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... cannabinergic [7] systems for the nervous system, which constitute two fundamental neuro-endocrine functional units, consisting of the opioid system-pituitary axis and the later the cannabinoid-pineal axis. In fact, brain opioid system is mainly functionally associated with the pituitary and the adrenal glands, and it exerts an immunosuppressive action mainly on the anticancer immunity [6], whereas the cannabinergic system is namely linked to the pineal gland, by representing a functional unit stimulating the immune system [8], and by playing a fundamental role in the maintenance of the natural immuno-biological resistance against cancer development. Then, the major limit of the ancient Immunology, preceding the discovery of cytokines, is to consider the in vivo immune reactions as identical to the same immune reactions observed in vitro, by completely excluding the in vivo existence of a psychoneuroendocrine modulation of immune response themselves, which may either amplify or counteract the same in vitro immune reactions by influencing the functional status of the immune cells. ...
... The opioid system may stimulate T reg cell generation by acting on muopioid receptor, whereas it plays an inhibitory role of TH1 cell functions, with a consequent decline in the endogenous production of IL-2 [16]. On the contrary, the cannabinoid system stimulates TH1 cell functions and counteract T reg cell activation [17] by acting in connection with the pineal gland [8]. Moreover, it has to be taken into consideration within the complex neuroimmune interactions that some endocrine feedback mechanisms are under an immune modulation mediated by specific cytokines, the most important of them is the circuit existing between pro-inflammatory cytokines and the HPA-axis, which is essential in the control of the intensity of the immuno-inflammatory responses. ...
... Since PNEI may be defined as the study of the interactions between psycho-spiritual status and neuroimmune systems, the main anatomic structure responsible for the modulation of the interactions between immune and neuroendocrine systems is the pineal gland [4,5,8,18], which represents on the same time the most important endogenous anticancer organ. Then, the pineal gland has been proven to play a fundamental role in maintaining the natural resistance against tumor onset and dissemination by acting as a central regulator of the cytokine network [18], since the pineal endocrine functions are at least in part under an immune regulatory control. ...
... During the long history of the human war against cancer, several experimental strategies have been elaborated to promote both spontaneous and carcinogen-induced cancer onset and to stimulate cancer dissemination in tumor-bearing animals, the most important of them would be represented by stress conditions [21] and by pinealectomy. [22] Each hormone, neurohormone and neurotransmitter may potentially influence the immune system, but the recent discoveries of PNEI [23][24][25] have allowed to identify three main anatomic structures responsible for the physiological PNE regulation of the immune responses, consisting of brain opioid system, brain cannabinergic system, and the pineal gland. Pineal gland and cannabinergic system would constitute a functional axis, [23] which plays an important role in the stimulation of the anticancer immunity, namely, by directly promoting IL-2 production by TH-1 lymphocytes. ...
... Pineal gland and cannabinergic system would constitute a functional axis, [23] which plays an important role in the stimulation of the anticancer immunity, namely, by directly promoting IL-2 production by TH-1 lymphocytes. [24] In contrast, brain opioid system may inhibit the anticancer immune response by stimulating the immunosuppressive function of T reg lymphocytes. [25] Stress condition -promotion of cancer growth would be due to a chronic-enhanced production of cortisol, whose immunosuppressive effects are well known, and to an enhanced brain opioid system activity, [21] which may be abrogated by the administration of mu-opioid antagonists. ...
... On the basis of the fact that cancer growth is inhibited by the pineal gland and is stimulated by brain opioid system, namely, through the activation of mu-opioid receptors, [21][22][23][24][25][26][27] the PNE therapy of cancer is consisting of the administration of endogenous human neuroendocrine molecules provided by anticancer activity, due to a direct antiproliferative action and/or a stimulation of the anticancer immunity, in association with pharmacological strategies performed to counteract its suppression, such as the use of the mu-opioid antagonist naltrexone (NTX). ...
Chapter
The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno-inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases.
... During the long history of the human war against cancer, several experimental strategies have been elaborated to promote both spontaneous and carcinogen-induced cancer onset and to stimulate cancer dissemination in tumor-bearing animals, the most important of them would be represented by stress conditions [21] and by pinealectomy. [22] Each hormone, neurohormone and neurotransmitter may potentially influence the immune system, but the recent discoveries of PNEI [23][24][25] have allowed to identify three main anatomic structures responsible for the physiological PNE regulation of the immune responses, consisting of brain opioid system, brain cannabinergic system, and the pineal gland. Pineal gland and cannabinergic system would constitute a functional axis, [23] which plays an important role in the stimulation of the anticancer immunity, namely, by directly promoting IL-2 production by TH-1 lymphocytes. ...
... Pineal gland and cannabinergic system would constitute a functional axis, [23] which plays an important role in the stimulation of the anticancer immunity, namely, by directly promoting IL-2 production by TH-1 lymphocytes. [24] In contrast, brain opioid system may inhibit the anticancer immune response by stimulating the immunosuppressive function of T reg lymphocytes. [25] Stress condition -promotion of cancer growth would be due to a chronic-enhanced production of cortisol, whose immunosuppressive effects are well known, and to an enhanced brain opioid system activity, [21] which may be abrogated by the administration of mu-opioid antagonists. ...
... On the basis of the fact that cancer growth is inhibited by the pineal gland and is stimulated by brain opioid system, namely, through the activation of mu-opioid receptors, [21][22][23][24][25][26][27] the PNE therapy of cancer is consisting of the administration of endogenous human neuroendocrine molecules provided by anticancer activity, due to a direct antiproliferative action and/or a stimulation of the anticancer immunity, in association with pharmacological strategies performed to counteract its suppression, such as the use of the mu-opioid antagonist naltrexone (NTX). ...
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The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology.
... 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]. ...
... 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. ...
... Early studies from the 1970s indicate that THC causes a drastic increase in the production of melatonin, up to 4000% in some instances (Lissoni et al. 1986). It should be no surprise then that it has a profound effect on sleep (Babson et al. 2017). ...
Chapter
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The use of cannabis for animal species is an area of growing interest, largely due to the therapeutic benefits being observed for humans and animals in the era of cannabis legalization. The close relationship humans have with their pets and other veterinary species has led to a renewed interest in the possibility and promise of cannabis to treat similar health issues in the animal community. This chapter explores the literature available on cannabis, its interactions with the endocannabinoid system, and how animal species interact with various formulations and cannabis treatments. A brief overview of the biology, chemistry, and history of cannabis is discussed with the relevance to veterinary species in mind. The pharmacologically active components are discussed with both anecdotal and objective, evidence-based, and clinical data.
... [1][2][3] Cannabis alters the sleep-wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB 1 ) receptors in the basal forebrain and other wakepromoting centers. [9][10][11][12] Investigations have shown that the major psychoactive compound in cannabis, ∆ 9 -tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset. 9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls. ...
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Nicole P Bowles, Maya X Herzig, Steven A Shea Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USAThe recent legalization of cannabis for medical and recreational use in many states in the United States and internationally4,5 has resulted in a decrease in stigma and of perceived risk of cannabis use, more frequent use of cannabis, use of higher potency cannabis products, and increased dependence on cannabis use.6–8 Cannabis sativa and its derivatives are often used for improved sleep and relaxation; characteristics originally attributed to Indian hemp in the nineteenth century.1–3 Cannabis alters the sleep–wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB1) receptors in the basal forebrain and other wakepromoting centers.9–12 Investigations have shown that the major psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset.9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls.15 The contrasting benefits of THC exposure may represent the biphasic influence of THC on CB1 receptors whereby acute use causes more activation of CB1 receptors and tendency toward sleep, but long-term use results in desensitization of the CB1 receptor and decreased downstream signaling.
Chapter
After reading this chapter, one is able to use a short screener for ADHD and has been informed about diagnostic assessment using a semi-structured diagnostic interview for ADHD in adults, based on the DSM-IV criteria for ADHD (DIVA 2.0). The use of additional collateral information and neuropsychological testing is described. Symptoms, subtypes, influence of intelligence, impairment in work and relationships, sexuality, criminality, as well as over- and underdiagnosis of this disorder are discussed. Comorbidity with obesity and sleep problems; mood, anxiety, addictive, and personality disorders; autism spectrum disorder; tics; and dyslexia is addressed, as well as differential diagnostic considerations.
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Cannabis derives from the hemp plant or Cannabis sativa. It has been used for more than 4000 years because of its psychoactive and therapeutic effects and its industrial uses. Cannabis sativa contains more than 400 compounds, 60 of which are known as cannabinoids. In the recent years an increasing knowledge of the molecular basis of cannabis's actions has been achieved, leading to the discovery of an endocannabinoid system. At the same time, several studies have been published regarding cannabis's pharmacological effects, adverse effects and therapeutic potential. Despite the high amount of information available, only few studies deal exclusively with the effects of cannabis in humans. The main purpose of this paper is to review the clinical pharmacology of cannabis. Epidemiological issues, pharmacokinetics, mechanism of action, pharmacological effects, adverse effects, endocannabinoid system, therapeutic uses and the future of cannabis and cannabinoids, are thoroughly discussed in this revision.
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Adult ADHD: Diagnostic Assessment and Treatment, Third Edition covers not only diagnostic assessment, but also comorbidity patterns as well as differential diagnosis of ADHD with for example bipolar disorder and borderline personality disorder. The symptom overlap and misdiagnosis of chronic fatigue syndrome in girls and women with the inattentive subtype of ADHD, ADD is explored. The chronic delayed sleep phase syndrome associated with ADHD based on disturbances in the circadian rhythm, and the possible consequences for general health (obesity, diabetes, cardiovascular diseases and cancer) are discussed. There are sections on ADHD and intelligence, criminality, sexuality, dyslexia and autism. Adult ADHD can be treated effectively but as yet the disorder is not always recognised by professionals and this book aims to help correct this. Diagnostic tools are included, such as the structured Diagnostic Interview for Adult ADHD (DIVA), and an ultra-short and somewhat longer screening tool, all based on the DSM-IV criteria for ADHD. Treatment options cover psychoeducation and motivation and individual and group coaching; long-acting stimulants and other new drugs for treating ADHD; use of melatonin to treat the delayed sleep-phase disorder. Useful information is included on the setting up and organisation of a department for adult ADHD with a multidisciplinary team. References, websites and useful international addresses have all been updated. Adult ADHD: Diagnostic Assessment and Treatment, Third Edition is intended for students, junior doctors/residents, psychologists, psychiatrists, other mental healthcare professionals and interested parties and provides a quick overview of the current state of the science and of the methods used in diagnosis and treatment.
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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.