La anfetamina [nota 2] ( contraída de a lpha - metil fen etil amina ) es un estimulante del sistema nervioso central ( SNC) que se utiliza en el tratamiento del trastorno por déficit de atención con hiperactividad (TDAH), la narcolepsia y la obesidad . La anfetamina fue descubierta como sustancia química en 1887 por Lazăr Edeleanu , y luego como droga a fines de la década de 1920. [25] Existe como dos enantiómeros : [nota 3] levoanfetamina y dextroanfetamina . La anfetamina se refiere correctamente a una sustancia química específica, la base libre racémica , que es partes iguales de los dos enantiómeros en sus formas de amina pura . El término se usa con frecuencia de manera informal para referirse a cualquier combinación de los enantiómeros, o a cualquiera de ellos solo. Históricamente, se ha utilizado para tratar la congestión nasal y la depresión. La anfetamina también se utiliza como potenciador del rendimiento atlético y cognitivo , y de forma recreativa como afrodisíaco y euforizante . Es un fármaco de venta con receta en muchos países, y la posesión y distribución no autorizadas de anfetaminas suelen estar estrechamente controladas debido a los importantes riesgos para la salud asociados con su uso recreativo. [fuentes 1]
El primer fármaco de anfetamina fue Benzedrine , una marca que se utilizaba para tratar diversas afecciones. En la actualidad, la anfetamina farmacéutica se prescribe como anfetamina racémica, Adderall , [nota 4] dextroanfetamina o el profármaco inactivo lisdexanfetamina . La anfetamina aumenta la monoamina y la neurotransmisión excitatoria en el cerebro, y sus efectos más pronunciados se dirigen a los sistemas de neurotransmisores noradrenalina y dopamina . [fuentes 2]
En dosis terapéuticas, la anfetamina causa efectos emocionales y cognitivos como euforia , cambio en el deseo sexual , aumento del estado de vigilia y mejora del control cognitivo . Induce efectos físicos como mejor tiempo de reacción, resistencia a la fatiga, disminución del apetito , aumento de la frecuencia cardíaca y aumento de la fuerza muscular. Dosis mayores de anfetamina pueden perjudicar la función cognitiva e inducir una rápida degradación muscular . La adicción es un riesgo grave con el uso recreativo intenso de anfetamina, pero es poco probable que se produzca con el uso médico a largo plazo en dosis terapéuticas. Dosis muy altas pueden provocar psicosis (p. ej., alucinaciones , delirios y paranoia ) que rara vez se produce en dosis terapéuticas incluso durante el uso a largo plazo. Las dosis recreativas son generalmente mucho mayores que las dosis terapéuticas prescritas y conllevan un riesgo mucho mayor de efectos secundarios graves. [fuentes 3]
La anfetamina pertenece a la clase de las fenetilaminas . También es el compuesto original de su propia clase estructural, las anfetaminas sustituidas , [nota 5] que incluye sustancias importantes como el bupropión , la catinona , el MDMA y la metanfetamina . Como miembro de la clase de las fenetilaminas, la anfetamina también está relacionada químicamente con los neuromoduladores de aminas traza que se producen de forma natural , específicamente la fenetilamina y la N -metilfenetilamina , ambas producidas dentro del cuerpo humano. La fenetilamina es el compuesto original de la anfetamina, mientras que la N -metilfenetilamina es un isómero posicional de la anfetamina que difiere solo en la ubicación del grupo metilo . [fuentes 4]
La anfetamina se utiliza para tratar el trastorno por déficit de atención con hiperactividad (TDAH), la narcolepsia (un trastorno del sueño) y la obesidad , y a veces se prescribe fuera de etiqueta para sus indicaciones médicas anteriores , en particular para la depresión y el dolor crónico . [1] [36] [51]
Se sabe que la exposición prolongada a dosis suficientemente altas de anfetaminas en algunas especies animales produce un desarrollo anormal del sistema de dopamina o daño nervioso, [52] [53] pero, en humanos con TDAH, el uso prolongado de anfetaminas farmacéuticas en dosis terapéuticas parece mejorar el desarrollo cerebral y el crecimiento nervioso. [54] [55] [56] Las revisiones de estudios de imágenes por resonancia magnética (IRM) sugieren que el tratamiento prolongado con anfetaminas disminuye las anomalías en la estructura y función cerebral encontradas en sujetos con TDAH y mejora la función en varias partes del cerebro, como el núcleo caudado derecho de los ganglios basales . [54] [55] [56]
Las revisiones de la investigación clínica sobre estimulantes han establecido la seguridad y eficacia del uso continuo de anfetaminas a largo plazo para el tratamiento del TDAH. [44] [57] [58] Los ensayos controlados aleatorios de terapia estimulante continua para el tratamiento del TDAH que abarcan 2 años han demostrado la eficacia y seguridad del tratamiento. [44] [57] Dos revisiones han indicado que la terapia estimulante continua a largo plazo para el TDAH es eficaz para reducir los síntomas centrales del TDAH (es decir, hiperactividad, falta de atención e impulsividad), mejorar la calidad de vida y el rendimiento académico, y producir mejoras en una gran cantidad de resultados funcionales [nota 6] en 9 categorías de resultados relacionados con lo académico, el comportamiento antisocial, la conducción, el uso de drogas no medicinales, la obesidad, la ocupación, la autoestima, el uso de servicios (es decir, académicos, ocupacionales, de salud, financieros y legales) y la función social. [44] [58] Una revisión destacó un ensayo controlado aleatorio de nueve meses de tratamiento con anfetaminas para el TDAH en niños que encontró un aumento promedio de 4,5 puntos de CI , aumentos continuos en la atención y disminuciones continuas en conductas disruptivas e hiperactividad. [57] Otra revisión indicó que, con base en los estudios de seguimiento más largos realizados hasta la fecha, la terapia estimulante de por vida que comienza durante la infancia es continuamente efectiva para controlar los síntomas del TDAH y reduce el riesgo de desarrollar un trastorno por consumo de sustancias en la edad adulta. [44]
Los modelos actuales del TDAH sugieren que está asociado con deterioros funcionales en algunos de los sistemas de neurotransmisores del cerebro ; [59] estos deterioros funcionales implican una alteración de la neurotransmisión de dopamina en la proyección mesocorticolímbica y de la neurotransmisión de noradrenalina en las proyecciones noradrenérgicas desde el locus coeruleus hasta la corteza prefrontal . [59] Los psicoestimulantes como el metilfenidato y la anfetamina son eficaces en el tratamiento del TDAH porque aumentan la actividad de los neurotransmisores en estos sistemas. [27] [59] [60] Aproximadamente el 80% de los que usan estos estimulantes ven mejoras en los síntomas del TDAH. [61] Los niños con TDAH que usan medicamentos estimulantes generalmente tienen mejores relaciones con sus compañeros y familiares, tienen un mejor desempeño en la escuela, son menos distraídos e impulsivos y tienen períodos de atención más largos. [62] [63] Las revisiones Cochrane [nota 7] sobre el tratamiento del TDAH en niños, adolescentes y adultos con anfetaminas farmacéuticas afirmaron que los estudios a corto plazo han demostrado que estos fármacos disminuyen la gravedad de los síntomas, pero tienen tasas de interrupción más altas que los medicamentos no estimulantes debido a sus efectos secundarios adversos . [65] [66] Una revisión Cochrane sobre el tratamiento del TDAH en niños con trastornos de tics como el síndrome de Tourette indicó que los estimulantes en general no empeoran los tics , pero las dosis altas de dextroanfetamina podrían exacerbar los tics en algunos individuos. [67]
La narcolepsia es un trastorno crónico del sueño y la vigilia que se asocia con somnolencia diurna excesiva, cataplejía y parálisis del sueño . [68] Los pacientes con narcolepsia son diagnosticados como tipo 1 o tipo 2, y solo los primeros presentan síntomas de cataplejía. [69] La narcolepsia tipo 1 resulta de la pérdida de aproximadamente 70.000 neuronas liberadoras de orexina en el hipotálamo lateral , lo que conduce a niveles significativamente reducidos de orexina cerebroespinal ; [18] [70] esta reducción es un biomarcador diagnóstico para la narcolepsia tipo 1. [69] Las neuronas de orexina del hipotálamo lateral inervan cada componente del sistema activador reticular ascendente (ARAS), que incluye núcleos noradrenérgicos , dopaminérgicos , histaminérgicos y serotoninérgicos que promueven la vigilia . [70] [71]
El modo de acción terapéutico de la anfetamina en la narcolepsia implica principalmente aumentar la actividad del neurotransmisor monoamínico en el ARAS. [18] [72] [73] Esto incluye neuronas noradrenérgicas en el locus coeruleus , neuronas dopaminérgicas en el área tegmental ventral , neuronas histaminérgicas en el núcleo tuberomamilar y neuronas serotoninérgicas en el núcleo del rafe dorsal . [71] [73] La dextroanfetamina, el enantiómero más dopaminérgico de la anfetamina, es particularmente eficaz para promover la vigilia porque la liberación de dopamina tiene la mayor influencia en la activación cortical y la excitación cognitiva, en relación con otras monoaminas. [18] Por el contrario, la levoanfetamina puede tener un mayor efecto sobre la cataplejía, un síntoma más sensible a los efectos de la noradrenalina y la serotonina. [18] Los núcleos noradrenérgicos y serotoninérgicos en el ARAS están involucrados en la regulación del ciclo del sueño REM y funcionan como células "REM-off", con el efecto de la anfetamina sobre la noradrenalina y la serotonina contribuyendo a la supresión del sueño REM y una posible reducción de la cataplejía en dosis altas. [18] [69] [71]
La guía de práctica clínica de 2021 de la Academia Estadounidense de Medicina del Sueño (AASM) recomienda condicionalmente la dextroanfetamina para el tratamiento de la narcolepsia tipo 1 y tipo 2. [74] El tratamiento con anfetaminas farmacéuticas generalmente es menos preferido en relación con otros psicoestimulantes (p. ej., modafinilo ) y se considera una opción de tratamiento de tercera línea . [47] [75] [76] Las revisiones médicas indican que la anfetamina es segura y eficaz para el tratamiento de la narcolepsia. [18] [47] [74] La anfetamina parece ser más eficaz para mejorar los síntomas asociados con la hipersomnolencia , y tres revisiones encontraron reducciones clínicamente significativas en la somnolencia diurna en pacientes con narcolepsia. [18] [47] [74] Además, estas revisiones sugieren que la anfetamina puede mejorar de forma dosis-dependiente los síntomas de cataplejía. [18] [47] [74] Sin embargo, la calidad de la evidencia de estos hallazgos es baja y, en consecuencia, se refleja en la recomendación condicional de la AASM de la dextroanfetamina como una opción de tratamiento para la narcolepsia. [74]
En 2015, una revisión sistemática y un metaanálisis de ensayos clínicos de alta calidad encontraron que, cuando se usa en dosis bajas (terapéuticas), la anfetamina produce mejoras modestas pero inequívocas en la cognición, incluida la memoria de trabajo , la memoria episódica a largo plazo , el control inhibitorio y algunos aspectos de la atención , en adultos sanos normales; [77] [78] Se sabe que estos efectos de mejora de la cognición de la anfetamina están parcialmente mediados por la activación indirecta tanto del receptor de dopamina D 1 como del adrenoceptor α 2 en la corteza prefrontal . [27] [77] Una revisión sistemática de 2014 encontró que las dosis bajas de anfetamina también mejoran la consolidación de la memoria , lo que a su vez conduce a una mejor recuperación de la información . [79] Las dosis terapéuticas de anfetamina también mejoran la eficiencia de la red cortical, un efecto que media las mejoras en la memoria de trabajo en todos los individuos. [27] [80] La anfetamina y otros estimulantes del TDAH también mejoran la relevancia de la tarea (motivación para realizar una tarea) y aumentan la excitación (vigilia), lo que a su vez promueve el comportamiento dirigido a objetivos. [27] [81] [82] Los estimulantes como la anfetamina pueden mejorar el rendimiento en tareas difíciles y aburridas y algunos estudiantes los utilizan como ayuda para estudiar y realizar exámenes. [27] [82] [83] Según estudios sobre el uso de estimulantes ilícitos autodeclarado, entre el 5 y el 35 % de los estudiantes universitarios utilizan estimulantes desviados para el TDAH, que se utilizan principalmente para mejorar el rendimiento académico en lugar de como drogas recreativas. [84] [85] [86] Sin embargo, las dosis altas de anfetamina que están por encima del rango terapéutico pueden interferir con la memoria de trabajo y otros aspectos del control cognitivo. [27] [82]
La anfetamina es utilizada por algunos atletas por sus efectos psicológicos y de mejora del rendimiento atlético , como el aumento de la resistencia y el estado de alerta; [28] [40] sin embargo, el uso no médico de anfetamina está prohibido en eventos deportivos que están regulados por agencias antidopaje universitarias, nacionales e internacionales. [87] [88] En personas sanas en dosis terapéuticas orales, se ha demostrado que la anfetamina aumenta la fuerza muscular , la aceleración, el rendimiento atlético en condiciones anaeróbicas y la resistencia (es decir, retrasa la aparición de la fatiga ), al tiempo que mejora el tiempo de reacción . [28] [89] [90] La anfetamina mejora la resistencia y el tiempo de reacción principalmente a través de la inhibición de la recaptación y la liberación de dopamina en el sistema nervioso central. [89] [90] [91] La anfetamina y otras drogas dopaminérgicas también aumentan la potencia de salida a niveles fijos de esfuerzo percibido al anular un "interruptor de seguridad", lo que permite que el límite de temperatura central aumente para acceder a una capacidad de reserva que normalmente está fuera de los límites. [90] [92] [93] En dosis terapéuticas, los efectos adversos de la anfetamina no impiden el rendimiento atlético; [28] [89] sin embargo, en dosis mucho más altas, la anfetamina puede inducir efectos que perjudican gravemente el rendimiento, como la rápida degradación muscular y la temperatura corporal elevada . [29] [89]
La anfetamina, específicamente el enantiómero dextrógiro más dopaminérgico ( dextroanfetamina ), también se usa de manera recreativa como euforizante y afrodisíaco, y al igual que otras anfetaminas ; se usa como droga de club por su efecto energético y eufórico. Se considera que la dextroanfetamina (d-anfetamina) tiene un alto potencial de uso indebido de manera recreativa, ya que las personas generalmente informan que se sienten eufóricas , más alertas y con más energía después de tomar la droga. [94] [95] [96] Una parte notable de la subcultura mod de la década de 1960 en el Reino Unido fue el uso recreativo de anfetaminas, que se usaba para alimentar bailes durante toda la noche en clubes como Twisted Wheel de Manchester . Los informes de los periódicos describían a bailarines que salían de los clubes a las 5 a. m. con las pupilas dilatadas. [97] Los mods usaban la droga para la estimulación y el estado de alerta , lo que consideraban diferente de la intoxicación causada por el alcohol y otras drogas. [97] El Dr. Andrew Wilson sostiene que para una minoría significativa, "las anfetaminas simbolizaban la imagen inteligente, activa y tranquila" y que buscaban "estimulación, no intoxicación [...] mayor conciencia, no escape" y " confianza y elocuencia" en lugar de la " algarabía borracha de generaciones anteriores". [97] Las propiedades dopaminérgicas (gratificantes) de la dextroanfetamina afectan al circuito mesocorticolímbico ; un grupo de estructuras neuronales responsables de la prominencia del incentivo (es decir, "querer"; deseo o ansia de una recompensa y motivación), el refuerzo positivo y las emociones con valencia positiva , particularmente las que involucran placer . [98] Grandes dosis recreativas de dextroanfetamina pueden producir síntomas de sobredosis de dextroanfetamina. [96] Los usuarios recreativos a veces abren cápsulas de dexedrina y trituran el contenido para insuflarlo (inhalarlo) o posteriormente disolverlo en agua e inyectarlo. [96] Las formulaciones de liberación inmediata tienen un mayor potencial de abuso por insuflación (inhalación) o inyección intravenosa debido a un perfil farmacocinético más favorable y una fácil trituración (especialmente los comprimidos). [99] [100] La inyección en el torrente sanguíneo puede ser peligrosa porque los rellenos insolubles dentro de los comprimidos pueden bloquear los vasos sanguíneos pequeños. [96] El uso excesivo crónico de dextroanfetamina puede provocar una dependencia grave del fármaco ., lo que provoca síntomas de abstinencia cuando se interrumpe el consumo de la droga. [96]
Según el Programa Internacional de Seguridad Química (IPCS) y la Administración de Alimentos y Medicamentos de los Estados Unidos (FDA), [nota 8] la anfetamina está contraindicada en personas con antecedentes de abuso de drogas , [nota 9] enfermedad cardiovascular , agitación severa o ansiedad severa. [36] [29] [102] También está contraindicada en individuos con arteriosclerosis avanzada (endurecimiento de las arterias), glaucoma (aumento de la presión ocular), hipertiroidismo (producción excesiva de hormona tiroidea) o hipertensión moderada a severa . [36] [29] [102] Estas agencias indican que las personas que han experimentado reacciones alérgicas a otros estimulantes o que están tomando inhibidores de la monoaminooxidasa (IMAO) no deben tomar anfetamina, [36] [29] [102] aunque se ha documentado el uso concurrente seguro de anfetamina e inhibidores de la monoaminooxidasa. [103] [104] Estas agencias también establecen que cualquier persona con anorexia nerviosa , trastorno bipolar , depresión, hipertensión, problemas hepáticos o renales, manía , psicosis , fenómeno de Raynaud , convulsiones , problemas de tiroides , tics o síndrome de Tourette debe controlar sus síntomas mientras toma anfetamina. [29] [102] La evidencia de estudios en humanos indica que el uso terapéutico de anfetamina no causa anomalías del desarrollo en el feto o los recién nacidos (es decir, no es un teratógeno humano ), pero el abuso de anfetaminas sí plantea riesgos para el feto. [102] También se ha demostrado que la anfetamina pasa a la leche materna, por lo que el IPCS y la FDA aconsejan a las madres que eviten la lactancia materna cuando la usen. [29] [102] Debido al potencial de alteraciones reversibles del crecimiento, [nota 10] la FDA aconseja controlar la altura y el peso de los niños y adolescentes a los que se les prescribe un fármaco de anfetamina. [29]
Los efectos secundarios adversos de la anfetamina son muchos y variados, y la cantidad de anfetamina utilizada es el factor principal para determinar la probabilidad y la gravedad de los efectos adversos. [29] [40] Los productos de anfetamina como Adderall , Dexedrine y sus equivalentes genéricos están actualmente aprobados por la FDA de EE. UU. para uso terapéutico a largo plazo. [37] [29] El uso recreativo de anfetamina generalmente involucra dosis mucho mayores, que tienen un mayor riesgo de efectos adversos graves del fármaco que las dosis utilizadas con fines terapéuticos. [40]
Los efectos secundarios cardiovasculares pueden incluir hipertensión o hipotensión debido a una respuesta vasovagal , fenómeno de Raynaud (flujo sanguíneo reducido a las manos y los pies) y taquicardia (aumento de la frecuencia cardíaca). [29] [40] [105] Los efectos secundarios sexuales en los hombres pueden incluir disfunción eréctil , erecciones frecuentes o erecciones prolongadas . [29] Los efectos secundarios gastrointestinales pueden incluir dolor abdominal , estreñimiento , diarrea y náuseas . [1] [29] [106] Otros posibles efectos secundarios físicos incluyen pérdida de apetito , visión borrosa , boca seca , rechinamiento excesivo de dientes , hemorragia nasal, sudoración profusa, rinitis medicamentosa (congestión nasal inducida por fármacos), umbral convulsivo reducido , tics (un tipo de trastorno del movimiento) y pérdida de peso . [fuentes 5] Los efectos secundarios físicos peligrosos son raros en dosis farmacéuticas típicas. [40]
La anfetamina estimula los centros respiratorios medulares , produciendo respiraciones más rápidas y profundas. [40] En una persona normal en dosis terapéuticas, este efecto no suele ser perceptible, pero cuando la respiración ya está comprometida, puede ser evidente. [40] La anfetamina también induce la contracción en el esfínter de la vejiga urinaria , el músculo que controla la micción, lo que puede provocar dificultad para orinar. [40] Este efecto puede ser útil para tratar la enuresis y la pérdida del control de la vejiga . [40] Los efectos de la anfetamina en el tracto gastrointestinal son impredecibles. [40] Si la actividad intestinal es alta, la anfetamina puede reducir la motilidad gastrointestinal (la velocidad a la que el contenido se mueve a través del sistema digestivo); [40] sin embargo, la anfetamina puede aumentar la motilidad cuando el músculo liso del tracto está relajado. [40] La anfetamina también tiene un ligero efecto analgésico y puede mejorar los efectos analgésicos de los opioides . [1] [40]
Estudios encargados por la FDA en 2011 indican que en niños, adultos jóvenes y adultos no existe asociación entre eventos cardiovasculares adversos graves ( muerte súbita , ataque cardíaco y accidente cerebrovascular ) y el uso médico de anfetaminas u otros estimulantes del TDAH. [fuentes 6] Sin embargo, los fármacos de anfetamina están contraindicados en personas con enfermedad cardiovascular . [fuentes 7]
En dosis terapéuticas normales, los efectos secundarios psicológicos más comunes de la anfetamina incluyen aumento del estado de alerta , aprensión, concentración , iniciativa, confianza en uno mismo y sociabilidad, cambios de humor ( estado de ánimo eufórico seguido de estado de ánimo levemente deprimido ), insomnio o vigilia y disminución de la sensación de fatiga. [29] [40] Los efectos secundarios menos comunes incluyen ansiedad , cambio en la libido , grandiosidad , irritabilidad , comportamientos repetitivos u obsesivos e inquietud; [fuentes 8] estos efectos dependen de la personalidad del usuario y del estado mental actual. [40] La psicosis por anfetamina (p. ej., delirios y paranoia ) puede ocurrir en usuarios habituales. [29] [41] [42] Aunque es muy poco común, esta psicosis también puede ocurrir en dosis terapéuticas durante la terapia a largo plazo. [29] [42] [43] Según la FDA, "no hay evidencia sistemática" de que los estimulantes produzcan comportamiento agresivo u hostilidad. [29]
También se ha demostrado que la anfetamina produce una preferencia condicionada por el lugar en los seres humanos que toman dosis terapéuticas, [65] [113] lo que significa que los individuos adquieren una preferencia por pasar el tiempo en lugares donde han consumido anfetamina previamente. [113] [114]
La adicción es un riesgo grave con el uso recreativo intenso de anfetaminas, pero es poco probable que ocurra con el uso médico a largo plazo en dosis terapéuticas; [45] [46] [47] de hecho, la terapia estimulante de por vida para el TDAH que comienza durante la infancia reduce el riesgo de desarrollar trastornos por uso de sustancias en la edad adulta. [44] La hiperactivación patológica de la vía mesolímbica , una vía de dopamina que conecta el área tegmental ventral con el núcleo accumbens , juega un papel central en la adicción a las anfetaminas. [123] [124] Las personas que frecuentemente se autoadministran altas dosis de anfetamina tienen un alto riesgo de desarrollar una adicción a las anfetaminas, ya que el uso crónico en dosis altas aumenta gradualmente el nivel de ΔFosB accumbal , un "interruptor molecular" y "proteína de control maestro" para la adicción. [115] [125] [126] Una vez que el ΔFosB del núcleo accumbens se sobreexpresa lo suficiente, comienza a aumentar la gravedad de la conducta adictiva (es decir, la búsqueda compulsiva de la droga) con aumentos adicionales en su expresión. [125] [127] Si bien actualmente no existen medicamentos efectivos para tratar la adicción a las anfetaminas, la participación regular en ejercicio aeróbico sostenido parece reducir el riesgo de desarrollar dicha adicción. [128] [129] La terapia con ejercicios mejora los resultados del tratamiento clínico y puede usarse como terapia complementaria con terapias conductuales para la adicción. [128] [130] [fuentes 9]
El uso crónico de anfetamina en dosis excesivas provoca alteraciones en la expresión génica en la proyección mesocorticolímbica , que surgen a través de mecanismos transcripcionales y epigenéticos . [126] [131] [132] Los factores de transcripción más importantes [nota 11] que producen estas alteraciones son el homólogo B del oncogén viral del osteosarcoma murino Delta FBJ ( ΔFosB ), la proteína de unión al elemento de respuesta a AMPc ( CREB ) y el factor nuclear kappa B ( NF-κB ). [126] ΔFosB es el mecanismo biomolecular más significativo en la adicción porque la sobreexpresión de ΔFosB (es decir, un nivel anormalmente alto de expresión genética que produce un fenotipo pronunciado relacionado con el gen ) en las neuronas espinosas medianas de tipo D1 en el núcleo accumbens es necesaria y suficiente [nota 12] para muchas de las adaptaciones neuronales y regula múltiples efectos conductuales (por ejemplo, sensibilización a la recompensa y autoadministración creciente de drogas ) involucrados en la adicción. [115] [125] [126] Una vez que ΔFosB se sobreexpresa suficientemente, induce un estado adictivo que se vuelve cada vez más severo con aumentos adicionales en la expresión de ΔFosB. [115] [125] Se ha relacionado con adicciones al alcohol , cannabinoides , cocaína , metilfenidato , nicotina , opioides , fenciclidina , propofol y anfetaminas sustituidas , entre otros. [fuentes 10]
ΔJunD , un factor de transcripción, y G9a , una enzima metiltransferasa de histonas , se oponen a la función de ΔFosB e inhiben los aumentos en su expresión. [115] [126] [136] La sobreexpresión suficiente de ΔJunD en el núcleo accumbens con vectores virales puede bloquear por completo muchas de las alteraciones neuronales y conductuales observadas en el abuso crónico de drogas (es decir, las alteraciones mediadas por ΔFosB). [126] De manera similar, la hiperexpresión de G9a accumbal resulta en una dimetilación marcadamente aumentada del residuo 9 de lisina de la histona 3 ( H3K9me2 ) y bloquea la inducción de plasticidad neuronal y conductual mediada por ΔFosB por el uso crónico de drogas, [fuentes 11] que ocurre a través de la represión mediada por H3K9me2 de factores de transcripción para ΔFosB y la represión mediada por H3K9me2 de varios objetivos transcripcionales de ΔFosB (por ejemplo, CDK5 ). [126] [136] [137] ΔFosB también juega un papel importante en la regulación de las respuestas conductuales a las recompensas naturales , como la comida sabrosa, el sexo y el ejercicio. [127] [126] [140] Dado que tanto las recompensas naturales como las drogas adictivas inducen la expresión de ΔFosB (es decir, hacen que el cerebro produzca más), la adquisición crónica de estas recompensas puede resultar en un estado patológico similar de adicción. [127] [126] En consecuencia, ΔFosB es el factor más significativo involucrado tanto en la adicción a las anfetaminas como en las adicciones sexuales inducidas por anfetaminas , que son conductas sexuales compulsivas que resultan de la actividad sexual excesiva y el uso de anfetaminas. [127] [141] [142] Estas adicciones sexuales están asociadas con un síndrome de desregulación de la dopamina que ocurre en algunos pacientes que toman fármacos dopaminérgicos . [127] [140]
Los efectos de la anfetamina sobre la regulación genética dependen tanto de la dosis como de la vía de administración. [132] La mayor parte de la investigación sobre la regulación genética y la adicción se basa en estudios en animales con administración intravenosa de anfetamina en dosis muy altas. [132] Los pocos estudios que han utilizado dosis terapéuticas humanas equivalentes (ajustadas al peso) y administración oral muestran que estos cambios, si ocurren, son relativamente menores. [132] Esto sugiere que el uso médico de la anfetamina no afecta significativamente a la regulación genética. [132]
A diciembre de 2019, [update]no existe una farmacoterapia eficaz para la adicción a las anfetaminas. [143] [144] [145] Las revisiones de 2015 y 2016 indicaron que los agonistas selectivos de TAAR1 tienen un potencial terapéutico significativo como tratamiento para las adicciones a los psicoestimulantes; [39] [146] sin embargo, a febrero de 2016, [update]los únicos compuestos que se sabe que funcionan como agonistas selectivos de TAAR1 son medicamentos experimentales . [39] [146] La adicción a las anfetaminas está mediada en gran medida por una mayor activación de los receptores de dopamina y los receptores NMDA colocalizados [nota 13] en el núcleo accumbens; [124] los iones de magnesio inhiben los receptores NMDA al bloquear el canal de calcio del receptor . [124] [147] Una revisión sugirió que, basándose en pruebas con animales, el uso patológico (que induce a la adicción) de psicoestimulantes reduce significativamente el nivel de magnesio intracelular en todo el cerebro. [ 124] Se ha demostrado que el tratamiento con magnesio suplementario [nota 14] reduce la autoadministración de anfetaminas (es decir, las dosis que uno mismo se administra) en humanos, pero no es una monoterapia eficaz para la adicción a las anfetaminas. [124]
Una revisión sistemática y un metanálisis de 2019 evaluaron la eficacia de 17 farmacoterapias diferentes utilizadas en ensayos controlados aleatorios (ECA) para la adicción a la anfetamina y la metanfetamina; [144] solo encontró evidencia de baja fuerza de que el metilfenidato podría reducir la autoadministración de anfetamina o metanfetamina. [144] Hubo evidencia de baja a moderada fuerza de que no hubo beneficio para la mayoría de los otros medicamentos utilizados en ECA, que incluyeron antidepresivos (bupropión, mirtazapina , sertralina ), antipsicóticos ( aripiprazol ), anticonvulsivos ( topiramato , baclofeno , gabapentina ), naltrexona , vareniclina , citicolina , ondansetrón , prometa , riluzol , atomoxetina , dextroanfetamina y modafinilo . [144]
Una revisión sistemática y un metanálisis en red de 2018 de 50 ensayos que involucraron 12 intervenciones psicosociales diferentes para la adicción a la anfetamina, la metanfetamina o la cocaína encontraron que la terapia combinada con un enfoque de manejo de contingencias y refuerzo comunitario tuvo la mayor eficacia (es decir, tasa de abstinencia) y aceptabilidad (es decir, tasa de abandono más baja). [148] Otras modalidades de tratamiento examinadas en el análisis incluyeron monoterapia con manejo de contingencias o enfoque de refuerzo comunitario, terapia cognitivo conductual , programas de 12 pasos , terapias basadas en recompensas no contingentes, terapia psicodinámica y otras terapias combinadas que involucran estos. [148]
Además, la investigación sobre los efectos neurobiológicos del ejercicio físico sugiere que el ejercicio aeróbico diario, especialmente el ejercicio de resistencia (p. ej., correr maratones ), previene el desarrollo de la adicción a las drogas y es una terapia complementaria eficaz (es decir, un tratamiento complementario) para la adicción a las anfetaminas. [fuentes 9] El ejercicio conduce a mejores resultados del tratamiento cuando se utiliza como tratamiento complementario, en particular para las adicciones a los psicoestimulantes. [128] [130] [149] En particular, el ejercicio aeróbico disminuye la autoadministración de psicoestimulantes, reduce el restablecimiento (es decir, la recaída) de la búsqueda de drogas e induce una mayor densidad del receptor de dopamina D 2 (DRD2) en el cuerpo estriado . [127] [149] Esto es lo opuesto al uso patológico de estimulantes, que induce una disminución de la densidad del DRD2 estriatal. [127] Una revisión señaló que el ejercicio también puede prevenir el desarrollo de una adicción a las drogas al alterar la inmunorreactividad de ΔFosB o c-Fos en el cuerpo estriado u otras partes del sistema de recompensa . [129]
La tolerancia a las drogas se desarrolla rápidamente en el abuso de anfetaminas (es decir, uso recreativo de anfetaminas), por lo que los períodos de abuso prolongado requieren dosis cada vez mayores de la droga para lograr el mismo efecto. [150] [151] Según una revisión Cochrane sobre la abstinencia en personas que consumen anfetaminas y metanfetaminas compulsivamente, "cuando los consumidores crónicos intensos interrumpen abruptamente el consumo de anfetaminas, muchos informan un síndrome de abstinencia limitado en el tiempo que ocurre dentro de las 24 horas posteriores a su última dosis". [152] Esta revisión señaló que los síntomas de abstinencia en los consumidores crónicos de dosis altas son frecuentes, ocurren en aproximadamente el 88% de los casos y persisten durante 3 a 4 semanas con una marcada fase de "caída" que ocurre durante la primera semana. [152] Los síntomas de abstinencia de anfetaminas pueden incluir ansiedad, ansia por la droga , estado de ánimo deprimido , fatiga , aumento del apetito , aumento del movimiento o disminución del movimiento , falta de motivación, insomnio o somnolencia y sueños lúcidos . [152] La revisión indicó que la gravedad de los síntomas de abstinencia está correlacionada positivamente con la edad del individuo y el grado de dependencia. [152] Los síntomas de abstinencia leves por la interrupción del tratamiento con anfetaminas en dosis terapéuticas se pueden evitar reduciendo gradualmente la dosis. [1]
Una sobredosis de anfetamina puede provocar muchos síntomas diferentes, pero rara vez es mortal con el cuidado adecuado. [1] [102] [153] La gravedad de los síntomas de sobredosis aumenta con la dosis y disminuye con la tolerancia a la droga anfetamina. [40] [102] Se sabe que las personas tolerantes toman hasta 5 gramos de anfetamina en un día, que es aproximadamente 100 veces la dosis terapéutica diaria máxima. [102] Los síntomas de una sobredosis moderada y extremadamente grande se enumeran a continuación; la intoxicación mortal por anfetaminas generalmente también implica convulsiones y coma . [29] [40] En 2013, la sobredosis de anfetamina, metanfetamina y otros compuestos implicados en un " trastorno por consumo de anfetaminas " resultó en un estimado de 3.788 muertes en todo el mundo ( 3.425–4.145 muertes, 95% de confianza ). [nota 15] [154]
En roedores y primates, dosis suficientemente altas de anfetamina causan neurotoxicidad dopaminérgica , o daño a las neuronas de dopamina, que se caracteriza por la degeneración terminal de la dopamina y la reducción de la función del transportador y receptor. [156] [157] No hay evidencia de que la anfetamina sea directamente neurotóxica en humanos. [158] [159] Sin embargo, grandes dosis de anfetamina pueden causar neurotoxicidad dopaminérgica indirectamente como resultado de la hiperpirexia , la formación excesiva de especies reactivas de oxígeno y el aumento de la autooxidación de la dopamina. [fuentes 13] Los modelos animales de neurotoxicidad por exposición a altas dosis de anfetamina indican que la aparición de hiperpirexia (es decir, temperatura corporal central ≥ 40 °C) es necesaria para el desarrollo de la neurotoxicidad inducida por anfetamina. [157] Las elevaciones prolongadas de la temperatura cerebral por encima de los 40 °C probablemente promueven el desarrollo de neurotoxicidad inducida por anfetamina en animales de laboratorio al facilitar la producción de especies reactivas de oxígeno, alterar la función de las proteínas celulares y aumentar transitoriamente la permeabilidad de la barrera hematoencefálica . [157]
Una sobredosis de anfetamina puede provocar una psicosis estimulante que puede implicar una variedad de síntomas, como delirios y paranoia. [41] [42] Una revisión Cochrane sobre el tratamiento de la psicosis por anfetamina, dextroanfetamina y metanfetamina afirma que entre el 5 y el 15 % de los usuarios no se recuperan por completo. [41] [162] Según la misma revisión, hay al menos un ensayo que muestra que los medicamentos antipsicóticos resuelven eficazmente los síntomas de la psicosis anfetamínica aguda. [41] La psicosis rara vez surge del uso terapéutico. [29] [42] [43]
Se sabe que muchos tipos de sustancias interactúan con la anfetamina, lo que resulta en una acción alterada del fármaco o del metabolismo de la anfetamina, la sustancia interactuante o ambos. [29] Los inhibidores de las enzimas que metabolizan la anfetamina (p. ej., CYP2D6 y FMO3 ) prolongarán su vida media de eliminación , lo que significa que sus efectos durarán más. [6] [29] La anfetamina también interactúa con los IMAO , en particular los inhibidores de la monoaminooxidasa A , ya que tanto los IMAO como la anfetamina aumentan las catecolaminas plasmáticas (es decir, noradrenalina y dopamina); [29] por lo tanto, el uso concurrente de ambos es peligroso. [29] La anfetamina modula la actividad de la mayoría de las drogas psicoactivas. En particular, la anfetamina puede disminuir los efectos de los sedantes y depresores y aumentar los efectos de los estimulantes y antidepresivos . [29] La anfetamina también puede disminuir los efectos de los antihipertensivos y antipsicóticos debido a sus efectos sobre la presión arterial y la dopamina respectivamente. [29] La suplementación con zinc puede reducir la dosis mínima efectiva de anfetamina cuando se utiliza para el tratamiento del TDAH. [nota 16] [167]
En general, no existe una interacción significativa al consumir anfetamina con alimentos, pero el pH del contenido gastrointestinal y de la orina afecta la absorción y excreción de anfetamina, respectivamente. [29] Las sustancias ácidas reducen la absorción de anfetamina y aumentan la excreción urinaria, y las sustancias alcalinas hacen lo contrario. [29] Debido al efecto que tiene el pH sobre la absorción, la anfetamina también interactúa con reductores de ácido gástrico como los inhibidores de la bomba de protones y los antihistamínicos H 2 , que aumentan el pH gastrointestinal (es decir, lo hacen menos ácido). [29]
La anfetamina ejerce sus efectos conductuales alterando el uso de monoaminas como señales neuronales en el cerebro, principalmente en las neuronas de catecolaminas en las vías de recompensa y función ejecutiva del cerebro. [38] [60] Las concentraciones de los principales neurotransmisores involucrados en el circuito de recompensa y la función ejecutiva, dopamina y norepinefrina, aumentan dramáticamente de manera dependiente de la dosis por la anfetamina debido a sus efectos sobre los transportadores de monoamina . [38] [60] [168] Los efectos promotores de la prominencia motivacional y de refuerzo de la anfetamina se deben principalmente a la actividad dopaminérgica mejorada en la vía mesolímbica . [27] Los efectos eufóricos y estimulantes del aparato locomotor de la anfetamina dependen de la magnitud y velocidad con la que aumenta las concentraciones sinápticas de dopamina y norepinefrina en el cuerpo estriado . [2]
La anfetamina ha sido identificada como un potente agonista completo del receptor 1 asociado a aminas traza (TAAR1), un receptor acoplado a proteína G (GPCR) acoplado a G s y G q descubierto en 2001, que es importante para la regulación de las monoaminas cerebrales. [38] [174] La activación de TAAR1 aumenta el AMPc.producción a través de la activación de la adenilil ciclasa e inhibe la función del transportador de monoamina . [38] [175] Los autorreceptores de monoamina (p. ej., D 2 short , α 2 presináptico y 5-HT 1A presináptico ) tienen el efecto opuesto de TAAR1, y juntos estos receptores proporcionan un sistema regulador para las monoaminas. [38] [39] En particular, la anfetamina y las aminas traza poseen altas afinidades de unión para TAAR1, pero no para los autorreceptores de monoamina. [38] [39] Los estudios de imágenes indican que la inhibición de la recaptación de monoamina por anfetamina y aminas traza es específica del sitio y depende de la presencia de la co-localización de TAAR1 en las neuronas monoaminérgicas asociadas. [38]
Además de los transportadores de monoamina neuronales , la anfetamina también inhibe ambos transportadores de monoamina vesicular , VMAT1 y VMAT2 , así como SLC1A1 , SLC22A3 y SLC22A5 . [fuentes 14] SLC1A1 es el transportador de aminoácidos excitatorios 3 (EAAT3), un transportador de glutamato ubicado en las neuronas, SLC22A3 es un transportador de monoamina extraneuronal que está presente en los astrocitos , y SLC22A5 es un transportador de carnitina de alta afinidad . [fuentes 14] Se sabe que la anfetamina induce fuertemente la expresión del gen de transcripción regulada por cocaína y anfetamina (CART) , [11] [181] un neuropéptido involucrado en el comportamiento alimentario, el estrés y la recompensa, que induce aumentos observables en el desarrollo neuronal y la supervivencia in vitro . [11] [182] [183] El receptor CART aún no se ha identificado, pero hay evidencia significativa de que CART se une a un GPCR acoplado a G i /G o único . [183] [184] La anfetamina también inhibe las monoaminooxidasas en dosis muy altas, lo que resulta en un menor metabolismo de monoaminas y trazas de aminas y, en consecuencia, mayores concentraciones de monoaminas sinápticas. [23] [185] En los humanos, el único receptor postsináptico al que se sabe que se une la anfetamina es el receptor 5-HT1A , donde actúa como un agonista con baja afinidad micromolar . [186] [187]
El perfil completo de los efectos a corto plazo de la anfetamina en los seres humanos se deriva principalmente a través del aumento de la comunicación celular o neurotransmisión de dopamina , [38] serotonina , [38] noradrenalina , [38] epinefrina , [168 ] histamina , [168] péptidos CART , [11] [181] opioides endógenos , [188] [189] [190] hormona adrenocorticotrópica , [191] [192] corticosteroides , [191] [192] y glutamato , [172] [177] al que afecta a través de interacciones con CART , 5-HT1A , EAAT3 , TAAR1 , VMAT1 , VMAT2 y posiblemente otros objetivos biológicos . [Fuentes 15] La anfetamina también activa siete enzimas anhidrasas carbónicas humanas , varias de las cuales se expresan en el cerebro humano. [193]
La dextroanfetamina es un agonista más potente de TAAR1 que la levoanfetamina. [194] En consecuencia, la dextroanfetamina produce una mayor estimulación del SNC que la levoanfetamina, aproximadamente tres o cuatro veces más, pero la levoanfetamina tiene efectos cardiovasculares y periféricos ligeramente más fuertes. [40] [194]
En ciertas regiones del cerebro, la anfetamina aumenta la concentración de dopamina en la hendidura sináptica . [38] La anfetamina puede entrar en la neurona presináptica ya sea a través de DAT o difundiéndose a través de la membrana neuronal directamente. [38] Como consecuencia de la captación de DAT, la anfetamina produce una inhibición competitiva de la recaptación en el transportador. [38] Al entrar en la neurona presináptica, la anfetamina activa TAAR1 que, a través de la señalización de la proteína quinasa A (PKA) y la proteína quinasa C (PKC), causa la fosforilación de DAT . [38] La fosforilación por cualquiera de las proteínas quinasas puede resultar en la internalización de DAT ( inhibición no competitiva de la recaptación), pero la fosforilación mediada por PKC por sí sola induce la reversión del transporte de dopamina a través de DAT (es decir, eflujo de dopamina). [nota 16] [38] [195] También se sabe que la anfetamina aumenta el calcio intracelular, un efecto que está asociado con la fosforilación de DAT a través de una vía dependiente de la proteína quinasa dependiente de Ca2+/calmodulina (CAMK) no identificada, que a su vez produce un eflujo de dopamina. [174] [172] [173] A través de la activación directa de los canales de potasio rectificadores internos acoplados a la proteína G , TAAR1 reduce la tasa de activación de las neuronas dopaminérgicas, lo que previene un estado hiperdopaminérgico. [170] [171] [196]
La anfetamina también es un sustrato para el transportador de monoamina vesicular presináptico , VMAT2 . [168] [169] Después de la captación de anfetamina en VMAT2, la anfetamina induce el colapso del gradiente de pH vesicular, lo que resulta en la liberación de moléculas de dopamina de las vesículas sinápticas al citosol a través del eflujo de dopamina a través de VMAT2. [168] [169] Posteriormente, las moléculas de dopamina citosólica se liberan de la neurona presináptica a la hendidura sináptica a través del transporte inverso en DAT . [38] [168] [169]
De manera similar a la dopamina, la anfetamina aumenta de manera dosis-dependiente el nivel de norepinefrina sináptica, el precursor directo de la epinefrina . [48] [60] Con base en la expresión neuronal del ARNm de TAAR1 , se cree que la anfetamina afecta a la norepinefrina de manera análoga a la dopamina. [38] [168] [195] En otras palabras, la anfetamina induce el eflujo mediado por TAAR1 y la inhibición no competitiva de la recaptación en el NET fosforilado , la inhibición competitiva de la recaptación del NET y la liberación de norepinefrina de VMAT2 . [38] [168]
La anfetamina ejerce efectos análogos, aunque menos pronunciados, sobre la serotonina como sobre la dopamina y la noradrenalina. [38] [60] La anfetamina afecta a la serotonina a través de VMAT2 y, al igual que la noradrenalina, se cree que fosforila SERT a través de TAAR1 . [38] [168] Al igual que la dopamina, la anfetamina tiene una afinidad baja, micromolar, en el receptor 5-HT1A humano . [186] [187]
La administración aguda de anfetamina en humanos aumenta la liberación endógena de opioides en varias estructuras cerebrales en el sistema de recompensa . [188] [189] [190] Se ha demostrado que los niveles extracelulares de glutamato , el principal neurotransmisor excitatorio en el cerebro, aumentan en el cuerpo estriado después de la exposición a la anfetamina. [172] Este aumento en el glutamato extracelular presumiblemente ocurre a través de la internalización inducida por anfetamina de EAAT3 , un transportador de recaptación de glutamato, en las neuronas de dopamina. [172] [177] La anfetamina también induce la liberación selectiva de histamina de los mastocitos y el eflujo de las neuronas histaminérgicas a través de VMAT2 . [168] La administración aguda de anfetamina también puede aumentar los niveles de hormona adrenocorticotrópica y corticosteroides en el plasma sanguíneo al estimular el eje hipotálamo-hipofisario-suprarrenal . [36] [191] [192]
En diciembre de 2017, se publicó el primer estudio que evaluó la interacción entre la anfetamina y las enzimas anhidrasa carbónica humana; [193] de las once enzimas anhidrasa carbónica que examinó, encontró que la anfetamina activa potentemente siete, cuatro de las cuales están altamente expresadas en el cerebro humano , con efectos activadores nanomolares bajos a micromolares bajos. [193] Con base en la investigación preclínica, la activación de la anhidrasa carbónica cerebral tiene efectos de mejora cognitiva; [198] pero, con base en el uso clínico de inhibidores de la anhidrasa carbónica , la activación de la anhidrasa carbónica en otros tejidos puede estar asociada con efectos adversos, como la activación ocular que exacerba el glaucoma . [198]
La biodisponibilidad oral de la anfetamina varía con el pH gastrointestinal; [29] se absorbe bien en el intestino y la biodisponibilidad es típicamente del 90%. [10] La anfetamina es una base débil con un p K a de 9,9; [3] en consecuencia, cuando el pH es básico, más del fármaco está en su forma de base libre soluble en lípidos y más se absorbe a través de las membranas celulares ricas en lípidos del epitelio intestinal . [3] [29] Por el contrario, un pH ácido significa que el fármaco está predominantemente en una forma catiónica (sal) soluble en agua y se absorbe menos. [3] Aproximadamente el 20% de la anfetamina que circula en el torrente sanguíneo está unida a las proteínas plasmáticas . [11] Después de la absorción, la anfetamina se distribuye fácilmente en la mayoría de los tejidos del cuerpo, con altas concentraciones en el líquido cefalorraquídeo y el tejido cerebral . [17]
Las vidas medias de los enantiómeros de anfetamina difieren y varían con el pH de la orina. [3] A un pH urinario normal, las vidas medias de la dextroanfetamina y la levoanfetamina son de 9 a 11 horas y de 11 a 14 horas, respectivamente. [3] La orina muy ácida reducirá las vidas medias de los enantiómeros a 7 horas; [17] La orina muy alcalina aumentará las vidas medias hasta 34 horas. [17] Las variantes de liberación inmediata y liberación prolongada de las sales de ambos isómeros alcanzan concentraciones plasmáticas máximas a las 3 y 7 horas después de la dosis respectivamente. [3] La anfetamina se elimina por los riñones , y entre el 30 y el 40 % de la droga se excreta sin cambios a un pH urinario normal. [3] Cuando el pH urinario es básico, la anfetamina está en su forma de base libre, por lo que se excreta menos. [3] Cuando el pH de la orina es anormal, la recuperación urinaria de anfetamina puede variar desde un mínimo de 1% hasta un máximo de 75%, dependiendo principalmente de si la orina es demasiado básica o ácida, respectivamente. [3] Después de la administración oral, la anfetamina aparece en la orina dentro de las 3 horas. [17] Aproximadamente el 90% de la anfetamina ingerida se elimina 3 días después de la última dosis oral. [17]
La lisdexanfetamina es un profármaco de la dextroanfetamina. [199] [200] No es tan sensible al pH como la anfetamina cuando se absorbe en el tracto gastrointestinal. [200] Después de la absorción en el torrente sanguíneo, la lisdexanfetamina es completamente convertida por los glóbulos rojos en dextroanfetamina y el aminoácido L -lisina por hidrólisis a través de enzimas aminopeptidasas indeterminadas . [200] [199] [201] Este es el paso limitante de la velocidad en la bioactivación de la lisdexanfetamina. [199] La vida media de eliminación de la lisdexanfetamina es generalmente inferior a 1 hora. [200] [199] Debido a la conversión necesaria de lisdexanfetamina en dextroanfetamina, los niveles de dextroanfetamina con lisdexanfetamina alcanzan su punto máximo aproximadamente una hora más tarde que con una dosis equivalente de dextroanfetamina de liberación inmediata. [199] [201] Presumiblemente debido a su activación limitada por la velocidad por los glóbulos rojos, la administración intravenosa de lisdexanfetamina muestra un tiempo muy retrasado hasta el pico y niveles máximos reducidos en comparación con la administración intravenosa de una dosis equivalente de dextroanfetamina. [199] La farmacocinética de la lisdexanfetamina es similar independientemente de si se administra por vía oral, intranasal o intravenosa. [199] [201] Por lo tanto, a diferencia de la dextroanfetamina, el uso parenteral no mejora los efectos subjetivos de la lisdexanfetamina. [199] [201] Debido a su comportamiento como profármaco y sus diferencias farmacocinéticas, la lisdexanfetamina tiene una mayor duración del efecto terapéutico que la dextroanfetamina de liberación inmediata y muestra un potencial de mal uso reducido. [199] [201]
CYP2D6 , dopamina β-hidroxilasa (DBH), monooxigenasa que contiene flavina 3 (FMO3), butirato-CoA ligasa (XM-ligasa) y glicina N -aciltransferasa (GLYAT) son las enzimas conocidas por metabolizar la anfetamina o sus metabolitos en humanos. [fuentes 16] La anfetamina tiene una variedad de productos metabólicos excretados, incluyendo 4-hidroxianfetamina , 4-hidroxinorefedrina , 4-hidroxifenilacetona , ácido benzoico , ácido hipúrico , norefedrina y fenilacetona . [3] [12] Entre estos metabolitos, los simpaticomiméticos activos son 4-hidroxianfetamina , [202] 4-hidroxinorefedrina , [203] y norefedrina. [204] Las principales vías metabólicas implican la parahidroxilación aromática, la alfa y beta hidroxilación alifática, la N -oxidación, la N -desalquilación y la desaminación. [3] [205] Las vías metabólicas conocidas, los metabolitos detectables y las enzimas metabolizadoras en humanos incluyen los siguientes:
El metagenoma humano (es decir, la composición genética de un individuo y todos los microorganismos que residen en o dentro del cuerpo del individuo) varía considerablemente entre individuos. [211] [212] Dado que el número total de células microbianas y virales en el cuerpo humano (más de 100 billones) supera en gran medida a las células humanas (decenas de billones), [nota 18] [211] [213] existe un potencial considerable de interacciones entre los fármacos y el microbioma de un individuo, incluyendo: fármacos que alteran la composición del microbioma humano , metabolismo de fármacos por enzimas microbianas que modifican el perfil farmacocinético del fármaco y metabolismo microbiano de fármacos que afecta la eficacia clínica y el perfil de toxicidad de un fármaco . [211] [212] [214] El campo que estudia estas interacciones se conoce como farmacomicrobiómica . [211]
De manera similar a la mayoría de las biomoléculas y otros xenobióticos administrados por vía oral (es decir, medicamentos), se predice que la anfetamina experimentará un metabolismo promiscuo por parte de la microbiota gastrointestinal humana (principalmente bacterias) antes de su absorción en el torrente sanguíneo . [214] La primera enzima microbiana que metaboliza la anfetamina, la tiramina oxidasa de una cepa de E. coli que se encuentra comúnmente en el intestino humano, se identificó en 2019. [214] Se descubrió que esta enzima metaboliza la anfetamina, la tiramina y la fenetilamina con aproximadamente la misma afinidad de unión para los tres compuestos. [214]
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain.[38][48][215] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, a structural isomer of amphetamine (i.e., it has an identical molecular formula).[38][48][216] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[48][216] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[48][216] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[38][215][216] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[48][216]
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers.[11] This racemic mixture can be separated into its optical isomers:[note 19] levoamphetamine and dextroamphetamine.[11] At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[22] Frequently prepared solid salts of amphetamine include amphetamine adipate,[217] aspartate,[29] hydrochloride,[218] phosphate,[219] saccharate,[29] sulfate,[29] and tannate.[220] Dextroamphetamine sulfate is the most common enantiopure salt.[49] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[4][11] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[221]
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[4][50][222] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[4][50][223] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[4][50][222]
Since the first preparation was reported in 1887,[224] numerous synthetic routes to amphetamine have been developed.[225][226] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[49][227] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[227][228]
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[225] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[229] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[230] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[230]
A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[225][226] One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).[231] Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.[232][233] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).[234]
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups.[226] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).[227][235] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).[227]
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 17] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[239] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[240] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 20] or illicitly obtained substituted amphetamines.[240][243][244] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][245][246] These compounds may produce positive results for amphetamine on drug tests.[245][246] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.[239]
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry.[243] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[240] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[240] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.[240]
Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[224][248][249] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[249] Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant.[30] Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others.[51][30] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[224][250][251] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[224] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[252][253] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[254] musicians,[255] mathematicians,[256] and athletes.[28]
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[257] Among European Union (EU) member states in 2018,[update] 11.9 million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year.[258] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[259] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[259] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[257]
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties.[31] Consequently, it is heavily regulated in most countries.[260][261] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[262][263] In other nations, such as Canada (schedule I drug),[264] the Netherlands (List I drug),[265] the United States (schedule II drug),[29] Australia (schedule 8),[266] Thailand (category 1 narcotic),[267] and United Kingdom (class B drug),[268] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[257][32]
Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis,[note 1] Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine".[1][36][106] Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine.[37][200] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[2] Levoamphetamine was previously available as Cydril.[2] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[2][37][49] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[106][269][270] Some of the current brands and their generic equivalents are listed below.
The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
Onset of action: 30–60 min
Table 9.2 Dextroamphetamine formulations of stimulant medication
Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
Adderall [Peak:2–3 h] [Duration:5–7 h]
Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
Adderall XR [Peak:7–8 h] [Duration:12 h]
Vyvanse [Peak:3–4 h] [Duration:12 h]
Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30 %) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible. ...
Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses. ...
The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses. ...
Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances.
One of a pair of molecular entities which are mirror images of each other and non-superposable.
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task
However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.
Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...
Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).
When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease. ...
Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication. ...
Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.
Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. ... For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014). ... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1. ...
All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014). ...
In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.
More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward,aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin,dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.
All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.
Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain. ...
Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively. ...
The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system. ...
Sympathomimetic drugs have long been used to treat narcolepsy
The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy.
Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness.
The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant)
The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
Rewards in operant conditioning are positive reinforcers. ... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions. ... Rewards are attractive. They are motivating and make us exert an effort. ... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior. ... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward. ... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory) ... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning) ... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions. ... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards. ... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward. ... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward.
statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
– Sympathomimetic:
• Amphetamine
This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
[Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
{{cite journal}}: CS1 maint: DOI inactive as of September 2024 (link)ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. ... ΔFosB serves as one of the master control proteins governing this structural plasticity.
Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.
Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.
Physical Exercise
There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...
Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
Amphetamine use disorders ... 3,788 (3,425–4,145)
Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40 °C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
Although the monoamine transport cycle has been resolved in considerable detail, kinetic knowledge on the molecular actions of synthetic allosteric modulators is still scarce. Fortunately, the DAT catalytic cycle is allosterically modulated by an endogenous ligand (namely, Zn2+; Norregaard et al., 1998). It is worth consulting Zn2+ as an instructive example, because its action on the DAT catalytic cycle has been deciphered to a large extent ... Zn+ binding stabilizes the outward-facing conformation of DAT ... This potentiates both the forward-transport mode (i.e., DA uptake; Li et al., 2015) and the substrate-exchange mode (i.e., amphetamine-induced DA release; Meinild et al., 2004; Li et al., 2015). Importantly, the potentiating effect on substrate uptake is only evident when internal Na+ concentrations are low ... If internal Na+ concentrations rise during the experiment, the substrate-exchange mode dominates and the net effect of Zn2+ on uptake is inhibitory. Conversely, Zn2+ accelerates amphetamine-induced substrate release via DAT. ... t is important to emphasize that Zn2+ has been shown to reduce dopamine uptake under conditions that favor intracellular Na+ accumulation
—Fig. 3. Functional selectivity by conformational selection.
Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.
The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET). ... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10 μM Zn2+ to the superfusion buffer (Fig. 2 A, open squares). ... The concentrations of Zn2+ shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30 μM. ... Thus, when Zn2+ is co-released with glutamate, it may greatly augment the efflux of dopamine.
Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking
With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110
VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.
The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.
Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. ... The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART
Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels ...
More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [11C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration of d-amphetamine, 0.5 mg/kg, 3 h before [11C]carfentanil injection, reduced BPND values by 2–10%. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [11C]carfentanil binding when d-amphetamine, 0.3 mg/kg, was administered intravenously directly before injection of [11C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).
Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012).
Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans
Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27. ... We investigated psychotropic amines based on the phenethylamine scaffold, such as amphetamine 5, methamphetamine 6, phentermine 7, mephentermine 8, and the structurally diverse chlorphenteramine 9, for their activating effects on 11 CA isoforms of human origin ... The widespread hCA I and II, the secreted hCA VI, as well as the cytosolic hCA XIII and membrane-bound hCA IX and XIV were poorly activated by these amines, whereas the extracellular hCA IV, the mitochondrial enzymes hCA VA/VB, the cytosolic hCA VII, and the transmembrane isoform hCA XII were potently activated. Some of these enzymes (hCA VII, VA, VB, XII) are abundant in the brain, raising the possibility that some of the cognitive effects of such psychoactive substances might be related to the activation of these enzymes. ... CAAs started to be considered only recently for possible pharmacologic applications in memory/cognition therapy27. This work may bring new lights on the intricate relationship between CA activation by this type of compounds and the multitude of pharmacologic actions that they can elicit.
—Table 1: CA activation of isoforms hCA I, II, IV, VII, and XIII [5: amphetamine]
—Table 2: CA activation of isoforms hCA VA, VB, VI, IX, XII, and XIV [5: amphetamine]
CARBONIC ANHYDRASE INHIBITORS (CAIs). The design and development of CAIs represent the most prolific area within the CA research field. Since the introduction of CAIs in the clinical use in the 40', they still are the first choice for the treatment of edema [9], altitude sickness [9], glaucoma [7] and epilepsy [31]. ... CARBONIC ANHYDRASE ACTIVATORS (CAAs) ... The emerging class of CAAs has recently gained attraction as the enhancement of the kinetic properties in hCAs expressed in the CNS were proved in animal models to be beneficial for the treatment of both cognitive and memory impairments. Thus, CAAs have enormous potentiality in medicinal chemistry to be developed for the treatment of symptoms associated to aging, trauma or deterioration of the CNS tissues.
Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).
Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
The hundred trillion microbes and viruses residing in every human body, which outnumber human cells and contribute at least 100 times more genes than those encoded on the human genome (Ley et al., 2006), offer an immense accessory pool for inter-individual genetic variation that has been underestimated and largely unexplored (Savage, 1977; Medini et al., 2008; Minot et al., 2011; Wylie et al., 2012). ... Meanwhile, a wealth of literature has long been available about the biotransformation of xenobiotics, notably by gut bacteria (reviewed in Sousa et al., 2008; Rizkallah et al., 2010; Johnson et al., 2012; Haiser and Turnbaugh, 2013). This valuable information is predominantly about drug metabolism by unknown human-associated microbes; however, only a few cases of inter-individual microbiome variations have been documented [e.g., digoxin (Mathan et al., 1989) and acetaminophen (Clayton et al., 2009)].
The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial23,24 and is higher than the temporal variability seen at most sites in a single individual25. ... How does the microbiome affect the pharmacology of medications? Can we "micro-type" people to improve pharmacokinetics and/or reduce toxicity? Can we manipulate the microbiome to improve pharmacokinetic stability?
Some metagenomic studies have suggested that less than 10% of the cells that comprise our bodies are Homo sapiens cells. The remaining 90% are bacterial cells. The description of this so-called human microbiome is of great interest and importance for several reasons. For one, it helps us redefine what a biological individual is. We suggest that a human individual is now best described as a super-individual in which a large number of different species (including Homo sapiens) coexist.
Particularly in the case of the human gut, which harbors a large diversity of bacterial species, the differences in microbial composition can significantly alter the metabolic activity in the gut lumen.4 The differential metabolic activity due to the differences in gut microbial species has been recently linked with various metabolic disorders and diseases.5–12 In addition to the impact of gut microbial diversity or dysbiosis in various human diseases, there is an increasing amount of evidence which shows that the gut microbes can affect the bioavailability and efficacy of various orally administrated [sic] drug molecules through promiscuous enzymatic metabolism.13,14 ... The present study on the atomistic details of amphetamine binding and binding affinity to the tyramine oxidase along with the comparison with two natural substrates of this enzyme namely tyramine and phenylalanine provides strong evidence for the promiscuity-based metabolism of amphetamine by the tyramine oxidase enzyme of E. coli. The obtained results will be crucial in designing a surrogate molecule for amphetamine that can help either in improving the efficacy and bioavailability of the amphetamine drug via competitive inhibition or in redesigning the drug for better pharmacological effects. This study will also have useful clinical implications in reducing the gut microbiota caused variation in the drug response among different populations.
A single dose of amphetamine or methamphetamine can be detected in the urine for approximately 24 hours, depending upon urine pH and individual metabolic differences. People who use chronically and at high doses may continue to have positive urine specimens for 2–4 days after last use (SAMHSA, 2010b).
Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.
1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year
ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.
