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Effects of Tetrahydrocannabinol on Melatonin Secretion in Man

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  • RETIRED from ASST Monza – San Gerardo Hospital
... In this pathway, noradrenaline release is maximal at night, then MLT is mainly released during the dark period of the day. In addition, MLT secretion is also influenced by several other factors, since it is simulated by cannabinoids [28], while the alpha-2 agonists play an inhibitory action. More complex and controversial are the effects of opioids on MLT secretion, since both inhibitory and stimulatory actions have been reported, depending on the different experimental conditions, dose, and the type of opioid agonists. ...
... More complex and controversial are the effects of opioids on MLT secretion, since both inhibitory and stimulatory actions have been reported, depending on the different experimental conditions, dose, and the type of opioid agonists. The activity of the pineal gland is mainly connected to that of brain cannabinoid system [28,29], while the brain opioid system is more linked to the activity of the adrenal gland. Therefore, it is possible to identify two fundamental neuroendocrine functional axes, represented by pineal-cannabinoid axis, and opioid-adrenal axis. ...
... stress and depressive mood [30], while the pineal-cannabinoid one is active in the pleasure perception and expansion of consciousness [28,29]. In addition, the neurohypophysis is also involved in neuroimmunomodulation through the release of vasopressin and oxytocin [31], which are respectively connected to the opioidadrenal axis, and to the pineal-cannabinoid axis. ...
... On the contrary, according to the recent discoveries in the area of psychoneuro-endocrino-immunology (PNEI) demonstrating hat the immune responses are physiologically under a psycho-neuroendocrine control, it could be possible from at least a theoretical point of view to influence the immune response by influencing the cytokine network not only by directly acting on the secretion or on the activity of some specific cytokine, but also by influencing the neuroendocrine control of the cytokine network. According to the knowledgments available up to now, within the complexity of the neuroimmunology, it is possible to identify two major neuroendocrine functional systems involved in the psychoneuroendocrine regulation of the immune system, consisting of the brain opioid system-pituitary axis [8][9][10] and the brain cannabinergic system-pineal axis [11][12][13], respectively provided by an immunosuppressive and an immunostimulatory role, respectively. ...
... Therefore, beta-adrenergic antagonists could potentially improve the immune functions. On the other hand, the pineal gland, which is connected to the brain cannabinergic system [11],has appeared to stimulate IL-2 and IL-12 secretion by melatonin (MLT) [12], that represents its most investigated indole hormone [14], while the cannabinoid agents, including the endogenous cannabinoid agonists anandamide and 2-arachydonil-glycerol [15], and the exogenous ones, namely tetra-hydro-cannabinol (THC), may inhibit IL-17 secretion from TH-17 lymphocytes, as well that of TNF-alpha and IL-6 from macrophages [16]. With respect to the endogenous cannabinoid system, Cannabis plant may produce another biologically important molecule, the cannabidiol (CBD), which is not a cannabinoid agonist, and this activity is due to the inhibition of the fatty acid amide hydrolase (FAAH), the enzyme involved in cannabinoid degradation, with a consequent increase in brain cannabinoid content [17,18]. ...
... Further studies have suggested that cancer progression is associated with a progressive decline in the endocannabinoid function, which could explain cancer-related anhedonia, because of the fundamental role of cannabinoids in the perception of pleasure [35]. This finding is not surprising, since the pineal and brain cannabinoid system would constitute a functional axis involved in the control of the inflammatory response and cell proliferation [36]. Cancer-related pineal hypofunction would allow a progressive concomitant endocannabinoid deficiency. ...
... In another study, pineal gland cell cultures treated with cannabinol metabolite showed reduced sensitivity to noradrenaline induced melatonin secretion (Koch et al., 2006). This evidence suggests a role for THC in melatonin biosynthesis (Lissoni et al., 1986). ...
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As interest in circadian rhythms and their effects continues to grow, there is an increasing need to perform circadian studies in humans. Although the constant routine is the gold standard for these studies, there are advantages to performing more naturalistic studies. Here, a review of protocols for such studies is provided along with sample inclusion and exclusion criteria. Sleep routines, drug use, shift work, and menstrual cycle are addressed as screening considerations. Regarding protocol, best practices for measuring melatonin, including light settings, posture, exercise, and dietary habits are described. The inclusion/exclusion recommendations and protocol guidelines are intended to reduce confounding variables in studies that do not involve the constant routine. Given practical limitations, a range of recommendations is provided from stringent to lenient. The scientific rationale behind these recommendations is discussed. However, where the science is equivocal, recommendations are based on empirical decisions made in previous studies. While not all of the recommendations listed may be practical in all research settings and with limited potential participants, the goal is to allow investigators to make well-informed decisions about their screening procedures and protocol techniques and to improve rigor and reproducibility, in line with the objectives of the National Institutes of Health.
... Certainly, derivatives of cannabis with relaxing and sleep promoting effects can be legally purchased in many countries (Bowles et al., 2017). These derivatives can increase melatonin production and inhibit wakefulness by activating the cannabinoid type-1 (CB1) receptors in the wake promoting regions of the brain (Nicholson et al., 2004;Lissoni et al., 1986;Murillo-Rodrigez et al., 2003). ...
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This study examined the prevalence of illegal drug use in UK students and motivators behind such behaviour. Additionally, we explored possible relationships between substance use, psychosocial motivators, and psychiatric distress. N=543 students completed online measures of substance use, anxiety, depression, perceived stress, insomnia. A series of reasons behind their use were ranked based on importance. Reported cannabis, cocaine, nitrous oxide, ketamine and MDMA use were most prevalent based on lifetime, past year, and month assessments. The experience of anxiety, depression, perceived stress, and insomnia were related to increased reports of substance use. Poor self-confidence and self-medication were key motivators of illicit drug use in those presenting greater psychiatric distress. These outcomes add to the sparse body of literature concerning illicit substance use in relation to psychiatric distress amongst UK students. Furthermore, we provided novel insight into the psychosocial motivators of such use.
... Se han descrito diferentes variables que afectan a los niveles de MLT. Estas variables abarcan un amplio rango, tal y como las variables genéticas 6 , el medio ambiente 7 , el estilo de vida 8 , la toma de algunas medicinas 9 o el consumo de drogas 10 . ...
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Introducción. La búsqueda de marcadores biológicos que se relacionen con características específicas de las personas no ha producido grandes resultados. Los niveles sanguíneos de la melatonina (MLT), principal producto hormonal de la glán-dula pineal, han sido utilizados como marcador biológico del neuroticismo, la introversión-extroversión y la matutinidad-vespertinidad. El concepto de matutinidad hace referencia a la preferencia de las personas para realizar actividades por las mañanas, mientras que la vespertinidad hace referencia a la preferencia para realizar actividades por la noche. El objetivo de este trabajo consiste en estudiar si los niveles séricos de MLT se relacionan con la matutinidad o vespertinidad. Metodología. La muestra está compuesta por 44 volun-tarios sanos, de los cuales 23 son del tipo matutino y 21 del tipo vespertino. La matutinidad-vespertinidad fue valorada con la Escala Compuesta de Matutinidad. Se analizaron 3 muestras de sangre, extraídas a las 09:00, 12:00 y 00:00 h. Los niveles de MLT fueron determinados mediante un ELISA. Resultados. A las 09:00 h, los sujetos vespertinos tenían niveles de MLT significativamente más altos que los sujetos matutinos (8,4±3,6 pg/ml vs 4,6±3,2 pg/ml, p<0,02). Conclusiones. Los niveles séricos de MLT a las 09:00 h. pueden ser usados como un marcador biológico periférico de vespertinidad-matutinidad. Nuestros resultados enfatizan la conveniencia de alargar los estudios de MLT al menos hasta las 09:00 h, cuando aun se pueden encontrar diferencias en los niveles séricos de MLT entre los tipos matutinos y vespertinos. Background. The search for biological markers of individual characteristics has produced scanty results. Melatonin (MLT), the main hormonal product of the pineal gland, has been used as a biological marker of neuroticism, introversion-extroversion and morningness-eveningness. Morningness-eveningness indicates preferences associated with morning or evening activities. The goal of this research is to study if serum MLT levels are related to morningness-eveningness preference.
... Then, the evidence of a normal light/dark rhythm of MLT secretion, with higher levels during the night and lower concentrations during the day, would constitute a fundamental clinical parameter of the status of health. The main stimulus for MLT secretion is represented by beta-adrenergic receptor agonists [8], but MLT release is also stimulated by alpha-1 agonists, alpha-2 antagonists [8], mu-opioid agonists [13], cannabinoid agents [14], oxytocin [15], and the cardiac hormone atrial natriuretic peptide (ANP) [16], whereas it is inhibited by beta-blockers and alpha-2 agonists [8]. The main mechanism, which may explain the great number of biological effects played by MLT, including anticancer cytotoxic activity, immunostimulatory action, modulation of blood pressure in a hypotensive way, and cardio-neuroprotective properties [8] may be simply explained on the basis of the ability of MLT to modulate DNA expression [8]. ...
... The evidence of abnormally high blood levels of FAAH, with a consequent endocannabinoid deficiency, has appeared to be associated with a worse prognosis in most systemic human inflammatory diseases, including cancer and cardiovascular diseases 26 , and this finding is not surprising by taking into consideration the fundamental role of the cannabinoid agents in the modulation of the immuno-inflammatory biological response by regulating the cytokine network [23][24][25][26] . In particular, it has been shown that the activation of the endocannabinoid system may stimulate the anticancer immunity 23,24 through its connection with the pineal gland 27 , which plays an essential role in the natural immunobiological resistance against cancer onset and development 28 through several and complex mechanisms, including a modulatory effect on the cytokine network with stimulation of IL-2 and IL-12 release, and inhibition of macrophage-related cytokines, such as IL-6 and TNF-alpha 29 , an anti-angiogenic activity, and a direct cytostatic cytotoxic antitumor activity 30 . Therefore, FAAH blood levels may be considered as a synthetic biomarker of the whole function of the endocannabinoid system. ...
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Today, it is known that the prognosis of human neoplasms depends not only on the genetic characteristics of tumor cells, but also on the immunobiological response of patients. Moreover, despite its complexity, at present it is known that the antitumor immunity is generally suppressed by the macrophage system, and stimulated by T lymphocytes, with the only exception of regulatory T cells, which in contrast inhibit the anticancer immunity through the release of immunosuppressive cytokines, the most important of them is TGF-beta. Finally, it is known that lymphocytopenia may predict a negative prognosis in the advanced neoplasms, and a more negative significance is played by the occurrence of abnormally low values of lymphocyte-to-monocyte ratio (LMR), whose decline could depend on both lymphocyte decrease and monocyte increase. At present, the only cytokine able to enhance lymphocyte count still remains IL-2. Therefore, because of the negative prognostic significance of cancer-related lymphocytopenia, the use of IL-2 to correct cancer-related lymphocytopenia could constitute a new strategy in the immunotherapy of cancer. On these bases, a study was planned to evaluate the effects of a neuro-immunotherapeutic combination with SC very-low dose IL-2 in association with the antitumor immunostimulating pineal hormone melatonin (MLT) on lymphocyte count, and their persistence on time in a group of untreatable lymphocytopenic advanced cancer patients. The study included 14 lymphocytopenic cancer patients, who were eligible for the only palliative therapy. IL-2 was SC injected at 1.8 MIU/day for 5 days/week for 2 consecutive weeks, in association with MLT at 100 mg/day orally during the dark period of the day. A normalization of lymphocyte count was achieved in 9/14 (64%) patients within the two weeks of therapy. Both lymphocyte and LMR mean values significantly increased on therapy with respect to the pre-treatment values. On the other hand, monocyte mean values diminished on therapy, without, however, significant differences. The median duration of lymphocyte count normalization was 160 days (range 39-240 days). These preliminary results would suggest a new possible clinical use of IL-2 immunotherapy to counteract advanced cancer-related lymphocytopenia, because of its well documented negative effects on the survival, in an attempt to control tumor growth by activating the natural antitumor immunobiological response, which is fundamentally an IL-2-dependent phenomenon, and which is altered in the advanced human neoplasms. Keywords: Cancer immunotherapy, Interleukin-2, Lymphocytopenia, Immunosuppression, Melatonin, Pineal gland
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A simplified and rapid radioimmunoassay (RIA) for melatonin is presented. Melatonin is extracted from seru, plasma or urine and RIA is performed by using [3H]melatonin as the tracer. The standard curve covers the range 0.2--4.3 nmol/l. By increasing the sample volume the range can be extended to 0.06 nmol/l. The intra-assay variability is 7% (relative standard deviation = rsd) and the inter-assay variability is 10% (rsd). The recovery of melatonin added to calf serum is 96%. The long term variability of the assay (43 assays on aliquots of one serum sample during 6 months) is 13.5% (rsd). The serum levels in man after one oral dose of 430 mumol melatonin have been measured. The peak value, 620 nmol/l, was noted after 0.5 h and the melatonin concentration was still above the normal range at 24 h (2.1 nmol/l).
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The past 3 years of renewed research on the effects of marihuana in man has added little not previously known about the clinical syndromes produced by the drug. The major advance has been a quantification of dose in relation to clinical phenomena, and a beginning of an understanding of the drug's metabolism. The crucial clinical experiments in regard to the social questions about marihuana, such as the possible deleterious effects from chronic use, cannot be answered by laboratory experiments. These must be settled by close observations made on those who experiment on themselves. It should be possible, within a relatively short time, to determine whether marihuana has any medical utility, but the future would appear to be no more promising than the past in this regard. The mechanisms by which marihuana alters mental functions are not likely to be answered in man, nor even answered soon by animal studies. As marihuana may be unique among drugs in that more experimentation has been accomplished in man than in animals, it may be necessary to look to additional animal studies to provide leads for pertinent future studies in man.