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Observations About Baseline Cortisol Based on Single Estimates of Plasma or Saliva

Investigations of single plasma and salivary cortisol levels have become increasingly popular in the last decade given the relative ease in acquiring samples. However, the use of a single sampling of cortisol, particularly at a set time of the day, may not represent an appropriate method for estimating cortisol levels because of moment-to-moment fluctuations in cortisol levels due to transient stressors in the environment (including the actual stress of venipuncture or anticipatory anxiety). Variability in single sampling estimates of cortisol may also reflect individual variation in sleep cycles. Because cortisol levels steadily decline from their peak, which is usually observed at 30 min post-awakening (Hucklebridge et al. 1999), differences in wake-time of several minutes to an hour may increase the variability substantially. Table 2 provides a summary of cortisol levels in studies that specifically obtained 8 00 a.m. cortisol concentrations, and highlights the lack of uniform...

Correlates of Cortisol in PTSD

Even in cases where there is failure to find group differences, there are often correlations within the PTSD group with indices of PTSD symptom severity. Baker et al. (1999) failed to find group differences between Vietnam veterans with PTSD compared to non-exposed controls, but did report a negative correlation between 24-h urinary cortisol and PTSD symptoms in combat veterans. A negative correlation between baseline plasma cortisol levels and PTSD symptoms, particularly avoidance and hyperarousal symptoms, were observed in adolescents with PTSD (Goenjian et al. 2003). Rasmusson et al. (2003) failed to observe a significant difference in urinary cortisol between premenopausal women with PTSD and healthy women, but noted an inverse correlation between duration since the trauma and cortisol levels, implying that low cortisol is associated with early traumatization. This finding is consisted with Yehuda and colleagues' observation of an inverse relationship between childhood emotional...

Findings of Cortisol in the Acute Aftermath of Trauma

Recent data have provided some support for the idea that low cortisol levels may be an early predictor of PTSD rather than a consequence of this condition. Low cortisol levels in the immediate aftermath of a motor vehicle accident predicted the development of PTSD in a group of 35 accident victims consecutively presenting to an emergency room (Yehuda et al. 1998). Delahanty et al. (2000) also reported that low cortisol levels in the immediate aftermath of a trauma contributed to the prediction of PTSD symptoms at 1 month. In a sample of 115 people who survived a natural disaster, cortisol levels were similarly found to be lowest in those with highest PTSD scores at 1 month post-trauma, however cortisol levels were not predictive of symptoms at 1 year (Anisman et al. 2001). Similarly, lower morning, but higher evening cortisol levels were observed in 15 subjects with high levels of PTSD symptoms 5 days following a mine accident in Lebanon compared to 16 subjects with lower levels of...

Cortisol Levels in Response to Stress

The potential significance of the findings of an increased range of cortisol is that the HPA axis may be maximally responsive to stress-related cues in PTSD, whereas major depressive disorder may reflect a condition of minimal responsiveness to the environment. That is, an enhanced amplitude-to-mesor ratio describes a system with particularly low background activity and, accordingly, a potentially increased capacity to respond to environmental cues. In support of this, Liberzon et al. observed an increased cortisol but not increased corticotropin (ACTH) response in combat veterans with PTSD compared to controls who were exposed to white noise and combat sounds (Liberzon et al. 1999). Elizinga et al. also observed that women with PTSD related to childhood abuse had substantially higher salivary cortisol levels in response to hearing scripts related to their childhood experiences compared to controls, who had relatively lower cortisol levels in response to hearing scripts of other...

Cortisol Levels Over the Diurnal Cycle in PTSD

Among the many potential methodologic problems associated with 24-h urine collections is the possibility that persons who are asked to collect 24-h samples at home may not provide complete collections. To the extent that there may be a systematic bias in protocol nonadherence between subjects with and without PTSD, in that the former might be more likely to miss collections than the latter, this could contribute to observed low cortisol levels. One of the initial rationales for performing a comprehensive circadian rhythm analysis was to corroborate and extend findings from the 24-h urine excretion studies and those using single-point estimates (Yehuda et al. 1990). An initial study of cir-cadian parameters in PTSD was conducted by obtaining 49 consecutive blood samples from three groups of subjects Vietnam combat veterans with PTSD, subjects (largely veterans) with major depression, and non-psychiatric comparison subjects every 30 min over a 24-h period under carefully controlled...

Urinary Cortisol Levels in PTSD

The initial report of sustained, lower urinary cortisol levels in PTSD highlighted the disassociation between cortisol and catecholamine levels in PTSD. Norepinephrine and epinephrine levels assayed from the same urine specimens revealed elevations in both of these catecholamines, while cortisol levels in PTSD fell within the normal range of 20-90 pg day, indicating that the alteration was not in the hypoadrenal or endocrinopathologic range (Mason et al. 1986). This finding established the expectation that alterations in basal levels of cortisol might be subtle, and not easily differentiated from normal values (Mason et al. 1986). Table 1 shows that this is in fact the case. Whereas the majority of studies has found evidence of low Cortisol in PTSD, it is clear that group differences are not always present between subjects with and without PTSD. The inconsistency in published reports examining urinary 24-h cortisol levels has been widely noted. There are numerous sources of potential...

CB1 Receptors in the Control of Feeding Behaviour

The body weight of adult CB1 receptor knockout mice was, however, similar to that of control animals, indicating that the endocannabinoid system is not critical for maintaining regular food intake under normal laboratory conditions (Zimmer et al. 1999). In contrast, when animals were food deprived for 18 h, wild-type mice consumed significantly more food at the end of the fasting period than CB1-deficient animals (Di Marzo et al. 2001). Wild-type mice that were treated with 3 mg kg SR141716A10 min before the start of the testingperiod also showed alower food intake, similar to that of CB1 knockouts. The orexigenic effects of cannabi-noids are thought to be mediated by hypothalamic CB1 receptors, although the CB1 receptor density in the hypothalamus is lower than in many other brain regions (Marsicano and Lutz 1999 Harrold and Williams 2003). The endocannabinoid system in the hypothalamus seems to be part of a leptin-sensitive regulatory pathway, as leptin decreases hypothalamic...

Comparative studies

Metformin and troglitazone have been compared in 21 patients with type 2 diabetes unresponsive to glibencla-mide 10 mg bd (10). Metformin stabilized weight and reduced adipocyte size, leptin concentrations, and glucose transport. GLUT1 and GLUT4 in isolated adipocytes were not changed. Insulin-stimulated whole-body glucose disposal rate increased by 20 . Troglitazone caused increases in body weight, adipocyte size, leptin concentrations, and basal and insulin-stimulated glucose transport. GLUT4 protein expression was increased two-fold and insulin-stimulated whole-body glucose disposal rate increased by 44 .

Enzymatic Hydrolysis 321

Membranes what was originally thought to be the hydrophobic domain responsible for this localization is instead important for the formation of active oligomers, whereas its localization on intracellular membranes might be regulated by an SH3 (Src homology region 3) consensus proline-rich sequence also necessary for enzymatic activity. Furthermore, judging from the recently elucidated X-ray structure of FAAH crystals in complex with its substrate (Bracey et al. 2002), one more domain may exist conferring the enzyme with the ability to associate with the plasma membrane. The catalytic amino acid of FAAH has been identified as Ser241, and two other residues of the amidase consensus sequence, Ser217 and Cys249, contribute to its enzymatic activity through a catalytic mechanism different from that of other amidases and Ser hydrolases (Patricelli and Cravatt 2000). The promoter region on the FAAH gene has been identified (Puffenbarger et al. 2001 Waleh et al. 2002), and is up-regulated by...

The Stress Hormone Hypothalamic PituitaryAdrenocortical System

Every disturbance of the body, either real or imagined, either physical or psychological, evokes a stress response. This stress response involves a large number of mechanisms and processes that, altogether, serve to restrain the body's defense reactions to stress, so as to restore homeostasis and to facilitate adaptation. CRH is the primary hypothalamic hypophysiotropic factor that regulates both basal and stress-induced release of pituitary corticotropin (ACTH) and is the major constituent of the HPA system (Vale et al. 1981). At the pituitary level, the effects of CRH are amplified by AVP, which, after prolonged stress, is increasingly co-expressed and co-secreted from hypothalamic CRH neurons (Antoni et al. 1993 Keck et al. 2000,2002). CRH triggers the immediate release of ACTH from the anterior pituitary, subsequently leading to release of glucocorticoid hormones (GC, cortisol in humans and corticosterone in rats and mice) from the adrenal cortex (Fig. 1). Fig. 1 The regulation of...

Reproductive system

Since amenorrhea is a symptom of Cushing's syndrome, disorders of menstruation are common in fertile women taking higher doses of glucocorticoids (SEDA-3, 305). On the other hand, plasma cortisol concentrations in normally menstruating women have marked circadian variation, the extent of which can reach 200 or more (247), with the peak of the cortisol plasma concentrations at mid-cycle and near its end. Inhibition of ovulation by triamcinolone 25 mg has been reported when the drug is given on day 1 or 2 of the cycle. How glucocorticoids interfere with the hormonal control of the menstrual cycle is still unknown (248).

Systemic availability of inhaled glucocorticoids

Plasma concentrations have been measured in 13 healthy subjects and eight patients with mild asthma using inhaled fluticasone propionate 1000 micrograms bd via Diskus or pressurized metered-dose inhaler and of budesonide 1000 micrograms bd daily via Turbuhaler for 7 days. Twenty-four-hour plasma cortisol concentrations were determined to assess the systemic activity of fluticasone propionate and budesonide. At steady state, the systemic availability of budesonide via Turbuhaler (39 ) was significantly higher than that of fluticasone propionate via Diskus (13 ) or inhaler (21 ). Fluticasone propionate had a larger distribution volume and slower rates of absorption and clearance. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, plasma cortisol suppression was less than that of fluticasone propionate via inhaler and similar to that of fluticasone propionate via Diskus. There were no differences between healthy subjects and patients with mild asthma in...

General Information

The adrenocorticotropic hormone ACTH (corticotropin) stimulates the adrenal cortex to secrete the glucocorticoids hydrocortisone (cortisol) and corticosterone, the mineralocorticoid aldosterone, and a number of weakly androgenic substances, as well as a small amount of testosterone. Aldosterone synthesis is also regulated by renin and angiotensin.

Neural Mechanisms of Anxiety and Fear

Inhibitory NE p-adrenergic avoidance receptor, Cortisol Excessive stress-mediated release of CRH, Cortisol, and NE will facilitate development of indelible fear memories. Chronic anxiety and phobic symptoms may result from excessive contextual fear conditioning Interactions among corticotropin-releasing hormone (CRH), cortisol, and NE have very important effects on memory consolidation, which is likely to These results support the concept that CRH via an interaction with gluco-corticoids interacts with the noradrenergic system to consolidate traumatic memories. Individuals with excessive stress-induced release of CRH, cortisol, and NE are likely to be prone to the development of indelible traumatic memories and associated re-experiencing symptoms. Administration of CRH antagonists, glucocorticoid receptor antagonists, and -adrenergic receptor antagonists may prevent these effects in vulnerable subjects.

Posttraumatic Stress Disorder

There is some evidence that baseline levels of NE are consistently altered in combat-related PTDS. Women with PTSD secondary to childhood sexual abuse had significantly elevated levels of catecholamines (NE, epinephrine, DA) and cortisol in 24-h urine samples (Lemieux and Coe 1995). Sexually abused girls excreted significantly greater amounts of catecholamine metabolites, metanephrine, vanilmandelic acid, and homovanillic acid (HVA) than girls who were not sexually abused (DeBellis et al. 1994). Plasma levels of NE were elevated throughout a 24-h period collection period (Yehuda et al. 1995b) as were CSF levels of NE in PTSD patients (Baker et al. 1997). In the latter case, exposure to traumatic reminders in the form of combat films resulted in increased epinephrine (McFall et al. 1992) and NE (Blanchard et al. 1991) release.

What Does 5ht Do In The Brain

Clearly, this is a complex physiological system, involving multiple feedback and feedforward pathways that interacts with other 'food-factors' (e.g. NPY, leptin, orexins, corticosteroids and other monoamines) and it will take a great deal of research to unravel all these networks. However, the progress that has been made so far underlines the crucial role played by 5-HT in this process and reinforces the view that drugs targeting specific 5-HT receptors could turn out to be effective anti-obesity agents that lack the adverse effects of 5-HT releasing agents.

Drug Administration Drug formulations

In the estrophasic'' form of administration, ethinyles-tradiol 20 micrograms is given on days 1-5 of the cycle, 30 micrograms on days 6-12, and 35 micrograms on days 13-21. Norethisterone acetate 1 mg is also given throughout this period. The literature to date has not shown that this regimen, although claimed to be more physiological'' in its composition, is in fact better tolerated than a comparable combination in which ethinylestradiol is given in a dose of 30 micrograms throughout (302). However, the reduction in what may at some phases of the cycle be an unnecessarily high estrogen dose, that is more than is needed to maintain cycle control, is a healthy step, and it may be useful to have a further alternative product for women who do not find any existing formulation fully satisfactory.

Use in noninfective conditions

Patients who had residual or recurrent Cushing's disease after surgical treatment have been reported (3). The dosage of ketoconazole was adjusted according to the clinical response and 24-hour urinary excretion of free cortisol. All three patients had good clinical and biochemical responses to therapy with ketoconazole and had no adverse effects.

Basal HPA Hormone Levels in PTSD

The first report on cortisol levels in PTSD was that of Mason et al. who found that the mean 24-h urinary excretion of cortisol was significantly lower in combat Vietnam veterans with PTSD compared to psychiatric patients in four other diagnostic groups (Mason et al. 1986). The authors noted surprise at the fact that cortisol levels were low, since certain clinical features such as depression and anxiety in PTSD might have been expected to be associated with increased activity of the pituitary-adrenal cortical system. Since this initial observation, the majority of the evidence supports the conclusion that cortisol alterations in PTSD are different from those observed in acute and chronic stress, and major depression, but more importantly, that the HPA axis appears to be regulated differently.

Corticosteroid Binding Globulin

Kanter et al. reported an increase concentration of the corticosteroid binding globulin (CBG) (Kanter et al. 2001). Most cortisol is bound to CBG, and is biologically inactive. A greater concentration of CBG is consistent with low levels of measurable free cortisol, and provides a putative explanation for how cortisol levels could be measurably low even though other aspects of HPA axis functioning do not seem hypoactive. However, the extent to which CBG levels are a contributing cause of low cortisol requires further examination.

Glucocorticoid Receptors in PTSD

Lymphocyte and brain GRs have been found to share similar regulatory and binding characteristics (Lowy 1989). A greater number of 8 00 a.m., but not 4 00 p.m., mononuclear leukocytes (presumably lymphocyte) type II GRs was reported in Vietnam veterans with PTSD compared to a normal comparison group (Yehuda et al. 1991b). Subsequently, Yehuda et al. reported an inverse relationship between 24-h urinary cortisol excretion and lymphocyte GR number in PTSD and depression (i.e., low cortisol and increased receptor levels were observed in PTSD, whereas in major depressive disorder, elevated cortisol and reduced receptor number were observed) (Yehuda et al. 1993a). Although it is not clear whether alterations in GR number reflect an adaptation to low cortisol levels or some other alteration, the observation of an increased number of lymphocyte GRs provided the basis for the hypothesis of an increased negative feedback inhibition of cortisol secondary to increased receptor sensitivity (Yehuda...

The Cholecystokinin Tetrapeptide Challenge Test in PTSD

Cholecystokinin tetrapeptide (CCK)-4 is a potent stimulator of ACTH. Kellner et al. administered a 50-pg bolus of CCK-4 to subjects with PTSD and found substantially attenuated elevations of ACTH in PTSD, which occurred despite comparable ACTH levels at baseline (Kellner et al. 2000). Cortisol levels were lower in PTSD at baseline, but rose to a comparable level in PTSD and control subjects. However, the rate of decline from the peak was faster, leading to an overall lower total cortisol surge. The attenuated ACTH response to CCK-4 is compatible with the idea of CRF overdrive in PTSD, and is a similar to the administration of CRF. That less ACTH can produce a similar activation of the adrenalgland, butamorerapid sensitive negative feedback inhibition secondary to increased glucocorticoid receptor activity at the pituitary. Although the comparatively greater effects on cortisol relative to ACTH is also compatible with an increased sensitivity of the adrenal gland to ACTH, rather than...

Drawing Conclusions from Challenge Studies Do They Provide a Window into the Brain

Although and cortisol, hypothalamic CRF release may be inferred from some of the results. For example, because metyrapone administration results in the elimination of negative feedback inhibition, its administration allows an exploration of suprapituitary release of ACTH, without the potentially confounding effects of differing ambient cortisol levels. To the extent that metyrapone administration results in a substantially higher increase in ACTH and 11-deoxycortisol Similarly, the CRF challenge test has also been used to estimate hypothalamic CRF activity, since a blunted ACTH response is suggestive of a downregu-lation of pituitary receptors secondary to CRF hypersecretion. Using this logic, an augmented ACTH response to CRF would reflect a decreased hypothalamic CRF release, or at least an upregulation of pituitary CRF receptors. Rasmusson et al. (2001) assert that the finding of an increased ACTH response to CRF is analogous to the increased ACTH response to metyrapone obtained by...

Putative Models of HPA Axis Alterations in PTSD

Cortisol levels are most often found to be lower than normal in PTSD, but can also be similar to or greater than those in comparison subjects. Findings of changes in circadian rhythm suggest that there may be regulatory influences that result in a greater dynamic range of cortisol release over the diurnal cycle in PTSD. Together, these findings imply that although cortisol levels may be generally lower, the adrenal gland is certainly capable of producing adequate amounts of cortisol in response to challenge. The model of enhanced negative feedback inhibition is compatible with the idea that there may be transient elevations in cortisol, but would suggest that when present, these increases would be shorter-lived due to a more efficient containment of ACTH release as a result of enhanced GR activation. This model posits that chronic or transient elevations in CRF release stimulate the pituitary release of ACTH, which in turn stimulates the adrenal release of cortisol. However, an...

Endocannabinoids In Relation To Feeding And Appetite

Several nuclei in the hypothalamus and brainstem act as input stations for hormonal and GI information and control several aspects of feeding (Halford and Blundell, 2000 Chiesi et al., 2001). During and after a meal, several peripheral satiety factors (such as cholesystokinin CCK , bombesin, gastrin-releasing peptide, and glucagons) are released from GI secretory cells in response to the physical and chemical presence of food in the GIT. Of these factors, CCK is thought to activate CCK1 receptors on vagal afferents that transmit signals to the hindbrain, particularly to the NTS. The NTS communicates with several hypothalamic nuclei that play critical roles in appetite regulation (Halford and Blundell, 2000 Broberger and Hokfelt, 2001 Chiesi et al., 2001). In addition, the hormone leptin, which is secreted from adipose tissue, enters the CNS and stimulates the arcuate nucleus within the hypothalamus. Leptin is the primary signal through which the hypothalamus senses nutritional state...

Physiological Changes After The Ingestion Of Hoasca

Neuroendocrine responses all increased well over basal levels for each volunteer, with maximum concentrations for Cortisol, growth hormone, and prolactin being achieved by 60, 90, and 120 minutes respectively. All of these measures were back down to baseline by 360 minutes. Such a sharp response is not unusual for other serotonergic drugs (e.g., MAO inhibitors).

Review of Endocrine Function

Subsequently, a more in-depth study of both sexes was undertaken to assess multiple hormone effects comparing subjects with different levels of cannabis usage vs. controls (Block, Farinpour, and Schlechte 1991). No significant effects were noted on testosterone, LH, FSH, prolactin or cortisol in young women and men.

Cannabinoids and Appetite and Feeding

Leptin, the 16-kDa product of the obese gene, has been implicated in the maintenance of feeding behaviour and energy balance (Campfield et al. 1995). Leptin is regarded as an appetite-reducing protein, and as the primary signal through which the hypothalamus regulates food intake and energy balance (Friedman and Halaas 1998). It is known that neurons in the ventromedial hypothalamic nucleus (VMH) and in the lateral hypothalamus (LHY) play a central role in the regulation of feeding and energy homeostasis (Oomura et al. 1969). The leptin receptor (LR) was first demonstrated in the choroid plexus and hypothalamus (Tartaglia 1995). Strong LR immunoreactivity was described in the hypothalamic arcuate nucleus (ARC), VMH and dorsomedial nucleus (DMN), and moderate immunoreactivity in the LHY (Maruta et al. 1999 Funahashi et al. 1999) (Fig. 4). It is interesting that leptin does not only regulate appetite and feeding, but also takes part in hypothalamic neuroendocrine regulation (Takashi et...

Why Chronic Stress Is Bad For Your Immune System

People with type A personalities (the kind of people who are always under the gun, working 80-hour weeks, stressed all the time) have a higher risk of developing health-related problems such as heart disease. They also can develop problems with their immune systems. The body produces its own anti-inflammatory corticosteroids, namely Cortisol. Production of this hormone by the adrenal gland is especially increased during times of psychological stress, whether it is a normal stress response (such as anticipating a final exam, being stuck in traffic, or being chased by a grizzly bear) or an abnormal stress response (such as being chronically depressed). Although the antiinflammatory actions of cortisol can be beneficial in the short run in relieving pain and inflammation, the increases in overall cortisol production in chronically stressed individuals can actually damage the immune system. Cortisol and other corticosteroids suppress the immune system by killing off immune cells and also...

Effect Scaling and MDMA Dosing Regimens

Administration of MDMA at doses of 1 to 3 mg kg causes marked elevations in extracellular 5-HT and DA in rat brain, as determined by in vivo microdialysis.33 3439 Although it is impossible to directly measure 5-HT and DA release in living human brain, clinical studies indicate that subjective effects of MDMA (1.5 mg kg, p.o.) are antagonized by SSRIs, suggesting the involvement of transporter-mediated release of 5-HT.1106 Nash et al.43 showed that i.p. injections of 1 to 3 mg kg of MDMA stimulate prolactin and corticosterone secretion in rats, and similar oral doses increase plasma prolactin and cortisol in human drug users.1112 The dose of MDMA discriminated by rats and humans is identical 1.5 mg kg, i.p., for rats107 108 and 1.5 mg kg, p.o., for humans.109 Schenk et al.110 demonstrated that rats can be trained to self-administer MDMA using i.v. doses ranging from 0.25 to 1.0 mg kg, indicating these doses possess reinforcing efficacy. Tancer and Johanson111 reported that 1 and 2 mg...

Noradrenergic Adrenergic Challenges

Clonidine normally stimulates the hypothalamic release of growth hormone through a2-agonism. The growth hormone release in panic patients, however, was found to be diminished, which could reflect downregulation of postsy-naptic a2-receptors in response to chronic noradrenergic discharge (e.g., Nutt et al. 1992). In addition, several studies indicated that the degree of blood pressure decrease, cortisol secretion, and noradrenergic turnover, as measured by plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations, regularly induced by clonidine administration, was exaggerated in panic disorder (e.g., Charney et al. 1992 Uhde et al. 1986 Coplan et al. 1997a,b). Altered a2-adrenoceptor sensitivity is also evidenced by findings that yohimbine produces exaggerated cardiovascular responses, enhanced plasma MHPG, and cortisol increases in panic disorder patients relative to control subjects (Cameron et al. 2000 Yeragani et al. 1992).

Serotonergic Challenges

Studies of 5-HT neurotransmission in panic disorder have principally employed the mixed serotonin agonist-antagonist mCPP and the indirect serotonin agonist fenfluramine (Table 1). mCPP has complex effects on brain 5-HT systems it appears to act as an agonist at the 5-HT1C and 5-HT1A receptors, whereas effects at the 5-HT3 receptor seem primarily antagonistic. Mixed agonist and antagonist activity has been found at the 5-HT2 site (e.g., Kahn et al. 1991). 5-HT-releasing properties and binding to a2-adrenergic sites have also been reported. Fenfluramine, a phenylethylamine derivative, potently releases presynaptic 5-HT and inhibits 5-HT reuptake, with weaker action as a postsy-naptic 5-HT agonist. In neuroimaging studies, cerebral blood flow significantly increased in the anterior cingulate cortex in healthy subjects but not in subjects with panic disorder during fenfluramine challenge (Meyer et al. 2000). Patients with panic disorder have demonstrated increased rates of anxiety, but...

Peripheral Endocrine Tissues

CB j receptor mRNA has been detected in the adrenal gland of the embryonic and adult rat (Galiegue et al., 1995 Buckley et al., 1998). Acute cannabinoid treatment increased plasma corticosterone levels in rats and cortisol in humans (Cone et al., 1986 Rodriguez de Fonseca et al., 1992 Weidenfeld et al., 1994 Jackson and Murphy, 1997) and decreased adrenal medulla contents of both norepinephrine and epinephrine in rats (Rodriguez de Fonseca et al., 1991) and plasma epinephrine levels in rabbits (Niederhoffer et al., 2001). In isolated rabbit adrenal glands, electrically evoked epinephrine release was inhibited by WIN55212 in a manner reversed by the CB1 receptor antagonist SR141716A (Niederhoffer et al., 2001). These results suggest that adrenal medullary function is directly affected by cannabinoids however, there is no evidence of direct cannabinoid action on adrenal cortical synthesis or release of glucocorticoids.

Estrogens and estrogencontaining contraceptives

Estrogens and estrogen-containing contraceptives prolong the action of suxamethonium. Plasma cholin-esterase activity is reduced, possibly by estrogenic inhibition of the hepatic synthesis of plasma cholinester-ase, and its isozymes are modified (262,296,297). Diethylstilbestrol, included in this group, is reported to have caused paralysis for 3 hours in a patient with other aggravating factors (SEDA-4, 89) (298). One would, however, expect little prolongation of suxamethonium paralysis since the decrease in plasma cholinesterase activity (after contraceptives, at least) averages only about 20 . Prednisone, cortisol, and dexamethasone also reduce plasma cholinesterase activity to a mild or moderate degree (SEDA-15, 122) (299-301).

An Overview Of The Neurochemistry Of Depression

Concentrating on the systems highlighted in this chapter, there is plenty of evidence for mutual interactions between the noradrenergic and serotonergic neuronal systems and the HPA hormones inappropriate release or dysfunctional receptors at any point in these interactions could easily disrupt the balance between these different factors. (Figure 20.7 incorporates some of the interactions that have been characterised so far, but there are doubtless many others.) For example, it is clear that either hyper-responsive a2-adrenoceptors or hyporesponsive -adrenoceptors could diminish the release of 5-HT evoked by noradrenaline. Conversely, hyporesponsive 5-HT1A receptors and possibly hyperresponsive 5-HT2 receptors would diminish noradrenaline release from neurons in the locus coeruleus. A disorder of the HPA axis could affect the monoamines in two ways either directly through effects of CRF on monoamine release or through its effects on glucocorticoid secretion. For instance, whereas CRF...

The Dexamethasone Suppression Test in PTSD

In contrast to observations regarding ambient cortisol and ACTH levels, results using the DEX suppression test (DST) have presented a more consistent view of reduced cortisol suppression in response to DEX administration. The DST provides a direct test of the effects of GR activation in the pituitary on ACTH secretion, and cortisol levels following DEX administration are thus interpreted an estimate of the strength of negative feedback inhibition, provided that the adrenal response to ACTH is not altered. There are several hundred published studies reporting on the use of the DST in depression, all reporting that approximately 40 -60 of patients with major depression demonstrate a failure to suppress cortisol levels below 5.0 p.g 100 dl in response to 1.0 mg of DEX (Ribeiro et al. 1993). Nonsuppression of cortisol results from a reduced ability of DEX to exert negative feedback inhibition on the release of CRF and ACTH (Holsboer 2000). The initial DST studies in PTSD using the 1.0-mg...

Lactate Infusion Challenge

An analysis of data from sodium lactate studies revealed that self-reported fear, high cortisol levels, and low partial pressure of CO2, due to hyperventilation prior to lactate infusion, were the strongest predictors of panic (Coplan et al. 1998a). These findings raise the possibility that a particular biological and emotional state sets the stage for the occurrence of a panic attack in predisposed subjects. Moreover, the individual components of the triad (fear, cortisol, CO2) were found to be correlated, suggesting the activation of a putative common neural substrate (Coplan et al. 1998a). This is consistent with central amyg-dalar activation affecting changes in cortical areas (cognitive misappraisal), the hypothalamic paraventricular nucleus (HPA system activation), and the pontine parabrachial nucleus, implicated in fear-driven hyperventilation (e.g., Davis et al. 1986). Hollander et al. 1989 Woods et al. 1988a Kellner et al. 1998). In general, in most studies Cortisol elevation...

Other diagnostic agents

Metyrapone is a competitive inhibitor of Cortisol biosynthesis, used for evaluation of ACTH secretion in the rare cases when Cushing disease is suspected (Morris 2003). There is no indication for its use during pregnancy, as other diagnostic methods exist, but no congenital abnormalities were reported after exposure to metyrapone during pregnancy.

Rimonabant and the Endocannabinoid System

The Endocannabinoid (EC) System is a newly discovered physiological system in the body that is believed to play a key role in the central and peripheral regulation of energy balance, glucose and lipid metabolism, as well as in the control of tobacco dependence. CB1 receptors are found in the brain as well as in peripheral tissues of the body, such as adipocytes (or fat cells), which are associated with lipid and glucose metabolism. Excessive food intake or chronic tobacco use results in an overactive EC system. This can trigger a cycle of increased eating and fat storage or, in the case of smoking, sustained tobacco dependence.

The Naloxone Stimulation Test in PTSD

Another strategy for examining CRF activity involves the assessment of ACTH and cortisol after administration of agents that normally block the inhibition of CRF. Naloxone increases CRF release by blocking the inhibition normally exerted by opioids in the hypothalamus. Naloxone was administered to 13 PTSD patients and 7 normal comparison subjects (Hockings et al. 1993). Of the PTSD subjects, 6 7 showed an increased ACTH and cortisol response to naloxone. These findings appear to contradict those of Smith et al. (1989) who showed a blunted ACTH response to CRF however, here too the absence of information about ambient CRF complicates the interpretation of these findings. This finding is noteworthy for illustrating that only a proportion of subjects in a particular group may exhibit evidence of pituitary adrenocortical alterations.

Atrial Natriuretic Peptide

Whereas several peptides besides AVP are known to act synergistically with CRH, the only peptide candidate in humans that inhibits the HPA system at all regulatory levels of the system seems to be atrial natriuretic peptide (ANP). ANPhasbeen showntoinhibitthestimulatedrelease ofCRHandACTH in vitro and in vivo. This could be observed in humans as well, where ANP inhibits the CRH-induced ACTH (Keller et al. 1992), prolactin (Wiedemann et al. 1995), and cortisol secretion (Strohle et al. 1998). ANP is not only synthesized by atrial myocytes (deBold et al. 1985) and released into the circulation, but is also found in neurons of different brain regions (Tanala et al. 1984) where specific receptors have been found. ANP receptors and immunoreactivity have been found in periventricular and paraventricular hypothalamic nuclei, the LC, and the central nucleus of the amygdala. In patients with panic disorder, basal ANP concentrations are lower when compared to healthy control subjects, but ANP...

Medical And Behavioral Toxicity Overview

Alcohol produces both acute and chronic effects on virtually all endocrine organs (hormone-producing glands). Acutely, alcohol raises plasma catechol-amines, which are chemicals released from nerve endings that are responsible for certain emotional reactions the so-called fear, flight, and fight. Epinephrine (adrenaline) is released from the inside (medulla) of the adrenal gland and norepinephrine (noradrenaline) from sympathetic neurons (nerve cells) and the adrenal glands. Alcohol also causes release of cortisol from the outside (cortex) of the adrenal gland both acutely and chronically. Cortisol is a hormone (chemical messenger) responsible for multiple effects on the body, including changes in the immune response, glucose regulation, fat breakdown, blood pressure, and mood. Alcohol-induced cortisol excess can mimic Cushing's disease (a condition associated with excess cortisol production, often caused by a tumor on the adrenals) and is known as...

The Neurochemical Basis of Fear and Anxiety

Specific neurotransmitters and neuropeptides act on brain areas noted above in the mediation of fear and anxiety responses. These neurochemicals are released during stress, and chronic stress results in long-term alterations in function of these systems. Stress axis neurochemical systems prepare the organism for threat in multiple ways, through increased attention and vigilance, modulation of memory (in order to maximize the utilization of prior experience), planning, and preparation for action. In addition, these systems have peripheral effects, which include increased heart rate and blood pressure (catecholamines) and rapid modulation of the body's use of energy (cortisol). The neurobiological responses to threat and severe stress are clearly adaptive and have survival value, but they also can have maladaptive consequences when they become chronically activated. Examination of the preclinical data concerning neurochemical substrates of the stress response, the long-term impact of...

The CRF Challenge Test and ACTH Stimulation Test in PTSD

Infusion of exogenous CRF increases ACTH levels and provides a test of pituitary sensitivity. In several studies of major depression, the ACTH response to CRF was shown to be blunted, reflecting a reduced sensitivity of the pituitary to CRF (e.g., Krishnan 1993). This finding has been widely interpreted as reflecting a downregulation of pituitary CRF receptors secondary to CRF hypersecretion, but may also reflect increased cortisol inhibition of ACTH secondary to hypercortisolism (Krishnan 1993 Yehuda and Nemeroff 1994). A study of eight PTSD subjects demonstrated that the ACTH response to CRF is also blunted (Smith et al. 1989). However, although the authors noted a uniform blunting of the ACTH response, this did not always occur in the context of hypercortisolism. Furthermore, although the ACTH response was significantly blunted, the cortisol response was not (however, though not statistically significant, it should be noted that the area under the curve for cortisol was 38 less...

Therapeutic studies

In a double-blind, crossover study 12 healthy subjects were randomized to receive either inhaled placebo or inhaled budesonide 1.2 mg bd for 7 days, with a minimum 7-day washout period between the two treatments (7). They used formoterol 24 micrograms bd during both treatment periods. A dose-response curve for systemic beta2-adrenoceptor responses to inhaled salbutamol (0.8-3.2 mg) was carried out before and after 7 days of each treatment. The pretreatment value of plasma cortisol averaged 407 nmol l and fell to 22 nmol l after 7 days of budesonide placebo had no effect. There was a significant reduction in the peak heart rate response to salbutamol when formoterol was given with placebo. This was partially reversed when formoterol was combined with budesonide. The peak rise in heart rate with salbutamol after formoterol and placebo was 24 minute and increased to 35 minute when formoterol was given with budesonide. The peak fall in potassium with salbutamol after formo-terol and...

Mechanisms of FAAH Regulation

Expression of FAAH is up-regulated by progesterone and leptin and down-regulated by estrogen and glucocorticoids (Maccarrone et al. 2001a, 2003b Waleh et al. 2002). Changes in FAAH protein concentrations are paralleled by changes in mRNA levels, consistent with transcription regulation by these factors. Although steroid hormone-response elements have been described in the promoter region of the FAAH gene in rodents and human, the precise mechanisms by which progesterone, estrogen, and glucocorticoids regulate FAAH transcription remain unclear (Maccarrone et al. 2001a, 200, 2003b Puffenbarger et al. 2001 Waleh et al. 2002). Regulation is tissue- and species-specific FAAH expression is decreased in mouse uterus, but increased in rat uterus, in response to sex hormones (Maccarrone et al. 2000b Xiao et al. 2002). The FAAH promoter region also contains a cyclic adenosine monophosphate (cAMP)-response element-like site, which is a transcriptional target of signal transducer and activator of...

Drug Drug Interactions General

In 40 healthy women oral contraceptives had a greater effect on prednisolone than on budesonide (44). In oral contraceptive users, the average plasma concentration of simultaneously administered prednisolone was 131 higher than in a control group, whereas the average plasma concentration of budesonide was only 22 higher. Mean plasma cortisol concentrations were suppressed by 90 and 82 with prednisolone and by 22 and 28 with budesonide in oral contraceptive users and controls, respectively. Ethinylestradiol plasma concentrations were not affected by either glucocorticoid. The authors concluded that the oral contraceptive made no difference to the plasma concentrations of budesonide or cortisol suppression after the administration of budesonide capsules. These findings suggest that oral budesonide can be used in the usual doses without problems in women using oral contraceptives.

Hypothalamus and Neuroendocrine Effects

The hypothalamus is the principal brain region controlling feeding and regulation of body weight. Several neurotransmitters are involved in the control of food intake. Serotonin and norepinephrine tend to inhibit feeding peptides such as NPY and orexins A and B tend to stimulate eating behaviors, whereas cocaine- and amphetamine-regulated transcripts and proopiomelanocortin-derived peptides are anorectic hormones such as insulin and leptin also play a role, with leptin preventing body weight gain and insulin increasing body weight. Endogenous cannabinoids participate in the control of food intake, in part through interaction with leptin. Animals with defective leptin signaling are obese and have been found to have more anandamide and 2-AG than normal animals (51). Giving leptin to normal rats results in decreased levels of endogenous cannabinoids. Further, rimonabant reduces food intake and causes weight loss, and CBj knockout mice eat less than wild-type mice. Cannabis use in humans...

Serotonin and Schizophrenia

Sion leads to an increase in body temperature, anxiety, and release of growth hormone, Cortisol, ACTH, and prolactin (Murphy et al. 1986, 1991). In a 1991 Yale study of unmedicated schizophrenics, mCPP caused a larger anxiety response in patients than in controls (Krystal et al. 1991). Furthermore, it was shown to exacerbate psychotic symptoms in the patient group (Krystal et al. 1991). Iqbal and associates (1991) corroborated the finding of psychotogenesis in schizophrenic patients exposed to an mCPP challenge (0.25 mg kg taken by mouth PO ). Kahn (1992), however, measured an improvement in symptoms (by the Brief Psychiatric Rating Scale) of those schizophrenics undergoing an mCPP challenge (0.35 mg kg PO).

Orexigenic and Anorexigenic Studies

A combination of central and peripheral mechanisms control food intake. Indeed, hypothalamic nuclei and the brainstem act as input stations for hormonal and gastrointestinal information (10,11). Furthermore, peripheral satiety factors such as cholecystokinin (CCK) activate CCK1 receptors on vagal afferents, which transmit signals to hindbrain nuclei such as the nucleus tractus soli-tarius (NTS). The NTS in turn communicates with several hypothalamic nuclei, which play critical roles in appetite regulation. In addition, adipose tissue secretes the hormone leptin, which enters the CNS and stimulates the arcuate nucleus within the hypothalamus. Leptin appears to be the main signal via which the hypothalamus senses nutritional states and modulates food intake. Leptin directly affects neurons in which either the anorexigenic (appetite-reducing) peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) or the orexigenic (appetite-stimulating) peptides...

The Metyrapone Stimulation Test

Ations do not directly imply that an enhanced negative feedback inhibition is a primary disturbance in PTSD. Yehuda et al. used the metyrapone stimulation test as a way of providing further support for the enhanced negative feedback hypothesis (Yehuda et al. 1996a). Metyrapone prevents adrenal steroidogenesis by blocking the conversion of 11-deoxycortisol to cortisol, thereby unmasking the pituitary gland from the influences of negative feedback inhibition. If a sufficiently high dose of metyrapone is used such that an almost complete suppression of cortisol is achieved, this allows a direct examination of pituitary release of ACTH without the potentially confounding effects of differing ambient cortisol levels. When metyrapone is administered in the morning when HPA axis activity is relatively high maximal pituitary activity can be achieved, facilitating an evaluation of group differences in pituitary capability. The administration of 2.5 mg metyrapone in the morning resulted in a...

Steroidal antiestrogens

Receptor Ligand Binding Johnson

Trilostane is another steroidal compound that has been occasionally employed in the treatment of breast cancer and is now under reevaluation. It is an inhibitor of 3p-hydroxysteroid dehydrogenase, the enzyme that transforms pregnenolone into progesterone, a gestagen and also a biosynthetic precursor to all other types of steroidal hormones. Because of this property, it has been employed in disorders due to high levels of these hormones, such as Cushing's disease, which is characterized by high levels of cortisol. Further studies have shown that the antitumor effects of trilostane are partially due to the inhibition of steroidogenesis and also to allosteric inhibition of the estrogen, probably binding directly to the DNA-binding domain.17 Because it modulates ERs differently to tamoxifen and is able to influence internal cell signals and gene expression, it is undergoing clinical trials in

Clinical Implications

Data of animal experiments discussed in this chapter suggest a variety of potential pharmacological targets for the treatment of pathological anxiety (Fig. 1). As the occurrence of traumatic events is usually unpredictable, it seems more promising to interfere with consolidation than with acquisition processes. In this context, the sympatho-adrenergic and the hypothalamic-pituitary-adrenal system are of particular interest. Both noradrenaline and corticosterone cortisol are known to facilitate memory consolidation, in par-

Pharmacological Action of Nicotine

Nicotine binds selectively to the nicotinic receptors that are present in the adrenal medulla, brain, autonomic ganglia, and neuromuscular junctions. It causes the release of several neurotransmitters and hormones such as acetylcholine, norepinephrine, dopamine, serotonin, arginine vasopressin, j3-endorphin, adrenocorticotropic hormone, and cortisol (187). This neuro-regulatory effect of nicotine is dose-dependent and occurs as plasma nicotine level rises when tobacco is smoked. The neurotransmitters released in the brain medi Peripheral Pharmacological Actions ofNicotine. Nicotine effects on the cardiovascular system include tachycardia and peripheral vasoconstriction, which leads to elevated blood pressure. Because the cardiovascular effects are mainly caused by elevated levels of catecholamines and cortisol, tolerance to these effects does not occur. Other pharmacological actions of nicotine include increased gastrointestinal motility caused by parasym-pathetic ganglionic...

See also Antifungal azoles General Information

In man, higher doses of ketoconazole affect cortisol cortisone and androgen testosterone substrates. This finding has led to the use of ketoconazole in Cushing's disease and prostate cancer, but the phenomenon is also responsible for some of the adverse effects, especially those associated with higher doses and prolonged use (SED-12, 677). The potency of ketoconazole in inhibiting P450 isozymes (such as CYP3A4) is a cause of interactions with several other drugs.

Susceptibility Factors

Drug metabolism is reduced in critically ill patients. When the serum from five critically ill patients was incubated with microsomes prepared from three different human livers, the activity of CYP3A4, assessed by metabolism of midazolam to 1-hydroxymidazolam, was significantly inhibited compared with serum from healthy volunteers (99). The authors pointed out that many other drugs are also metabolized by this enzyme, including alfentanil, ciclosporin, cortisol, erythromycin, lidocaine, and nifedi-pine. This observation accounts for past reports of very slow metabolism of midazolam in seriously ill patients, resulting in high blood concentrations and delayed awakening.

Adicto a drogas narcoticas Addicted to narcotics

Unlike the cortex, the medulla can be removed without endangering the life of an individual. The adrenal outer layer, cortex, secretes about 30 steroid hormones, but only a few are secreted in significant amounts. In the adult human the cortex comprises about 90 percent of the gland. The cortex is made up of three structurally different concentric zones- From the outermost inward they are zona glomeru-losa, zona fasciculata and zona reticularis. The zona glomerulosa is principally responsible for the secretion of aldesterone, one of the most important hormones. This steroid hormone is known as a minneralocorticoid - a regulator of sodium and potassium metabolism. The inner two zones - fasciculata and re-ticularis - operate almost as a physiological unit and are controlled by ACTH (adrenocor-ticotropic hormone), a hormone secreted by the pituitary gland (q.v.). Their principal function is the secretion of cortisol and of some adrenal androgens, or male hormones, which have a minor...

The skeleton stone bones and stoned heads

The synchronized occurrence of multiple remodeling sites has long been viewed as suggestive of a complex, local, autocrine paracrine 5 as well as endocrine regulation. Indeed, experiments in knockout (KO) and transgenic mice have demonstrated paracrine regulation of osteoclast differentiation and activity by factors such as receptor activator of NFkB (RANK) ligand, osteo-protegerin, macrophage colony-stimulating factor (M-CSF) and interleukin 6, which are derived from neighboring stromal cells, including osteoblasts and osteoblast precursors 6-11 . The most convincing evidence for local osteoblast regulation is by bone morphogenetic proteins 12 . Systemically, ablation of gonadal hormones in females and males has been repeatedly demonstrated to favor bone loss in humans, rats, and mice 13, 14 . In addition, parathyroid hormone 15, 16 , calcitonin 17 , insulin-like growth factor I 18 , and the osteogenic growth peptide 19 have been shown to regulate bone formation. More recently, it...

Anxiogenesis Activation of CRHR1 and Dual Mode of Action of CRHR2

Combining molecular genetics with behavioral pharmacology, however, studies with antisense probes that selectively reduce CRH receptor subtype levels and transgenic mouse models have indicated that CRHR1 might be the primary target of interest at which selective compounds should be directed to treat pathological anxiety (Keck and Holsboer 2001 Liebsch et al. 1995, 1998 Skutella et al. 1998 Timpl et al. 1998). One compound recently examined is R121919, a high-affinity non-peptide CRHR1 antagonist (Keck et al. 2001, 2003b Lancel et al. 2002 Heinrichs et al. 2002 Gutman et al. 2003). In an open-label trial in patients suffering from major depression, a dose escalation strategy was employed which led to a 50 reduction in anxiety and depression scores comparable to that obtained with the selective serotonin reuptake inhibitor paroxetine (Keck and Holsboer 2001). Such effects were achieved at dosages that did not hamper the ACTH and cortisol response to CRH stimulation (Zobel et al. 2000 K...

Neuroendocrine Aspects of PTSD

2.1 Urinary Cortisol Levels in 2.2 Cortisol Levels Over the Diurnal Cycle in 2.3 Cortisol Levels in Response to 2.4 Observations About Baseline Cortisol Based on Single Estimates 2.5 Correlates of Cortisol in 4 Cortisol and ACTH Responses to Neuroendocrine Challenge 383 6.1 Findings of Cortisol in the Acute Aftermath of Trauma 394 Abstract This chapter discussed how neuroendocrine findings in posttraumatic stress disorder (PTSD) potentially inform hypothalamic-pituitary-adrenal (HPA) alterations in PTSD and highlight alterations relevant to the identification of targets for drug development. Most studies demonstrate alterations consistent with an enhanced negative feedback inhibition of cortisol on the pituitary, an overall hyperreactivity of other target tissues (adrenal gland, hypothalamus), or both in PTSD. However, findings of low cortisol and increased reactivity Keywords Posttraumatic stress disorder Cortisol Neuroendocrine alterations Negative feedback inhibition Glucocorticoid...

Injectable anesthetics

This non-barbiturate imidazole derivative is inactivated by nonspecific esterases. It is an inhibitor of steroid biosynthesis, and has been found to reduce scrum Cortisol concentrations in neonates following the use of etomidate during delivery without any long-term consequences (Reddy 1988). Etomidate does not have cardio-depressive characteristics. Its half-life is very short, being in the serum for about 3 minutes. The brief duration of the effect, like that of barbiturates, is dependent on redistribution from the brain, with its large blood supply, to tissues such as muscle and fat, which are less wcll-vascularized. There arc no epidemiologic studies on the administration of etomidate in pregnancy, and there has been no long-term follow-up. Animal studies regarding congenital anomalies are inconclusive, and even high doses were not teratogenic in rats (USP DI 2003. Doenicke 1977).

Brain Derived Neurotrophic Factor

Some evidence of decreased concentrations of forebrain 5-HT concentrations and fiber densities at 18 months of age (Lyons et al. 1999). Furthermore, learning deficits and hyperactivity was revealed in BDNF+l mice (Kernie et al. 2000). They also develop intermale aggressiveness in the resident-intruder test (Lyons et al. 1999), but do not show increased anxiety in the elevated plus maze, nor differences in the antidepressant-sensitive forced swim test (MacQueen et al. 2001). However, conditional deletion of the BDNF gene in the postnatal brain leads to increased anxiety-like behavior in the light-dark box, deficits in context-dependent learning in a fear conditioning paradigm, and hyperactivity (Rios et al. 2001). Both conditional and constitutive BDNF KO mice also exhibit obesity, with hyperphagia, elevated serum glucose, insulin and leptin levels, and elevated cell fat content (Kernie et al. 2000 Rios et al. 2001).

Producing Clean Urine

THC is fat soluble, and it gets stored in your fat cells. Cleaning it out of your lipid tissue is very difficult. Many herbal products claim to clean out your system, yet they do nothing to remove THC byproducts from fat cells. A study was done in Germany in 1993 on 50 of the most common herbs used by people trying to pass the test. All 50 herbs failed to cause a negative. Unfortunately, this rumor will not die. Goldenseal is useless yet it's the most common thing for people to use. The only way to extract THC from fat cells is to exercise (5.8). Fat cells secrete fat with THC metabolites at a constant rate, regardless of what herbs you consume. You may be able to temporarily rid THC metabolites from your bloodstream, or dilute your fluids to yield a larger urine THC ratio, but your bloodstream will continue collecting THC metabolites from fat. Your urine will continue collecting THC metabolites from your bloodstream.


Various hormonal and metabolic effects of aldesleukin are temporally related to hypotension. Transient serum rises in ACTH, cortisol, beta-endorphin, adrenaline and noradrenaline have been found, whereas there were no significant changes in the plasma concentrations of several other hormones (4).

In A Class By Itself

Marijuana is also distinctive because it is soluble in oil, but not in water. As a result, THC accumulates in fat cells. Although many drugs enter the body's fat cells in a similar fashion to marijuana, most drugs exit the body quickly. Since THC exits the fat cells slowly, traces of THC are detectable in the body for days or weeks after inhaling or ingesting it. Several studies indicate that active THC can leave fat cells and re-enter the bloodstream, creating a subtle high for up to 24 hours. Other researchers cite evidence that the psychoactive effects of THC wear off within two to four hours after use, even in frequent users. Nevertheless, there is little evidence to suggest that there are harmful short-term or long-term effects on the fat cells where THC lingers.


Combined therapy with clozapine and fluvoxamine (n 11) and clozapine monotherapy (n 12) have been monitored before and during the first 6 weeks of medication (217). The co-administration of fluvoxamine attenuated and delayed the clozapine-induced increase in plasma concentrations of tumor necrosis factor-alpha, enhanced and accelerated the clozapine-induced increase in leptin plasma concentrations without a significant effect on clozapine-induced weight gain, and reduced granulocyte counts.

Relative potencies

The main human anti-inflammatory corticosteroid, the glucocorticoid cortisol (hydrocortisone), as secreted by the adrenal gland, has generally been replaced by related glucocorticoids of synthetic origin for therapeutic purposes. These D1-dehydrated glucocorticoids are designed to imitate the physiological hormone. They have marked glucocorticoid potency but only minor effects on sodium retention and potassium excretion the relative glucocor-ticoid and mineralocorticoid potencies of the best-known compounds, insofar as these potencies are agreed, are compared in Table 1.


Glucocorticoids can regulate hippocampal metabolism, physiological functions, and memory. Despite evidence of memory loss during glucocorticoid treatment (SEDA-23, 428), and correlations between memory and cortisol concentrations in certain diseases, it is unclear whether exposure to the endogenous glucocorticoid cortisol in amounts seen during physical and psychological stress in humans can inhibit memory performance in otherwise healthy individuals. In an elegant experiment on the effect of cortisol on memory, 51 young healthy volunteers (24 men and 27 women) participated in a double-blind, randomized, crossover, placebo-controlled trial of cortisol 40 mg day or 160 mg day for 4 days (77). The lower dose of cortisol was equivalent to the cortisol delivered during a mild stress and the higher dose to major stress. Cognitive performance and plasma cortisol were evaluated before and until 10 days after drug administration. Cortisol produced a dose-related reversible reduction in verbal...

Lipid metabolism

Altered fat deposition has been repeatedly reported. Fat can be deposited epidurally and at other sites. Adiposis dolora, which involves the symmetrical appearance of multiple painful fat deposits in the subcutaneous tissues, has on one occasion been attributed to glucocor-ticoids (SEDA-16, 451).

Structure of DLIS

Instead of being a single compound, DLIS may be a class of compounds. Several investigators identified nonesterified fatty acids, phospholipids, and lysophospholipids as DLIS (55,56). When the first anti-digoxin antibody was introduced, it was recognized that most steroids cross-react to some extent with these antibodies. Several investigators reported progesterone, 17-OH progesterone, cortisol, and glycodihydroxy and glycotrihydroxy bile salts as DLIS (57). Shaikh et al. (58) reported that DLIS has a molecular weight of 780 Da comprising one 390-Da aglycone and several sugar moieties. De Angelis et al. (59) characterized DLIS as a single peak by HPLC from human serum with similar retention time as digoxin and concluded that the structure of DLIS was similar to digoxin. Qazzaz et al. reported that subtle structural differences exist between DLIS and digoxin at or near the lactone ring as well as in the nature of sugar. Moreover, deglycosylated congeners of DLIS also exist in human...

Antifungal azoles

Itraconazole 200 mg day markedly increased plasma methylprednisolone concentrations and reduced morning plasma cortisol concentrations by over 80 in 10 healthy volunteers (412). The Cmax, AUC, and half-life of methyl-prednisolone were increased 1.9, 3.9, and 2.4 times respectively. Itraconazole 200 mg day orally for 4 days markedly reduced the clearance and increased the half-life of intravenous methylprednisolone from 2.1 to 4.8 hours in a double-blind, randomized, two-phase, crossover study in nine healthy volunteers (SEDA-23, 430) (413). The volume of distribution was not affected. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hours after methylprednisolone, was only 9 of that during the placebo phase (11 versus 117 ng ml).

Inhalation devices

The equivalence of inhaled glucocorticoids based on equipotent (cortisol suppression) effects has been studied by the Asthma Clinical Research Network (ACRN). Six different inhaled glucocorticoids and matched placebos (beclomethasone chlorofluorocar-bon, budesonide dry powder inhaler, fluticasone dry powder inhaler, fluticasone chlorofluorocarbon metered-dose inhaler, flunisolide chlorofluorocarbon, and triamcinolone chlorofluorocarbon) were compared by measuring their systemic effects (18). Glucocorticoid-na'ive patients with asthma (n 156) were enrolled at six centers and a one-week doubling dose design was used for each of the six inhaled glu-cocorticoids and matched placebos to a total of four doses. The best outcome variable for the reliable assessment of a systemic effect was the 12-hour AUC of the hourly overnight plasma cortisol measurements from 8 p.m. to 8 a.m. Microgram comparisons of the glucocorticoids could only be performed at 10 cortisol suppression, because...


Propionate was tolerated, as well as placebo, with few adverse effects and no clinically important effect on mean serum cortisol concentration. The authors suggested that inhaled glucocorticoids may have an important place in the long-term management of patients with COPD.


The levels of 2-AG in the brain changed following several treatments of experimental animals. Di Marzo, Hill, et al. (2000) demonstrated that the levels of 2-AG in the globus pallidus were markedly augmented in rats treated with reserpine, which induces immobility and Parkinson's-disease-like symptoms by causing a depletion of catecholamines including dopamine from the striatum. On the other hand, Lastres-Becker et al. (2001) reported that the level of 2-AG in the striatum was reduced and that in the mesencephalon was augmented in a rat model of Huntington's disease. Baker et al. (2001) demonstrated that the levels of 2-AG in the brain and spinal cord were elevated in spastic mice with chronic relapsing experimental allergic encephalomyelitis as in the case of anandamide. Furthermore, Gonzalez et al. (2002) recently reported that the chronic treatments of rats with nicotine, ethanol, and cocaine induced a number of changes in the amounts of 2-AG (increase or decrease) in various brain...

Panic Disorder

Tion to having exaggerated plasma 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Cortisol, and cardiovascular responses (Charney et al. 1984, 1987a, 1992 Gurguis and Uhde 1990 Albus et al. 1992 Yeragani et al. 1992). Children with a variety of anxiety disorders exhibit greater anxiogenic responses to yohimbine than normal comparison children (Sallee et al. 2000). The responses to the a2-adrenergic receptor agonist clonidine are also abnormal in panic disorder patients. Clonidine administration caused greater hypotension, greater decreases in plasma MHPG, and less sedation in panic patients than in controls (Uhde etal. 1988 Nutt 1989 Coplanetal. 1995a,b Marshalletal. 2002).

Fats And Oils

The largest number of fat cells in the body are found in the brain, where they make up 60 percent of the total brain mass. The body manufactures all the fats it needs, except for two alpha-linolenic acid (also known as Omega-3 or Alena, short for alpha-lino emc acid), and linoleic acid (also known as Omega-6 or CLA, short for conjugated linoleic acid), which are called the essential fatty acids (EFAs). There are different types of Omega-3 fatty acids, including eicos-apentaenoic acid or EPA (found in fish oil), gamma-linolenic acid (found in borage seed and primrose oil), docosa-hexaenoic acid (DHA), and docosapen-taenoic acid (DPA).


There is ample evidence that the endogenous cannabinoid system plays a role in appetite homeostasis. Although both marijuana and THC have been shown to stimulate appetite, direct evidence for the involvement of cannabinoid receptors was provided by a study in which CB1 receptor knockout mice ate less than wild-type mice following food restriction (42). The selective antagonist, rimonabant (SR 141716), provided additional support for CB1 receptor involvement in that this compound reduced food intake in wild-type but not CB1 knockout mice (42). There are several lines of evidence indicating that the brain is a prominent site for cannabinoid regulation of appetite. For example, the hypothalamus contains both CB1 receptors and the endocannabinoids anandamide and 2-arachidonoylglycerol. Direct injections of anandamide into the hypothalamus of rats induced hyperphagia, an effect that was blocked by the CB1 receptor antagonist rimonabant (43). In addition, there is evidence of an...


Metformin (Glucophage), currently the only biguanide, acts by reducing hepatic glucose production and increasing insulin sensitivity in muscle and fat cells. The liver normally releases glucose by detecting the level of circulating insulin. When insulin levels are high, glucose is available in the blood, and the liver produces little or no glucose. When insulin levels are low, there is little circulating glucose, so the liver produces more glucose. In type 2 diabetes, the liver may not detect levels of glucose in the blood and, instead of regulating glucose production, releases glucose despite blood sugar levels.

Under the Influence

DMT also stimulated sharp spikes in the release of vasopressin, prolactin, growth hormone, and corticotropin. The last is a hormone responsible for stimulating the adrenal glands, which then release Cortisol, a powerful, all-purpose stress steroid similar to cortisone. The elevations of these hormones may have exerted some psychological effects I'll discuss this in chapter 21.


Athletes have a big advantage over normal civilians. When fat is burned, THC byproducts are released into the blood. This is the only way to get THC metabolites out of lipid tissue. Normal living will burn them slowly, as your fat reserves get turned over (Dr. Grow). Due to an athletes high metabolic rate, THC moves through an athletes system significantly faster. Exercising between drug tests will clean THC metabolites from the system at a faster rate, thus lowering the detection period. It is important to stop burning fat cells near test time. On test day, it doesn't matter what's in your lipid tissue. What's in your blood and urine does matter. Exercise increases the amount of THC metabolites in the urine so quit exercising a week before the test. Be lazy, and eat big. This will put the body in an anabolic fat-storing stage. At this point, the buried THC metabolites won't escape and go the the urine. There are drugs that will increase metabolism the way exercise does, but these are...

Beta3 Agonists

Beta-3 agonists are drugs that stimulate the beta-3 andrenergic receptors on brown fat cells. The beta-3 andrenergic receptor is located on the surface of fat cells, and controls the amount of fat the cell releases into the bloodstream. When brown fat is stimulated, white fat is burned (converted into heat). Many people have mutant beta-3 andrenergic receptors, causing calories to be burned too slowly thus leading to obesity. These people will benefit most from beta-3 agonist drugs. If the drug works as claimed, I believe it would reduce the detection time of fat soluble drugs by continually excreting metabolites into the bloodstream at a faster pace. As with vitamin lecithin and exercise, you would take beta-3 agonists between tests, and quit a couple days prior to the test. Beta-3 agonists have been in the development phase for the past 13 years. One firm is already testing a beta-3 drug in early clinical trials. It's not on the market yet.

CRF Levels in PTSD

There have been three published reports examining the concentration of corticotrophin-releasing factor (CRF) in cerebrospinal fluid (CSF) in PTSD. The assessment of CSF CRF does not necessarily provide a good estimate of hypothalamic CRF release, but rather, an estimate of both hypothalamic and extrahypothalamic release of this neuropeptide (Yehuda and Nemeroff 1994). An initial report using a single lumbar puncture indicated that CRF levels were elevated in combat veterans with PTSD (Bremner et al. 1997). A second study, examining serial CSF sampling over a 6-h period by means of an indwelling catheter, also reported significantly higher CSF CRF concentrations, but did not observe a relationship between CRF and 24-h urinary cortisol release (Baker et al. 1999). A third report demonstrated that PTSD subjects with psychotic symptoms had significantly higher mean levels of CRF than either subjects with PTSD without psychotic symptoms or controls subjects (Sautter et al. 2003).


The HPA axis alterations in PTSD support the idea that HPA axis alterations are complex and might be associated with different aspects of PTSD, including risk for the development of this disorder. For the findings to coalesce into an integrative neuroendocrine hypothesis ofPTSD, it would be necessary to assert that (1) some features of the HPA axis may be altered prior to the exposure to a focal trauma (2) that components of the HPA axis are not uniformly regulated (e.g., circadian rhythm patterns, tonic cortisol secretion, negative feedback inhibition, and the cortisol response to stress are differentially mediated (3) that the system is dynamic, and may therefore show transient increases or hyperre-sponsivity under certain environmental conditions that (4) other regulatory influences might affect HPA axis regulation in PTSD and probably (though not necessarily), that (5) there might be different biologic variants of PTSD with relatively similar phenotypic expressions, as is the case...


Blood levels of a hormone called Cortisol. In the 1990s nalbuphine was popular among bodybuilders using anabolic steroids. These individuals mainly used nalbuphine to reduce pain caused by exercise regimens. Interviews with such users revealed that many were suffering unwanted physical and mental effects from nalbuphine and that many of these persons were abusing other drugs as well. A case report tells of illicit nalbuphine injection causing muscle damage the opposite of what bodybuilders seek.


John Henry's group in England was the first to report not only a case series on hyperthermia but also the discovery of MDMA-induced hyponatremia (low sodium). Discovering and publicizing the occurrence of elevated body temperature in the dancing population of Ecstasy users has saved countless lives, as has reporting the danger of drinking too much water, which leads to low sodium levels. See the section on the risks of MDMA for more details. Dr. Henry and colleagues, who are affiliated with the Drug Control Centre and Department of Pharmacy, King's College London, published two MDMA studies in 1998 and 1999. In the first of these investigations, Henry and coworkers administered 40 mg of MDMA to eight men in a nonblind study, to analyze MDMAs physiological effects. The study looked specifically at secreted plasma arginine vasopressin (also called ADH, or antidiurectic hormone). This substance inhibits the kidneys from making urine and so causes a dilution of the blood and an...


The reported findings clearly show that in mammals ligand-receptor signalling with endocannabinoids is intimately associated with embryo-uterine interactions during implantation, and that in humans low FAAH in lymphocytes correlates with spontaneous abortion. This calls for attention to AEA-hydrolase as a key point in the control of the endocannabinoid system during pregnancy. Moreover, the results seem to add the endocannabinoids to the hormone-cytokine networks responsible for embryo-uterine interactions, and might represent a useful framework for the interpretation of novel interactions between progesterone, FSH, leptin, Th1 Th2 cytokines and (endo)cannabinoids, which appear to regulate both female sexual receptivity and male reproduction.


Metformin and troglitazone have been compared in 21 patients with type 2 diabetes unresponsive to glibenclamide 10 mg bd (62C). Met-formin stabilized weight and reduced adipocyte size, leptin concentrations, and glucose transport. GLUT1 and GLUT4 in isolated adipocytes were not changed. Insulin-stimulated whole-body glucose disposal rate increased by 20 . Troglitazone caused increases in body weight, adipocyte size, leptin concentrations, and basal and insulin stimulated glucose transport. GLUT4 protein expression was increased twofold and insulin-stimulated whole-body glucose disposal rate increased by 44 .


Troglitazone has been withdrawn because of hepatotoxicity. However, some data that may be relevant to other thiazolidinediones have recently been reported. In one study body weight, adipocyte size, leptin concentrations, GLUT4 protein expression, basal and insulin-stimulated glucose transport, and insulin-stimulated whole-body glucose disposal rate were increased by troglitazone (62C).


Uterine physiology and pregnancy appear to be regulated by cross-talk between signaling by hormones and endocannabinoids. FAAH levels in the mouse uterus are modulated by progesterone and estrogen (Maccarrone et al., 2000a, 2002a). Consistent with these findings, levels of AEA, 2-AG, and N-arachidonoylglycine in the rat uterus change as a function of hormonal status during the estrous cycle (Bradshaw and Walker, 2003). In women, low FAAH levels and high AEA levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer and increased incidence of miscarriage (Maccarrone et al., 2000a 2002b). Leptin knockout (ob ob) mice are obese and infertile (Cunningham et al., 1999 Ahima and Flier, 2000). These mice show elevated levels of uterine AEA and 2-AG, the former resulting lower FAAH activity and the latter resulting from elevated synthesis via higher diacylglycerol lipase activity and lower removal via monoacyl glycerol lipase activity (Maccarrone et al.,...

Ht1a 5ht2a

Chronic excess Cortisol) (Augmented by chronic excess Cortisol) inhibition. This is the 'dexamethasone suppression test (Carroll, Curtis and Mendels 1976). For most patients whose depression is relieved by antidepressants or electroconvulsive therapy, both the raised concentration of circulating cortisol and the negative 'dexamethasone suppression' response are resolved. This suggests that depression is associated with a defect in the regulation of glucocorticoid secretion and the locus of this disorder could be glucocorticoid receptors in the hippocampus. Evidence that CRF secretion is increased in depressives supports the idea that these receptors, which depress CRF secretion, are hypofunctional in depression (Ritchie and Nemeroff 1991). Also, transgenic mice which are deficient in glucocorticoid receptors exhibit many features of depression these extend to disruption of feeding and cognitive deficits as well as abnormal HPA function. Antidepressant treatment causes a long-latency...


Dexamethasone (DEX) is a synthetic adreno-corticosteroid with similar properties to the naturally occurring hydrocortisone and cortisol, being about 20-30 times more potent than hydrocortisone in its anti-inflammatory effect. This compound, however, has been chemically modified with a fluorine substituent on the steroid ring structure, allowing the drug to have reduced side-effects. The drug is a potent anti-inflammatory medication, lacking the unwanted effect of sodium retention by the body. The chemical structure of dexamethasone is depicted in Figure 1. Typically, dexametha-sone is administered orally or topically, but it can also show effectiveness when administered to the lungs of asthmatics.

Glycyrrhiza glabra

The active ingredients of licorice inhibit the breakdown of mineralocorticoids by inhibiting 11-beta-hydroxysteroid dehydrogenase type 2, and its adverse effects relate mainly to mineralocorticoid excess, with sodium retention, potassium loss, and inhibition of the renin-angiotensin-aldosterone system (36). In six male volunteers who took glycyrrhizinic acid for 7 days, serum, urinary, and sweat electrolytes values were consistent with a mineralocorticoid-like effect (41). Plasma renin activity was suppressed, and plasma cortisol and aldosterone progressively fell during treatment. The authors proposed that glycyrrhizinic acid initially acts by increasing the effect of endogenous mineralo-corticoids, and then when it or its metabolites accumulate it may also have a direct mineralocorticoid-like effect itself.

Specific propellants

Beclomethasone dipropionate and budesonide Modulite formulations have been compared with equivalent chloro-fluorocarbon products in small groups of healthy volunteers and asthmatic patients (18) there was no significant difference in morning serum cortisol or urinary cortisol excretion, suggesting that the systemic availability of the inhaled corti-costeroids with different propellants is similar. Moreover, plasma profiles of beclomethasone dipropionate and B17MP were similar after inhalation of beclomethasone dipropionate Modulite and beclomethasone dipropionate-chlorofluorocarbon, suggesting that pulmonary delivery to the lung is comparable with the two propellants (18).

ACTH Levels in PTSD

The majority of studies has reported no detectible differences in ACTH levels between PTSD and comparison subjects even when cortisol levels obtained from the same sample were found to be significantly lower. This pattern was observed in Kellner et al. who reported that cortisol levels were 41 lower, but that ACTH levels were only 7.4 lower in PTSD compared to normals (Kellner et al. 2000), and Hockings et al. who showed that cortisol levels were 12 lower in PTSD but ACTH levels identical to controls (Hockings et al. 1993). Kanter et al. also reported that cortisol levels were substantially lower in PTSD, while ACTH levels were comparable to controls (Kanter et al. 2001). In Yehuda et al. cortisol levels were lower at baseline on the placebo day in PTSD, but not at the baseline time point on the metyrapone day (i.e., prior Lower cortisol levels in the face of normal ACTH levels can reflect a relatively decreased adrenal output. Yet under circumstances of classic adrenal insufficiency,...

Stress Hormones

The hypothalamic-pituitary-adrenal axis is the major endogenous hormonal system responsible for maintaining homeostatic balance in response to stress. Beginning in the central nervous system, corticotropin-releasing hormone (CRH), synthesized in the hypothalamic parvocellular paraventricular nuclei of the hypothalamus, regulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary gland. ACTH release stimulates the synthesis and secretion of the adrenal glucocorticoids (cortisol in humans and corticosterone in rats), which, in turn, inhibit CRH and ACTH release, thus completing the negative feedback loop necessary for regulation of the stress axis. Smoking marijuana or the administration of an acute dose of cannabinoid stimulates the release of CRH (Weidenfeld et al., 1994), ACTH (Rodr guez de Fonseca et al, 1992a Jackson and Murphy, 1997) and glucocorticoids (Cone et al., 1986 Rodr guez de Fonseca et al., 1992a) in experimental animals and humans. An acute...


Steroid Synthesis Brain

Figure 13.5 Structure and interrelationship of the major neurosteroids. Pregnenolone (PREG) (1) is synthesised from cholesterol and is then either metabolised, reduced to 20a dihydropregnenolone (7) or sulphated (6), or converted by 3 -hydroxysteroid dehydrogenase to progesterone (PROG) (2) or to dehydroepiandrosterone (DHEA) (3). The former (PROG) can then be reduced to allopregnanolone (3a5aThPROG) (4) and DHEA sulphated to dehydroepiandrosterone sulphate (5). It is PREG, DHEA and 3a5aThPROG which appear to be important centrally. The structures of alphaxalone, a steroid anaesthetic and tetrahydrodeoxy-corticosterone, which is formed in the brain from deoxycorticosterone of peripheral origin, are also shown Figure 13.5 Structure and interrelationship of the major neurosteroids. Pregnenolone (PREG) (1) is synthesised from cholesterol and is then either metabolised, reduced to 20a dihydropregnenolone (7) or sulphated (6), or converted by 3 -hydroxysteroid dehydrogenase to progesterone...

Concluding Remarks

Di Marzo, V., Goparaju, S.K., Wang, L. Liu, J., Batkai, S., Jarai, Z., Fezza, F., Miura, G.I., Palmiter, R.D., Sugiura, T., and Kunos, G. (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake, Nature 410 822-825. Maccarrone, M., Di Rienzo, M., Finazzi-Agro, A., and Rossi, A. (2003) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3, Journal of Biological Chemistry 278 13318-13324.


The effects of itraconazole on the pharmacokinetics and cortisol-suppressing activity of budesonide by inhalation were further investigated in a randomized, doubleblind, two-phase, crossover study in 10 healthy subjects who took oral itraconazole 200 mg day or placebo for 5 days (93). On day 5, 1 hour after the last dose of itraconazole or placebo, they took budesonide 1000 micrograms by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours. Itraconazole increased the mean total AUC of inhaled budesonide 4.2-fold (range 1.7-9.8) and the peak plasma concentration 1.6-fold compared with placebo. The mean half-life of budesonide was prolonged from 1.6 to 6.2 hours. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole compared with placebo, with a 43 reduction in the AUC of plasma cortisol from 0.5 to 10 hours and a 12 reduction in the cortisol concentration measured 23 hours after budesonide, at...


Methylprednisolone The effects of oral itra-conazole (400 mg on the first day then 200 mg day for 3 days) on the pharmacokinetics of a single oral dose of prednisolone 60 mg or methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study (36c). Plasma cortisol concentrations were determined as a pharmacodynamic index. Itraconazole significantly increased the mean AUC of methylprednisolone from 2773 to 7011 h.ng ml and the half-life from 3.2 to 5.5 h. The disposition of prednisolone was unchanged. Cortisol concentrations at 24 hours were significantly lower after the administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 vs. 109 ng ml). The interaction of methylpred-nisolone with itraconazole is probably due to inhibition of hepatic CYP3A4 by itraconazole.


Inhaled budesonide has been studied in the management of moderately severe, acute asthma in children (24). After treatment with nebulized terbutaline, 11 children were randomly allocated to receive one dose of either budesonide 1600 micrograms by Turbuhaler or prednisolone 2 mg kg. There was no significant difference in the improvement of the pulmonary index score or peak expiratory flow rate. Children treated with budesonide had an earlier clinical response than those given predni-solone. Prednisolone caused a fall in serum cortisol concentration. The authors concluded that children with moderately severe asthma attacks could be effectively treated with a short-term course of inhaled budesonide, starting with a high dose and reducing over the following week.

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