotonina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Transporte Biológico/efeitos dos fármacos , Alucinógenos/química , Alucinógenos/farmacologia , Humanos , Modelos Moleculares , Conformação Proteica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/química , Relação Estrutura-Atividade
10.
Neuropharmacology ; 144: 368-376, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385253

RESUMO

In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 µmol/kg) and 2C-B (ED50 = 2.43 µmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 µmol/kg) and 2C-B-DFLY (ED50 = 1.07 µmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 µmol/kg) and 2C-B-FLY (ED50 = 1.79 µmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.


Assuntos
2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , Alucinógenos/farmacologia , 2,5-Dimetoxi-4-Metilanfetamina/química , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Alucinógenos/química , Movimentos da Cabeça/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular
11.
Artigo em Inglês | MEDLINE | ID: mdl-30481558

RESUMO

INTRODUCTION: The use of new psychoactive substances as drugs of abuse has dramatically increased over the last years. Hallucinogenic phenethylamines gained particular popularity as they have both stimulating and psychedelic effects. Although generally perceived as safe, these illicit drugs pose a serious health risk; they have been linked to cases of severe poisoning or even deaths. Therefore, simple, cost-effective and reliable methods are needed for rapid determination of abused hallucinogens. METHODS: For this purpose, two haptens derived from 2C-H were designed, synthesized and subsequently attached to a carrier protein. Polyclonal antibodies obtained from a rabbit immunized with one of the prepared immunogens were used for the development of two immunoassays. RESULTS: In this study, a lateral flow immunoassay (LFIA) and an enzyme linked immunosorbent assay (ELISA) for the detection of 2C-B and related hallucinogenic phenethylamines in urine were developed. The presented LFIA is primarily suitable for on-site monitoring as it is simple and can provide a visual evidence of 2C-B presence within a few minutes. Its reasonable sensitivity (LODLFIA = 15 ±â€¯7 ng mL-1) allows detection of the drug presence in urine after acute exposure. For greater accuracy, highly sensitive ELISA (LODELISA = 6 ±â€¯3 pg mL-1) is proposed for toxicological quantitative analyses of positive samples captured by the LFIA. DISCUSSION: The comparison of the ELISA with the well-established UHPLC-MS-MS method shows excellent agreement of results, which confirms good potential of the ELISA to be used for routine analyses of 2C-B and related hallucinogenic phenethylamines of both main sub-families.


Assuntos
Dimetoxifeniletilamina/análogos & derivados , Alucinógenos/urina , Drogas Ilícitas/urina , Imunoensaio/métodos , Detecção do Abuso de Substâncias/métodos , Dimetoxifeniletilamina/química , Dimetoxifeniletilamina/imunologia , Dimetoxifeniletilamina/urina , Feminino , Alucinógenos/química , Alucinógenos/imunologia , Haptenos/química , Haptenos/imunologia , Voluntários Saudáveis , Humanos , Drogas Ilícitas/química , Drogas Ilícitas/imunologia , Imunoensaio/economia , Masculino , Reprodutibilidade dos Testes , Detecção do Abuso de Substâncias/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
12.
Psychopharmacology (Berl) ; 236(2): 799-808, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30298278

RESUMO

RATIONALE: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds. OBJECTIVE: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens. METHODS: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes. RESULTS: ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA. CONCLUSIONS: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.


Assuntos
Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/análogos & derivados , Dietilamida do Ácido Lisérgico/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Relação Dose-Resposta a Droga , Alucinógenos/química , Alucinógenos/metabolismo , Humanos , Drogas Ilícitas/química , Drogas Ilícitas/metabolismo , Drogas Ilícitas/farmacologia , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/metabolismo
14.
J Chromatogr Sci ; 57(3): 230-237, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535186

RESUMO

The goal of this work was to investigate and compare the selectivity of three different hydrophilic interaction liquid chromatography (HILIC) charge modulated amide columns, iHILIC®-Fusion, iHILIC®-Fusion(+) and iHILIC®-Fusion(P), for analysis of compounds in hallucinogen mushrooms. An extract of a truffle-like fungus containing psilocin, psilocybin and baeocystin was chosen as test material. Three different modeling methods were applied to describe the retention times of constituents in isocratic separation mode as a function of mobile phase composition, pH and temperature. Two models using DryLab® 2010 assumed quadratic and exponential relationship between the retention time and solvent fraction of aqueous component of the mobile phase, respectively. These models also illustrate the van't Hoff like equation to describe the temperature-dependence of the retention factor and the theory of Snyder et al. to estimate the retention factor as a function of pH of the aqueous mobile phase component. The third model using STATISTICA® multivariate data analysis in a predefined experimental space was able to predict the retention times. All HILIC columns in this comparison were proved to be suitable for separation of the two hallucinogenic alkaloids from each other and from the matrix components. Majority of compounds were separated with satisfactory resolutions required by the comparative analysis despite some of them were not fully baseline separated. It was found the best modeling was obtained by using the quadratic approach to predict chromatograms for predefined chromatographic conditions (volumetric ratio of acetonitrile to buffer, pH of the buffer and temperature), while the exponential model proved to be the worst for prediction. The modeling with multivariate data analysis fell between the other two methods.


Assuntos
Agaricales/química , Alcaloides/análise , Cromatografia Líquida/métodos , Alucinógenos/análise , Alcaloides/química , Alcaloides/isolamento & purificação , Alucinógenos/química , Alucinógenos/isolamento & purificação , Interações Hidrofóbicas e Hidrofílicas , Modelos Químicos
16.
ACS Chem Neurosci ; 9(10): 2475-2483, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30216039

RESUMO

The West African iboga plant has been used for centuries by the Bwiti and Mbiri tribes to induce hallucinations during religious ceremonies. Ibogaine, the principal alkaloid responsible for iboga's psychedelic properties, was isolated and sold as an antidepressant in France for decades before its adverse effects precipitated its removal from the market. An ibogaine resurgence in the 1960s was driven by U.S. heroin addicts who claimed that ibogaine cured their opiate addictions. Behavioral pharmacologic studies in animal models provided evidence that ibogaine could blunt self-administration of not only opiates but cocaine, amphetamines, and nicotine. Ibogaine displays moderate-to-weak affinities for a wide spectrum of receptor and transporter proteins; recent work suggests that its actions at nicotinic acetylcholine receptor subtypes may underlie its reputed antiopiate effects. At micromolar levels, ibogaine is neurotoxic and cardiotoxic and has been linked to several deaths by cardiac arrest. Structure-activity studies led to the isolation of the ibogaine analog 18-methoxycoronaridine (18-MC), an α3ß4 nicotinic receptor modulator that retains ibogaine's anticraving properties with few or no adverse effects. Clinical trials of 18-MC treatment of nicotine addiction are pending. Ibogaine analogs may also hold promise for treating anxiety and depression via the "psychedelic-assisted therapy" approach that employs hallucinogens including psilocybin and methylenedioxymethamphetamine ("ecstasy").


Assuntos
Alucinógenos/química , Alucinógenos/farmacologia , Ibogaína/química , Ibogaína/farmacologia , Cardiotoxicidade , Alucinógenos/história , Alucinógenos/uso terapêutico , História do Século XX , História do Século XXI , Humanos , Ibogaína/análogos & derivados , Ibogaína/história , Ibogaína/uso terapêutico , Receptores Nicotínicos , Relação Estrutura-Atividade , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Tabernaemontana
17.
Sci Rep ; 8(1): 14280, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250104

RESUMO

Most clinical studies of Cannabis today focus on the contents of two phytocannabinoids: (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), regardless of the fact that the plant contains over 100 additional phytocannabinoids whose therapeutic effects and interplay have not yet been fully elucidated. This narrow view of a complex Cannabis plant is insufficient to comprehend the medicinal and pharmacological effects of the whole plant. In this study we suggest a new ESI-LC/MS/MS approach to identify phytocannabinoids from 10 different subclasses, and comprehensively profile the identified compounds in diverse medical Cannabis plants. Overall, 94 phytocannabinoids were identified and used for profiling 36 of the most commonly used Cannabis plants prescribed to patients in Israel. In order to demonstrate the importance of comprehensive phytocannabinoid analysis before and throughout medical Cannabis clinical trials, treatments, or experiments, we evaluated the anticonvulsant effects of several equally high-CBD Cannabis extracts (50% w/w). We found that despite the similarity in CBD contents, not all Cannabis extracts produced the same effects. This study's approach for phytocannabinoid profiling can enable researchers and physicians to analyze the effects of specific Cannabis compositions and is therefore critical when performing biological, medical and pharmacological-based research using Cannabis.


Assuntos
Canabinoides/genética , Cannabis/genética , Metaboloma/genética , Metabolômica , Canabidiol/química , Canabinoides/química , Cannabis/química , Cromatografia Líquida , Alucinógenos/química , Humanos , Maconha Medicinal/química , Maconha Medicinal/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/genética , Espectrometria de Massas em Tandem
18.
ACS Chem Neurosci ; 9(10): 2408-2427, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30001118

RESUMO

Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.


Assuntos
Alucinógenos/química , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/química , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Alucinógenos/história , Alucinógenos/uso terapêutico , História do Século XX , História do Século XXI , Humanos , N-Metil-3,4-Metilenodioxianfetamina/história , N-Metil-3,4-Metilenodioxianfetamina/uso terapêutico
19.
Exp Clin Psychopharmacol ; 26(4): 410-420, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29939048

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA) affects monoaminergic pathways that play a critical role in sleep-wake cycles. Dopaminergic mechanisms are thought to mediate the sleep-disrupting effects of stimulant drugs. However, the mechanisms underlying the effects of MDMA on sleep-wake cycles and the effects of R(-) MDMA, a stereoisomer that lacks dopaminergic activity, on sleep remain unknown. The aim of the present study was to investigate the effects of racemic MDMA and R(-) MDMA on daytime activity and sleep-like parameters evaluated with actigraphy in adult rhesus macaques (Macaca mulatta, n = 6). Actiwatch monitors were attached to the monkeys' collars and actigraphy recording was conducted during baseline conditions and after the administration of acute intramuscular injections of saline (vehicle), racemic MDMA (0.3, 1.0, or 1.7 mg/kg), or R(-) MDMA (0.3, 1.0, or 1.7 mg/kg) at 9 or 16 h (3 h before "lights off"). Morning treatments had no effects on sleep-like parameters. Racemic MDMA decreased general daytime activity during the first hour after injection and increased daytime activity at 3 hr posttreatment. Although afternoon administration of racemic MDMA increased sleep latency, it improved other sleep parameters, decreasing wake time after sleep onset (WASO) and increasing sleep efficiency for subjects with low baseline sleep efficiency. Afternoon treatment with R(-) MDMA improved sleep measures, increasing sleep efficiency and decreasing sleep latency and WASO, while having no effects on daytime activity. The stimulant and sleep-disrupting effects of racemic MDMA are likely mediated by dopaminergic and noradrenergic mechanisms, while serotonergic pathways appear to be involved in the sleep-promoting effects of MDMA. (PsycINFO Database Record


Assuntos
Actigrafia/métodos , Atividade Motora/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/química , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Feminino , Alucinógenos/química , Macaca mulatta , Masculino , Atividade Motora/fisiologia , Sono/fisiologia , Vigília/fisiologia
20.
ACS Chem Neurosci ; 9(10): 2459-2474, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29953199

RESUMO

Phencyclidine (PCP, "angel dust", an arylcyclohexylamine) was the first non-natural, man-made illicit drug of abuse, and was coined 'the most dangerous drug in America" in the late 1970s (amidst sensational horror stories of the drug's effects); however, few other illicit drugs have had such a significant and broad impact on society-both good and bad. Originally developed as a new class of anesthetic, PCP-derived psychosis gave way to the PCP hypothesis of schizophrenia (later coined the NMDA receptor hypofunction hypothesis or the glutamate hypothesis of schizophrenia), which continues to drive therapeutic discovery for schizophrenia today. PCP also led to the discovery of ketamine (and a new paradigm for the treatment of major depression), as well as other illicit, designer drugs, such as methoxetamine (MXE) and a new wave of Internet commerce for illicit drugs (sold as research chemicals, or RCs). Furthermore, PCP is a significant contaminant/additive of many illegal drugs sold today, due to its ease of preparation by clandestine chemists. Here, we will review the history, importance, synthesis (both legal and clandestine), pharmacology, drug metabolism, and folklore of PCP, a true DARK classic in chemical neuroscience.


Assuntos
Alucinógenos/química , Alucinógenos/farmacologia , Fenciclidina/química , Fenciclidina/farmacologia , Ácido Glutâmico/metabolismo , Alucinógenos/história , História do Século XX , História do Século XXI , Humanos , Fenciclidina/história , Psicoses Induzidas por Substâncias/etiologia , Psicoses Induzidas por Substâncias/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo
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