Subacute Withdrawal Research Articles

Differences in serum orexin-A levels between the acute and subacute withdrawal phases in individuals who use methamphetamine.

Orexin has been suggested to play a role in regulating the reward circuits and enhancing drug-seeking behaviors; however, its role in methamphetamine (METH) addiction remains unclear. We previously found that blood orexin-A levels are upregulated in individuals with recent METH exposure. Whether the levels would be altered following withdrawal is unknown. In this study, we compared the levels of serum orexin-A in individuals who use METH between the acute withdrawal (AW) phase and the subacute withdrawal (SAW) phase at baseline (T1) and examined the alterations in these levels after 2 weeks of abstinence (T2). In total, 60 participants (51 men and 9 women) were enrolled in the study; 20 participants with METH-positive urine test results were included in the AW group, and 40 participants with METH-negative urine test results who had self-reportedly last taken METH within the preceding 1-2 months were included in the SAW group. Serum orexin-A levels were measured using enzyme-linked immunosorbent assay. No significant differences in orexin-A levels were observed between the AW and SAW groups at baseline (p = .06). After 2 additional weeks of abstinence, the levels decreased significantly in the SAW group (0.58 ± 0.13 ng/mL) but not in the AW group (0.50 ± 0.14 ng/mL, p = .004). Our results demonstrated that orexin-A levels might decrease after a longer period of METH withdrawal, indicating that the orexin system is dysregulated in the addictive process of METH. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cocaine withdrawal enhances pentobarbital-induced sleep in rats: Evidence of GABAergic modulation

We intended to clarify whether pentobarbital-induced sleep in rats is affected during cocaine withdrawal and whether GABAergic systems are involved in this sleep. Cocaine (20 mg/kg) was administered subcutaneously (s.c.) to rats once per day for 6 days. Pentobarbital (42 mg/kg) was administered intraperitoneally (i.p.) to the rats 1 day (acute withdrawal), 8 days (subacute withdrawal), or 14 days (subchronic withdrawal) after withdrawal from cocaine. All rats were fasted for 24 h prior to the pentobarbital injection. Pentobarbital-induced sleeping time was significantly increased during both acute and subacute withdrawal, while sleeping onset latency was not affected. However, sleeping time recovered to normal 14 days after withdrawal. Protein levels of GABA A receptor γ-subunits and glutamic acid decarboxylase (GAD) were increased in both acute and subacute cocaine withdrawal in the hypothalamus, but were normal after 14 days of withdrawal. These results indicate that pentobarbital-induced sleeping time in cocaine withdrawal is transiently increased. Hypersomnia in cocaine withdrawal might be influenced by functional changes in the GABAergic systems.

Sleep Electroencephalographic Spectral Power After Withdrawal from Alcohol in Alcohol‐Dependent Patients

Dysfunctional hyperarousal is suspected to be a neurophysiological determinant of relapse in abstinent alcohol-dependent patients. In the present study, we used spectral power analysis of the sleep electroencephalographic (EEG) to quantify brain activity during sleep in patients during subacute withdrawal as well as in control subjects. Our hypothesis was that the subgroup of patients who relapsed within the 3 months to follow-up would exhibit-increased dysfunctional arousal manifested by higher-frequency (beta) EEG power during sleep. Twenty-six alcohol-dependent in-patients were examined with polysomnography over 2 nights 2 to 3 weeks after withdrawal. At the 3-month clinical follow-up assessment, 12 of them had relapsed and 14 abstained. The control group consisted of 23 healthy subjects similar to the patients with alcohol dependence in age and gender distribution. Spectral sleep EEG analysis was performed on both nights (adaptation and baseline) of all subjects. Logarithmic artifact-controlled spectral band power of sleep stage 2 and rapid eye movement (REM) sleep was analyzed for Group, Gender, and Age effects using multiple analyses of covariance. Three groups were compared with the Group factor: relapsers, abstainers, and controls. Generally, both Group and Age effects were significant for the second, baseline night for the visually scored sleep parameters, while spectral EEG parameters showed significant differences in the adaptation night. In the adaptation night, a significant enhancement in the beta2 band (24-32 Hz) was seen in REM sleep in relapsers relative to both abstainers and controls. The beta2 increase could be interpreted as a sign of dysfunctional arousal during REM sleep "unmasked" by the additional stressor of sleep environment adaptation. Its determinants are likely to be both premorbid and drinking history related.

Family history of alcoholism and cognitive recovery in subacute withdrawal

A family history of alcoholism has been demonstrated to be an important factor affecting cognitive function. However, no studies have yet been conducted to compare cognitive recovery of family history-positive (FH+) and family history-negative (FH-) alcoholics in the subacute withdrawal period. To tackle this problem, a neuropsychological test battery consisting of six computerized tests was administered to 19 FH+ and 20 FH- alcoholics at 2 and 7 weeks after abstinence. At 2 weeks after abstinence, overall performance of both FH+ and FH- groups was significantly poorer than that of healthy controls. At 7 weeks, these performances tended to recover, but in Trail Making A and Figure Position, performances of FH+ alcoholics remained worse than those of controls, while those of FH- alcoholics did not. Thus cognitive recovery during the subacute withdrawal period was worse among FH+ alcoholics than FH- alcoholics, and this finding should be considered when planning alcohol rehabilitation programs.

Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: Evidence for opioid receptor modulation

In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic–pituitary–adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic–pituitary–adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) “binge” pattern cocaine administration (45mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic–pituitary–adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic “binge” cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic–pituitary–adrenal tolerance developed with chronic “binge” cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic–pituitary–adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.

Magnesium Treatment of Primary Alcohol‐Dependent Patients During Subacute Withdrawal: An Open Pilot Study With Polysomnography

Sleep electroencephalogram alterations and insomnia complaints persist after alcohol withdrawal in dependent patients and are considered strong predictors of relapse. Although disturbances of magnesium household due to alcohol consumption are well known, the relationship of magnesium metabolism and sleep disturbances has not been investigated in this patient group. We conducted an open pilot study to evaluate the effects of magnesium treatment on the sleep of primary alcohol-dependent patients during subacute withdrawal. Patients were treated with 30 mmol magnesium daily over 4 weeks. Eleven of the 14 included patients were evaluated. Patients were free of any kind of psychotropic medication or other substances known to influence sleep. Polysomnographic recordings with monitoring of periodic leg movements in sleep (PLMS) were performed for two consecutive nights 2 weeks after acute withdrawal (baseline) and 4 weeks later at the end of the treatment period. After the baseline polysomnography, patients were investigated by the magnesium loading test to verify magnesium depletion. We found a significant decrease of sleep onset latency from 40.6 to 21.7 min (p = 0.03) and a significant improvement of subjective sleep quality, as assessed by the Pittsburgh Sleep Quality Index, from 8.1 to 5.8 (p = 0.05) during magnesium treatment. Changes in PLMS indices revealed two subgroups of patients: one with an increase of PLMS from 30.7 to 39.4 per hour of sleep (n = 4) and the other one with a decrease of PLMS from 8.9 to 2.1 per hour of sleep (p = 0.04). Patients with PLMS decreases seemed to have a more favorable prognosis: total sleep time, gamma-glutamyltransferase, carbohydrate-deficient transferrin, and Beck Depression Inventory scores improved significantly during treatment in this group. The magnesium loading test revealed a magnesium deficiency in only one patient, five patients showed normal retention values, and the remaining five patients had an increased magnesium excretion, indicating a possible continued renal magnesium loss during abstinence. The results of this study should be interpreted with caution, because no control group with placebo was investigated. Both subjective and, partly, objective parameters of sleep improved during the 4-week study period. Further research is needed to clarify the relationship of magnesium metabolism and sleep alterations.

Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence

We hypothesized that stimulant abusers would sleep more and have more rapid eye movement (REM) sleep than primary alcoholics during acute withdrawal (first 10 days drug free) but would have opposite patterns during subacute withdrawal (days 11-14 drug free). We compared polygraphic sleep patterns during acute withdrawal (days 3-10) for 7 stimulant abusers and 8 alcoholics and during subacute withdrawal (days 11-14) for 7 different stimulant abusers and 8 different alcoholics. For comparison purposes, a group of normal controls from our preexisting database were matched for age and gender. Two statistically significant interactions were found: consistent with our hypothesis, stimulant abusers showed greater total sleep (TST) and REM sleep during acute withdrawal than subacute withdrawal, compared with alcoholics. In contrast, alcoholics showed less TST and REM sleep during acute withdrawal than during subacute withdrawal. Our polygraphic sleep data support the hypothesis that physiological withdrawal differs in alcoholics compared with stimulant abusers. Different mechanisms may underlie withdrawal in these two substances.

The effects of lisuride on mood and sleep during acute withdrawal in stimulant abusers: A preliminary report

Psychostimulant abusers often experience anhedonia, depression, fatigue, craving, and hypersomnia and increased propensity for rapid eye movement (REM) sleep during periods of acute and subacute withdrawal from cocaine and amphetamine. These signs and symptoms may reflect a state of relative functional dopamine depletion in the brain during abstinence. Lisuride, which has dopaminergic agonist effects, has been reported to reduce signs of psychostimulant withdrawal in rodent models of stimulant abuse. These observations prompted us to test the effects of oral administration of lisuride for 3 weeks (up to 4.0 mg daily) on mood and craving ratings in a double-blind, parallel design, controlled study in hospitalized stimulant abusers during acute withdrawal from cocaine or amphetamine. Although administration of lisuride significantly prolonged REM latency and reduced REM time, amelioration of other signs of withdrawal was not significantly greater in lisuride as compared with placebo treated patients. Self-rated craving ratings, however, were low in both groups throughout the hospital stay. Further studies, perhaps in patients with more severe symptoms during withdrawal, are needed to fully test the efficacy of lisuride in the treatment of stimulant withdrawal.

Effects of tetrabamate and of diazepam on sleep polygraphy during subacute withdrawal in alcohol‐dependent patients

AbstractWe have studied the effects of two anxiolytic drugs frequently prescribed in alcohol withdrawal, diazepam and tetrabamate, on sleep polygraphy of alcohol‐dependent patients hospitalized for alcohol detoxification. Twenty‐three inpatients (16 M and 7F) fulfilling the DSM 3R alcohol‐dependence criteria were included. Twelve patients were treated with tetrabamate and the other 11 with diazepam. Sleep polygraphy was carried out on average 15 days after alcohol withdrawal. The sleep of tetrabamate‐treated patients differs from that of diazepam‐treated patients in having a much longer duration of stage 4, at the expense mainly of stage 2. The two groups of patients had a greater total sleep time and duration of delta sleep than comparable untreated patients. These results suggest that the delta sleep deficit of abstinent alcoholics is paradoxically corrected by anxiolytic treatment. Tetrabamate seems to induce the production of delta waves during the sleep of abstinent alcoholics.

Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men

Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral, cognitive, and neurochemical changes observed following the cessation of heavy drinking, therefore, may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome, the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.

EEG sleep studies in “pure” primary alcoholism during subacute withdrawal: Relationships to normal controls, age, and other clinical variables

Electroencephalogram (EEG) sleep recordings were compared in 34 normal controls and 31 inpatients with relatively pure primary alcoholism who had been abstinent for about 17 days. Compared with normal controls, primary alcoholics took longer to fall asleep, slept less, and had poor sleep efficiency. Sleep loss reflected reduced non-rapid eye movement (NREM) sleep, especially stage 2 sleep, stage 4 sleep, and total delta (stage 3 and 4) sleep. Alcoholic patients had higher REM density of the first REM period. Sleep deteriorated with age in both normal controls and patients, with younger alcoholics showing sleep patterns typical of older controls. Among other clinical-demographic variables examined, the shorter the duration of sobriety at the time of the study, the later patients went to bed and fell asleep. The number of drinks per drinking day in the 3 months before admission was directly related to the duration of the first REM period. In addition, the maximum number of withdrawal symptoms the patient had ever experienced was inversely related to the amount of delta sleep. Sleep measures were not correlated with depression ratings, liver enzymes, or other measures of alcohol consumption.

Clinical conditions in alcoholics during long-term abstinence: A descriptive, longitudinal treatment study

After inpatient treatment for acute withdrawal during 1–2 weeks, twelve male alcoholics were treated as outpatients and received disulfiram per os. Clinical ratings using a scale with 14 items were performed three times a week during six months. After acute withdrawal had ceased, all patients had positive ratings for anxiety, sleeping problems and autonomic disturbances lasting for 4–8 weeks. They also scored for depressive symptoms, concentration difficulties and failing memory during this period. The following 8–12 weeks all patients but one had periods of mood changes with a duration of 1–3 weeks. During periods with low mood changes several other symptoms appeared, while other psychiatric symptoms were absent during periods with elevated mood. All relapses occurred in connection with periods of mood changes. To conclude, this rating scale made it possible to identify a protracted subacute withdrawal phase and phases characterized by changes of mood, depressive-astenic as well as hyperactive, during long-term abstinence. These clinical phases are suggested to be of importance for clinical treatment and research.

Studies on duration of a late recovery period after chronic abuse of ethanol. A cross-sectional study of biochemical and psychiatric indicators.

A cross-sectional study on patients with different abstinence time was performed to describe long-time biochemical and psychiatric changes due to withdrawal from heavy alcohol abuse. Physical, neurological, psychiatric and biochemical parameters were measured in 70 patients with a withdrawal period ranging from 2-90 days. The various parameters changed over time in different manners. Fatigability, reduced sleep, reduced sexual interest, apparent sadness, hostility and global ratings of abstinence improved significantly with the duration of the recovery period. Symptoms related to brain hyperexcitability such as fatigability, inner tension, insomnia and pains persisted for approximately 5 weeks. Of the biochemical parameters, the transaminases were normal in patients with more than 10 days of abstinence, while the levels of gamma-glutamyltransferase and HDL-cholesterol remained high for longer periods. The essential fatty acid status, measured by the fatty acid composition of serum lecithin, appeared to be normal only in patients with long recovery time. MAO in platelets was significantly lower than in the controls. The highest values were seen in the early recovery phase, which may indicate a temporary increase. Since polyunsaturated fatty acids are important constituents of synaptic membranes and since platelet MAO may reflect brain MAO, we consider these co-existing findings important in the interpretation of the psychiatric symptoms. The study demonstrated the existence of a subacute withdrawal syndrome lasting for 4-6 weeks.

Pseudo-Cushingʼs Syndrome

The mechanisms responsible for the genesis of pseudo-Cushing's syndrome are poorly understood. We studied the effect of acute ethanol administration on the hypothalamic-pituitary-adrenal axis in five chronic alcoholic patients and three normal volunteers. Ethanol was administered alone and together with beta 1-24 ACTH given intravenously. Baseline plasma ACTH and cortisol concentrations were significantly higher in the patients than in normal controls (p less than 0.05). Acute ethanol administration produced no significant change in the mean plasma ACTH concentration, failed to augment the effect of exogenous ACTH on the adrenal gland, and produced similar changes in the serum cortisol and aldosterone concentration in both the normal controls and the alcoholic patients. We speculate that pseudo-Cushing's syndrome may represent a state of stress-induced hypercortisolemia secondary to multiple episodes of subacute withdrawal from ethanol.

Persistence of a “subacute withdrawal syndrome” following chronic ethanol intake

Persistence of a “subacute withdrawal syndrome” following chronic ethanol intake

Early development of infants of heroin-addicted mothers.

The course of growth and development of 30 infants of heroin addicts was observed from 3 to 34 months. Eighty percent had signs of neonatal withdrawal, while 60% continued with subacute withdrawal signs for three to six months. Behavioral disturbances, predominantly hyperactivity, brief attention span, and temper outbursts, were identified in seven of 14 infants observed one year or longer, while two had neurological abnormality. Growth impairment was associated with behavioral disturbances in four of the seven. These disturbances appear to be unrelated to subsequent environmental factors. Infants performed at age-appropriate levels on developmental testing.