Efectos adversos y paliativos de los canabinoides

• Autores: Minerva Hernández Lozano, Carlos Manuel Contreras Pérez, Margarita Saavedra, Ana G. Gutiérrez García, Blandina Bernal-Morales, Juan Francisco Rodríguez Landa
• Localización: Salud mental, ISSN 0185-3325, Vol. 26, Nº. 6, 2003, págs. 62-75
• Idioma: español
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• Resumen
  • español

    En un sentido amplio, un paliativo es un remedio que mitiga los trastornos asociados a lo incurable, mientras que un agente terapéutico es aquel capaz de curar una enfermedad. La marihuana (Cannabis sativa) es una planta originaria de Asia Central y sus principales componentes activos (canabinoides) son tres: el tetrahidrocanabinol, el canabinol y el canabidiol, los cuales poseen propiedades psicotrópicas y vegetativas. Empíricamente, se les han atribuido ciertas acciones, en el manejo del dolor, del vómito y del aumento de la presión intraocular, entre otros síntomas.

    Particularmente en nuestro país y de acuerdo con datos oficiales del Consejo Nacional contra las Adicciones (CONADIC), durante el periodo comprendido de 1998 a 2000, las sustancias de consumo más extendido fueron la marihuana, la cocaína y los disolventes industriales. El consumo de marihuana en México se ha incrementado a través del tiempo, sin distinción de sexo, aunque predomina en el género masculino (13.9%) con respecto al femenino (6.9%) y entre adolescentes de 12 a 17 años que no viven con su familia; asimismo se documenta un mayor consumo en no estudiantes (4.2%) comparado con la población de estudiantes (1.3%). La prevalencia promedio del consumo de Cannabis Sativa en la población urbana de 12 a 65 años es de 5.3%. En particular, las ciudades con mayor consumo son Tijuana (14.7%), Ciudad Juárez (9.2%), Guadalajara (7.5%), Ciudad de México (7.3%), Monterrey (4.2%) y Matamoros (3.6%), reflejándose que la zona norte-centro del país es la más afectada. Así, el consumo de marihuana es un problema real de Salud Pública.

    Por otro lado, se ha aislado una serie de sustancias sintetizadas por el propio organismo cuyas propiedades farmacológicas se asemejan a las de los canabinoides y que, por ser agonistas de los receptores específicos también presentes en el organismo, reciben la denominación de endocanabinoides, cuya manipulación farmacológica podría ser de utilidad terapéutica.

    Estas observaciones han llevado a la legalización del uso de los canabinoides con fines terapéuticos, en algunos países. En la presente revisión se analizó bibliografía reciente a fin de ofrecer una perspectiva científica y objetiva acerca del uso médico de la marihuana. Se tienen cinco observaciones a considerar a propósito de aceptar o no a la marihuana como una alternativa terapéutica: 1) Los estudios documentan hallazgos positivos, carecen de controles adecuados; 2) los estándares de comparación, no son los más idóneos, por ejemplo, la potencia analgésica de los canabinoides suele ser comparada con la codeína, que es un analgésico en desuso por su baja potencia, en tanto que la eficacia antiemética de los canabinoides no es comparada con compuestos de eficacia comprobada, es decir, los agonistas al receptor serotonérgico 5-HT3, como el odansetrón; 3) algunas investigaciones arguyen que la planta puede actuar como un todo, por lo que los canabinoides sintéticos aprobados para su uso terapéutico en otros países, podrían carecer de efectos notables; 4) son pocos los pacientes que responden de manera eficaz al tratamiento en comparación con los que experimentan los efectos psicotrópicos; y 5) cuando la población blanco son pacientes que nunca antes habían consumido canabinoides, se deben considerar aspectos éticos.

    El hallazgo de los endocanabinoides abre caminos para la comprensión de los procesos homeostáticos relacionados con los afectos y ciertos aspectos de la motivación, y los avances recientes en medicina genómica han conducido a especular sobre la manipulación de receptores a endocanabinoides. Sin embargo, la manipulación de estos receptores, si bien puede suprimir el uso de la marihuana en adictos, quizá tenga repercusiones en el apetito, el talante, la percepción y el sentido del tiempo entre otros aspectos conductuales, toda vez que los endocanabinoides tienen acciones bien definidas sobre los puntos antes mencionados.

    Por lo tanto, se concluye que los canabinoides poseen algunos efectos paliativos, no terapéuticos, cuya administración a enfermos graves y debilitados podría representar riesgos innecesarios y su posible uso terapéutico debe ser precedido por el análisis exhaustivo de otras opciones terapéuticas.

  • English

    In a wide sense, a palliative agent is a remedy that attenuates some symptoms associated with a disease, whereas a therapeutic agent is the one capable of curing a disease. Marihuana (Cannabis sativa) is a plant from Central Asia and its main active components (cannabinoids) are three: tetrahydrocannabinol, cannabinol and cannabidiol. They possess psychotropic and vegetative effects and, empirically, are reputed to exert some supposedly therapeutic actions involving the control of pain, vomiting, intraocular pressure and many other ailments. In agreement with official data from the "Consejo Nacional contra las Adicciones" (CONADIC, Mexico), during 1998-2000, the most extensively abused substances were marihuana, cocaine and industrial solvents. The consumption of marihuana in Mexico has increased with time. The average prevalence of the use of cannabis among the urban population from 12 to 65 years of age is 5.3%. The cities with the highest consumption of marihuana are Tijuana (14.7%), Ciudad Juárez (9.2%), Guadalajara (7.5%), Mexico City (7.3%), Monterrey (4.1%) and Matamoros (3.6%), a fact that indicates that the north-central region of Mexico is the most affected. Marihuana is the main drug consumed by almost all age groups without any distinction of gender. The consumption is predominantly higher in males (13.9%) than in females (6.9%), and among children from 12 to 17 years old who do not live with their families. The percentage of adolescents consuming marihuana is larger among youths who are not students (4.2%) than in the student population (1.3%). Thus, marihuana consumption is a real problem of public health in Mexico. The existence of at least two receptors to cannabinoids is well known, as well as a group of substances synthesized by the organism itself, denominated endocannabinoids, whose pharmacological properties resemble those of the plant. These observations have caused some parliamentary discussions that have led some countries to approve the use of the synthetic cannabinoid-related substances for therapeutic purposes. In the present review, recent literature was analyzed in order to offer an objective scientific perspective about the use of marihuana. Five relevant observations are pointed out: 1) Studies with positive findings, lack adequate controls. 2) The standards of comparison used, are not the most suitable, for example, the supposed analgesic property of cannabinoids is commonly compared with codeine, and the possible antiemetic capability of cannabinoids is not compared with well-known commercial and safe drugs with verified potency, such as the 5HT3 receptor subtype agonist, odansetron. 3) Some authors claim that the plant may acts as a whole, and therefore some of the synthetic cannabinoids approved in other countries for therapeutic uses might not produce notable effects. 4) Only a few patients experience some improvement in their symptoms; however most of them experience the psychotropic actions of cannabinoids. And, 5) there are ethical aspects to reconsider in the case of patients who never before had consumed cannabinoids. The following aspects of the clinical use of cannabinoids are discussed in this review. For example, diverse reports suggest that marihuana increases food intake through CB1 receptor-stimulation producing hyperphage by itself, as well as anorexia related to immunodeficiency syndrome and cancer treatment. However, these patients also experience the psychotropic side-effects of marihuana and which lead them to leave the treatment. Regarding pain, cannabinoids produce spinal analgesia in experimental animals, which might be mediated by suppression of neuronal nocyceptive activity and the activation of opioid receptors. Nevertheless, most researchers who are exploring the efficacy of cannabinoids in pain treatment employ codeine as a reference, although codeine is in disuse due to its vegetative effects and poor potency, and do not compare it with other powerful analgesics such as opioids or prostaglandin inhibitors. In the immunologic system, cannabinoids act on CB2 receptors, decreasing the function of immune T and B cells, killer cells and macrophages. Therefore, infection processes might be increased in debilitated patients. By contrast, the immunosuppressant action of cannabinoids could be useful in hyperactivity of the immunologic system, as in the case of multiple sclerosis. On the other hand, recent findings suggest that a lipid imbalance (mainly with arachidonic acid) is a primary factor in the etiology of cystic fibrosis. Since the endocannabinoids are fatty acid derivatives, it has been hypothesized that the patients who suffer cystic fibrosis can receive benefits by the administration of cannabinoids (i.e. restoring the balance between fatty acids, reducing the symptoms and increasing life expectancies). Regardind reproduction research, prenatal cannabinoid exposure has been associated with a high perinatal morbidity but the possible long-term consequences are still poorly understood. Therefore, animal models of perinatal cannabinoid exposure have provided a useful tool for examining the developmental effects of the offspring. Results show alteration in the ontogeny of spontaneous locomotor activity and exploratory behavior. Adult animals exposed during pregnancy and lactation exhibited persistent alterations of the behavioral response to novelty, social interactions and sexual behavior. However, available data regarding the long-term behavioral and cognitive effects in humans are scarce to be compared with animal results. In other studies, some endocannabinoids generated in monocytes and platelets show that they are potent vasodilators and related to hypotension following hemorrhagic shock. Thus, animals treated with anandamide reduce their survival rate. In contrast, administration of the CB1 antagonist (SR141716A) increases the arterial pressure, the respiratory frequency and the survival rate in a dose-response manner. Thus, inhibition of the endogenous cannabinoids reverts the hemorrhagic shock with notorious efficacy, similar to endogenous opioids. In this sense, some other reports suggest that cannabinoids are useful to treat glaucoma, because cannabis reduces intraocular pressure in 60% of the users, although there are other drugs lacking psychotropic effects with proved and accepted efficacy in the treatment of glaucoma. Marihuana may also have certain anticonvulsivant properties; however delta-9THC alters sleep patterns in humans and could not be recommendable. In spite of some positive reports on the treatment of partial or tonic-clonic seizures, there is a lack of controlled studies. An apparent positive finding is that ligands to endocannabinoids receptors are suggested to exert neuroprotective effects because endocannabinoids reduce brain ischemic-induced lesion in rats and attenuate neuronal injuries produced by hypoxia and glucose deprivation in cultured cells. Once more, controlled studies are required to support or refuse these observations. The discovery of endocannabinoids and their receptors opens fields for comprehension of the processes involved in the psychophysiology of affective disorders and certain aspects of motivation; and recent advances in genomic medicine might lead us to speculate on the manipulation of endocannabinoid receptors. However, endocannabinoids exert well defined actions related with feeding, mood, sensorial perception and time sense; therefore, the genomic manipulation of these receptors, might suppress the use of marihuana in addicts, but probably also create problems concerning appetite and mood, among other behavioral aspects. In consequence, it is concluded that cannabinoids are substances that possess some palliative effects rather than therapeutic, and that their administration to seriously weakened patients should be preceded by exhaustive analysis of another therapeutics choices.