harmine and Alcoholism

Ayahuasca is a hallucinogenic botanical mixture originating in the Amazon area where it is used ritually, but is now being taken globally. The 2 main constituents of ayahuasca are N,N-dimethyltryptamine (DMT), a hallucinogen, and harmine, a monoamine oxidase inhibitor (MAOI) which attenuates the breakdown of DMT, which would otherwise be broken down very quickly after oral consumption. Recent developments in ayahuasca use include the sale of these compounds on the internet and the substitution of related botanical (anahuasca) or synthetic (pharmahuasca) compounds to achieve the same desired hallucinogenic effects. One intriguing result of ayahuasca use appears to be improved mental health and a reduction in recidivism to alternate (alcohol, cocaine) drug use. In this review we discuss the pharmacology of ayahuasca, with a focus on harmine, and suggest pharmacological mechanisms for the putative reduction in recidivism to alcohol and cocaine misuse. These pharmacological mechanisms include MAOI, effects at 5-HT(2A) and imidazoline receptors and inhibition of dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A) and the dopamine transporter. We also speculate on the therapeutic potential of harmine in other CNS conditions.

Topics: Alcoholism; Animals; Banisteriopsis; Cocaine-Related Disorders; Harmine; Humans; Monoamine Oxidase Inhibitors; N,N-Dimethyltryptamine; Secondary Prevention

Specific laboratory tests can be used to identify patients who are alcohol-dependent. The laboratory values of a number of biological 'markers', including carbohydrate-deficient transferrin, are often elevated in cases of chronic and acute alcohol abuse. Trait markers reflect a predisposition for alcoholism; state markers reflect actual alcohol consumption. It has been suggested that state markers can be subdivided into screening and relapse markers, and even further subdivided into pre-relapse markers, i.e. craving markers. We hypothesize that methanol metabolism and the presence of condensation products in the blood may serve as state and pre-relapse markers for alcoholism. Since the sensitivities and specificities of laboratory screening tests vary, and an absolute marker for alcoholism has yet to be identified, research in the area of biological markers for alcoholism should continue.

Topics: Alanine Transaminase; Alcoholism; Aspartate Aminotransferases; Biomarkers; Carbolines; Erythrocyte Indices; Harmine; Humans; Sensitivity and Specificity; Transferrin

We examined the effects of ethanol ingestion to rats on levels of the beta-carboline norharman in plasma, brain and liver at the end of ethanol ingestion and 10 h after withdrawal. We also investigated the effect of exogenously administered norharman on the behavioural signs of alcohol withdrawal. Ethanol was given by a liquid diet for 21 days. Norharman plasma levels in alcohol fed rats were significantly elevated compared to both control rats and to rats 10 h after withdrawal. Norharman levels in brains and livers showed a similar pattern. The capacity of the livers of both alcohol-dependent and withdrawal rats to catabolise norharman was significantly reduced compared to control rats. Norharman injected intraperitoneally (6.3 mg/kg) attenuated the behavioural signs of alcohol withdrawal significantly. The mechanism behind the increased norharman levels in alcohol-dependent rats may be inhibition of the synthesis and/or activity of liver enzyme(s) responsible for the breakdown of norharman.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Carbolines; Central Nervous System Depressants; Ethanol; Half-Life; Harmine; Liver; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Plasma norharman and harman levels were measured by solvent extraction and HPLC with fluorescence detection in alcohol-dependent patients undergoing in-patient abstinence treatment and in control subjects. In both groups, randomly collected samples from smokers contained higher mean norharman levels than those from non-smokers. In three volunteers norharman concentrations rose sharply after smoking of one or two cigarettes and declined to near-basal levels within one hour after one cigarette. When 12 patients kept a smoking-free interval of at least 6 h, they had similarly low plasma norharman concentrations (20 +/- 8 pg/ml) as 18 non-smoking control subjects (17 +/- 8 pg/ml) or as 13 smoking controls who had abstained from smoking (20 +/- 6 pg/ml). Ten of the patients smoked one cigarette and within 5-10 min attained norharman levels of 177 +/- 147 pg/ml plasma. The high prevalence of smokers among chronic alcoholics probably explains the previous finding of elevated norharman plasma levels in these patients.

Topics: Adult; Alcoholism; Carbolines; Chromatography, High Pressure Liquid; Female; Harmine; Humans; Male; Middle Aged; Nicotiana; Plants, Toxic; Smoking; Spectrometry, Fluorescence

In the search for mechanisms specific for alcoholism, it has become evident that beta-carbolines (BCs; e.g., harman and norharman) are compounds that may act on brain reward systems, thereby mediating an increase in voluntary ethanol (ETOH) drinking in animals. This study was undertaken to analyze relationships between these compounds and clinical variables (e.g., family history, personality data, and affect) in alcoholics and to trace the time course of blood concentrations in subjects abstaining from alcohol for at least 6 months. Nonalcoholics were investigated during sober and ETOH-loading conditions (1 g ETOH/kg body weight). Levels of harman were elevated in the chronically intoxicated alcoholics and correlated with the scores on the self-rating depression (SDS) and the self-rating anxiety (SAS) scales. The group of alcoholics with at least one alcoholic parent had higher levels than the group without such a history. Levels remained elevated for 6 months. Norharman levels were only slightly elevated on the day of admission. They were correlated to high harm avoidance and SDS scores. A family history of alcoholism and the severity of alcoholism as assessed by the number of ICD-10 criteria fulfilled were correlated with norharman levels. Long-term observation revealed elevated levels of norharman after 3 months of abstinence, but not after 6 months. The association of harman levels with anxiety and depression demonstrated in the present study suggests that alcoholics with high harman levels use alcoholic beverages as self-medication in an attempt to overcome possible anxiogenic/depressiogenic actions of harman. Norharman levels are less strongly associated with these mood states, but significantly correlated to harm avoidance tendencies. It has been suggested that the activity of the indolergic neurons is relatively high in individuals with a high harm avoidance score. Biosynthesis of norharman might be stimulated under these conditions (tryptamine serves as precursor).

Topics: Adult; Alcoholism; Anxiety; Carbolines; Depression; Ethanol; Harmine; Humans; Male; Middle Aged; Motivation; Self Medication

A growing number of studies have implicated the hypothalamic-pituitary-adrenal (HPA) axis in acute and chronic alcoholization and in ethanol withdrawal. In order to study the ethanol/HPA axis interaction during alcohol withdrawal, we performed experiments using adrenalectomized (ADX) male rats alcoholized by a chronic pulmonary alcoholization procedure. Eight hours after the 3 weeks of the alcoholization procedure, the rats were evaluated for a tremor activity. In order to reduce the great variability of the withdrawal tremors, we estimated the supersensitivity of the withdrawn rats to the tremorogenic compound harmine. We also studied the effect of a hydrocortisone treatment given in the drinking bottle during the alcoholization procedure on the harmine-induced tremors of ADX and sham rats. Alcohol withdrawal resulted in increased tremor response to 10 mg/kg harmine, and a protective effect of adrenalectomy on this effect was observed. Hydrocortisone administration to ADX or sham rats did not affect the tremor profile of the alcohol withdrawn rats.

Topics: Adrenal Glands; Adrenalectomy; Alcohol Withdrawal Delirium; Alcoholism; Animals; Harmine; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Rats; Rats, Wistar

Animal experiments suggest that endogenous substances that could result from the interaction between neurotransmitters (dopamine and indoleamines) and ethanol and its metabolite acetaldehyde might be involved in the pathogenesis and maintenance of alcohol dependence. Therefore, aromatic beta-carbolines (norharman and harman) were investigated repeatedly in 24-hr urine of 13 male severe alcoholics without any psychiatric comorbidity during a controlled inpatient abstention program of up to 8 weeks. Harman excretion was approximately 2-fold above levels in control subjects, with a steady decline after 3 weeks of abstinence and lower levels in patients with a longer duration of alcohol dependence. Severity of withdrawal symptoms and actual feelings of anxiety/depression were negatively associated with urinary harman excretion. Positive associations could be established with daily ethanol consumption the month before admission and the score on the scale "reward dependence" according to Cloninger's Tridimensional Personality Questionnaire. Moreover, patients without alcohol-dependent first-degree relatives and higher "reward dependence" exhibited an increased excretion of harman. Therefore, harman levels might characterize a distinct subgroup of alcoholic patients, who in part resemble the so-called type l alcoholics of Cloninger. However, this awaits further study in a larger number of individuals. In contrast, norharman excretion was elevated up to 6-fold, compared with nonalcoholics over 6 to 8 weeks of controlled abstention. No correlations to demographic or clinical variables could be observed. Therefore, increased norharman levels might be proposed as a "residual marker" or a trait variable. Whether the observed changes are specific markers of at least certain aspects of alcoholism or dependence remain to be elucidated.

Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Biomarkers; Carbolines; Harmine; Humans; Male; Middle Aged; Motivation; Patient Admission; Personality Inventory; Treatment Outcome

Both physical rehabilitation and the course of the alcoholism improve after orthotopic liver transplantation (OLT) in patients with end-stage alcoholic liver cirrhosis. In the present study including 17 alcoholics and 14 nonalcoholics, after OLT, three of the alcoholic patients resumed their pre-OLT alcohol drinking habits, 4 consumed alcohol occasionally, 10 remained abstinent over the observation period of 13 to 36 months. The laboratory parameters before OLT did not discriminate alcoholics from nonalcoholic patients. Furthermore, the blood levels of two so-called alcogens (harman and norharman) were determined to investigate whether they discriminate between the two groups. Alcogens are natural compounds that are presumed to induce alcohol abuse in predisposed individuals. Both alcogens measured were elevated in plasma from nonalcoholics and alcoholics before OLT, suggesting a disturbance in inactivation in end-stage liver disease. Following OLT, the alcogens normalized but in the alcoholics this process was slower with respect to harman. The present exploratory study suggests that the normalized metabolic capacity of the liver after OLT causes a normalization of the levels of alcogens, for which harman and norharman are representative. These changes could contribute to the observed benefit to the outcome in alcoholics with respect to the alcohol dependence.

Topics: Adult; Alcoholism; Analysis of Variance; Carbolines; Harmine; Humans; Liver Diseases, Alcoholic; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Neurotoxins; Time Factors

The prevalence of chronic alcoholism in patients with carcinomas of the upper digestive tract exceeds 60%. The patient's history and laboratory markers, preoperatively, are often not sensitive or specific enough to detect alcohol-dependent patients, preoperatively, who are at risk of developing alcohol withdrawal syndrome (AWS) during their postoperative intensive care unit (ICU) stay. Previously, it was found that plasma norharman was elevated in chronic alcoholics, suggesting marker characteristics for chronic ethanol misuse and possibly alcohol dependence. We investigated whether beta-carbolines (i.e., harman and norharman) were different between chronic alcoholics and nonalcoholics with carcinoma, and how the levels change in alcohol-dependent patients during their hospital stay. Ninety-seven patients with oral, pharyngeal, laryngeal, or esophageal carcinomas were evaluated regarding their drinking habits. Sixty patients were transferred to the ICU following tumor resection. Chronic alcoholics met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use. The daily ethanol intake in chronic alcoholics was > or = 60 g. Blood samples were collected on admission to the hospital, preoperatively, on admission to the ICU and on days 2, 4, and 7 in the ICU. Harman and norharman were determined by HPLC. Elevated norharman was found in chronic alcoholics on admission to the hospital, whereas harman did not differ between groups. On admission, the area under the receiver operating characteristics curve was significantly larger for carbohydrate-deficient transferrin and preoperatively for norharman. The preoperative norharman levels were significantly correlated with the period of mechanical ventilation and the length of ICU stay. Postoperatively, norharman decreased in all patients, except a group of 11 alcohol-dependent patients who developed AWS during their ICU stay. The finding that elevated norharman levels were found in chronic alcoholics on admission to the hospital and preoperatively supports the view of a specific marker for alcoholism. Preoperative norharman was superior to carbohydrate-deficient transferrin and was associated with a prolonged ICU stay and a prolonged period of mechanical ventilation. Further studies are required to determine whether norharman aids in the preoperative diagnosis of chronic alcohol misuse with respect to the prevention of postoperative complications.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Biomarkers; Carbolines; Critical Care; Esophageal Neoplasms; Harmine; Humans; Male; Middle Aged; Otorhinolaryngologic Neoplasms; Postoperative Complications; Risk Factors

1. Rats given a 10-% (v/v) alcohol liquid diet over long periods of time reach high blood alcohol levels of more than 200 mg/dl over several weeks. 2. Repeated discontinuation of the alcohol intake resulted, each time within 8 hr, in several withdrawal reactions including a reduction in exploratory behaviour and tremorogenic activity. 3. The inhibition of exploratory activity was measured in a neutral two-chamber model, both in terms of the number of transits into the open area as well as the time spent in the open space. The differences in exploration remained over the 4 successive withdrawal tests. 4. Rats in alcohol withdrawal were also consistently less active than control animals in the tremor cages equipped with a piezofilm floor, and this despite the presence of a clearly visible tremor in the hindpaws when lifted up. 5. Alcohol withdrawal rats revealed a more frequent tremor activity than controls after a challenge with 5 mg/kg harmine. This effect was independent of the length of the tremor bursts used to quantify harmine-induced tremor starting from the second withdrawal period onwards. 6. With a dose of 10 mg/kg harmine, ceiling effects were reached in both the alcohol withdrawal and control rats and differences between the two groups were only present during the first exposures. 7. Overall, these results indicate that it is possible to quantify some withdrawal reactions at repeated time intervals of alcohol cessation in rats chronically exposed to a 10-% alcohol liquid diet. As a consequence, these withdrawal reactions can be studied in a more systematic way.

Topics: Alcoholism; Animals; Behavior, Animal; Diet; Ethanol; Exploratory Behavior; Harmine; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Tremor

Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism, aromatic beta-carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC), newly developed radioreceptor assays, and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 +/- 26.6 pg/ml vs. 26.9 +/- 10.7 pg/ml; p less than 0.001) and did not change significantly during a 3-week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis, a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.

Topics: Adolescent; Adult; Alcoholism; Carbolines; Chromatography, High Pressure Liquid; Ethanol; Female; Follow-Up Studies; Harmine; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychopathology; Substance Withdrawal Syndrome

Based on the hypothesis of a relationship between the concentration of trace amines like tetrahydroisoquinolines (TIQ's) and beta-carbolines (BC's) in the brain and an increased voluntary ingestion of ethanol, the concentrations of ethanol, acetaldehyde and harman (a beta-carboline) were examined in a group of 20 alcoholics. The patients excreted a higher amount of harman into the urine than non-alcoholics on the day of admission (harman-1) as well as at the end of the detoxication period, 14 days later (harman-14). Certain factors were related to the increased excretion of harman by alcoholics: The younger the patient when he/she consumed ethanol for the first time, the higher the concentration of acetaldehyde in the blood and the amount of harman (harman-14) excreted in the urine. Furthermore, the younger the patient when he/she was intoxicated with ethanol for the first time the higher the amount of harman (harman-14) in the urine. Patients with first grade relatives who were alcoholics excreted more harman (harman-14) than those without such relatives. The following variables were not related to harman-14: The average amount of ethanol consumed daily during the 6 months prior to admission, the presence of signs of intoxication and symptoms of withdrawal at admission to hospital, and the consumption of other psychotropic substances. A negative correlation was found between the state of the liver, as assessed by liver histology and gamma-glutamate transferase (gamma-GT) levels, and the concentration of harman in the urine. Thus, some events in the patient's history as well as the state of the liver are important for the increased excretion of harman into urine of alcoholics.

Topics: Acetaldehyde; Adult; Alcoholism; Alkaloids; Analysis of Variance; Ethanol; Female; gamma-Glutamyltransferase; Harmine; Humans; Liver; Male; Middle Aged

Topics: Acetaminophen; Alcoholism; Animals; Biotransformation; Cytochrome P-450 Enzyme System; Glutathione; Harmine; Humans; In Vitro Techniques; Kidney; Liver; Male; Rats; Sulfhydryl Compounds