Interindividual variation in the pharmacokinetics of Delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9.

The impact of the CYP2C9 polymorphism on the pharmacokinetics of orally administered 9-tetrahydrocannabinol (THC) was studied in 43 healthy volunteers. THC pharmacokinetics did not differ by CYP2C9*2 allele status. However, the median area under the curve of THC was threefold higher and that of 11-nor-9-carboxy-9-tetrahydrocannabinol was 70% lower in CYP2C9*3/*3 homozygotes than in CYP2C9*1/*1 homozygotes. CYP2C9*3 carriers also showed a trend toward increased sedation following administration of THC. Therefore, the CYP2C9*3 variant may influence both the therapeutic and adverse effects of THC.

[Pain therapy in addicted patients]. / Schmerztherapie bei suchtmittelabhängigen Patienten.

Each individual is entitled to an adequate and sufficient pain therapy. However, only a few studies have examined the peculiarities of pain management in drug-dependent or formerly addicted patients. Any addiction is disadvantageous for a successful pain therapy, since some of the prescribed drugs may themselves cause addiction. Drug-dependent patients are often tolerant to opioids. Additionally, there is a risk of iatrogenic pain becoming chronic due to disregard for already known risk factors and comorbidities. However, a history of addiction should not prevent sufficient pain therapy, especially since there is no risk of addiction when the pain therapy employed is adequate for the pathophysiology involved. There are adequate pain therapies for addicted patients. The best results are achieved by taking into account the physiological and psychological peculiarities of drug-dependent patients. Importantly, this should be combined with a variety of different, optimized, multimodal therapeutic regimes, as well as with an interdisciplinary approach.

Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain.

Using immunohistochemistry, expression of erythropoietin (EPO), a hypoxia-inducible neuroprotective factor, and its receptor (EPOR) were investigated in human brain tissue after ischemia/hypoxia. Autopsy brains of neuropathologically normal subjects were compared to those with ischemic infarcts or hypoxic damage. In normal brain, weak EPO/EPOR immunoreactivity was mainly neuronal. In fresh infarcts, EPO immunoreactivity appeared in vascular endothelium, EPOR in microvessels and neuronal fibers. In older infarcts reactive astrocytes exhibited EPO/EPOR immunoreactivity. Acute hypoxic brain damage was associated with vascular EPO expression, older hypoxic damage with EPO/EPOR immunoreactivity in reactive astrocytes. The pronounced up-regulation of EPO/EPOR in human ischemic/hypoxic brains underlines their role as an endogenous neuroprotective system and suggests a novel therapeutic potential in cerebrovascular disease for EPO, a clinically well-characterized and safe compound.

Death attributed to methadone.

Besides its other effects, MMT (methadone maintenance treatment) reduces the high mortality of intravenous heroin addicts to about 30% of controls. On the other hand, deaths of patients and non-patients have been attributed to methadone. Here, we will report on the major reasons for deaths attributed to methadone and discuss suggestions for their prevention. 69% of deaths attributed to methadone occurred in subjects not on MMT at the time of their death. 51% of deaths attributed to methadone in subjects in MMT occurred during the dose-finding period of MMT. Further apparent risk situations are methadone intake in addition to that received for MMT, discharge from prison and intravenous injection of methadone. Intake of methadone in non-patients is almost entirely due to abuse of diverted take-home methadone. Not giving methadone as take-home should reduce methadone deaths most effectively. Replacing take-home methadone by substances acting longer than one day, such as LAAM (levacetylmethadol) or buprenorphine, should also be effective. Restriction of take-home prescriptions to substances with a slow onset of action, such as LAAM, or to partial agonists with an extended safety margin such as buprenorphine should be partly effective. Meticulous evaluation of substance history, slow dose increases and strict supervision of the patient by experienced personal should prevent methadone overdose during the dose-finding period. Discharge from prison closely corresponds to this situation; informing addicts shortly before discharge and psychosocial help during the first months out of prison may reduce this risk. Naloxone as an adjunct to oral agonist preparations should effectively prevent high-risk intravenous injection, for example of methadone syrup. This has been the case with tilidine plus naloxone in Germany. Reducing deaths attributable to methadone increases the net benefit of MMT. Also, reducing deaths attributable to methadone avoids decreases in the public acceptance of MMT.

[Follow-up study after enteral manganese poisoning: clinical, laboratory and neuroradiological findings]. / Verlaufsbeobachtung nach enteraler Manganintoxikation. Klinische, laborchemische und neuroradiologische Befunde.

Manganese intoxication is an unusual, severe form of intoxication. This report deals with a patient now 80 years old who accidentally ingested a solution of potassium permanganate for a period of at least 4 weeks 14 years ago. Since then, the patient suffers from a mild parkinsonian syndrome and distally accentuated polyneuropathies. Psychiatric disorders, especially demential or depressive symptoms, were not observed. Manganese analysis of his hair still shows a clear increase in manganese concentration. The MRI of his brain showed no pathological changes, in particular none of those often described with symmetric signal elevation in T1 in the area of the basal ganglia. In this study, we present clinical, laboratory, and neuroradiological findings. Unusual in this case with a short exposition is the long duration and clinical improvement without L-dopa treatment.

Haematological abnormalities in early abstinent alcoholics are closely associated with alterations in thrombopoietin and erythropoietin serum profiles.

Numerous reports exist on haematological pathology in alcoholism. However, no data are available regarding a potential involvement of haematopoietic growth factors in the recovery from alcohol-induced haematological abnormalities upon abstinence. Therefore, thrombopoietin (TPO) and erythropoietin (EPO) serum levels along with haematological and other routine laboratory parameters were closely followed in 14 thoroughly characterized male alcoholic patients over one to five months of controlled abstention from alcohol. Haematological changes in these early abstinent alcoholics consisted predominantly of (a) the well known rebound surge of platelets, (b) an early reticulocyte peak, and (c) persistently low haematocrit levels over months without signs of recovery. Observations on EPO and TPO during early abstinence can be summarized as follows: (1) Increased TPO levels precede the rebound thrombocytosis by several days, (2) both EPO and TPO concentrations are higher in anaemic than in nonanaemic alcoholics, with (3) nonanaemic subjects exhibiting levels of TPO in the range of healthy controls but levels of EPO below controls and (4) TPO concentrations show a stronger correlation with initial haematocrit values than with thrombocyte counts. To conclude, haematological recovery in early alcohol abstinence appears to be, at least in part, growth factor-driven, involving both TPO and EPO, and may reflect an intense interaction of erythro- and thrombopoiesis.

Specific attentional dysfunction in adults following early start of cannabis use.

RATIONALE AND OBJECTIVE: The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. METHODS: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physical examination, analysis of routine laboratory parameters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. RESULTS: Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49). CONCLUSIONS: These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.

Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics during early and medium term abstinence.

In alcoholics, disturbances of the autonomic nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (i.v.) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, i.v. human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n = 11) versus healthy men (n = 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to i.v. CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to i.v. CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to i.v. CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.

OLITA: an alternative in the treatment of therapy-resistant chronic alcoholics. First evaluation of a new approach.

The Outpatient Long-term Intensive Therapy for Alcoholics (OLITA) is a four-step program of care for severely affected chronic alcoholics which, after inpatient detoxification, extends over a total of 2 years. High-frequency short-term individual therapeutic contacts, initially daily, are followed by a slow tapering of individual contact frequency and resolve in a group session once weekly towards the end of the second abstinent year. Further elements of OLITA are: (a) induction of alcohol intolerance by the application of aldehyde dehydrogenase inhibitors; (b) introduction of control factors, i.e. controlled intake of deterrent medication and regular urine analysis for alcohol; and (c) allocation of responsibility to the patient with respect to the overall success of the therapeutic concept including his own physical rehabilitation. Thus far, 30 male alcoholic patients from two recruitment periods have been treated for 6-26 months with a success rate of 60% abstinent patients. In conclusion, OLITA, based on the gradual tapering of high-frequency therapeutic contacts, thus far unique among outpatient programs for alcoholics, represents a promising advance in the treatment of therapy-resistant chronic alcoholics.

Sustained elevation of vasopressin plasma levels in healthy young men, but not in abstinent alcoholics, upon expectation of novelty.

The role of vasopressin (AVP) as a stress hormone in man is still a matter of controversy. Thus, the response of plasma AVP, among other hormones, to either intravenously injected human corticotropin releasing factor (hCRF, in the absence or presence of the opioid antagonist naloxone) or a combined 5-minute stress test was compared in healthy men (n = 10) and short-term abstinent alcoholics (n = 11), a group with recognized abnormalities of humoral stress parameters. Stimuli were applied blindly and in random order, one per day, in a 3-day experimental block. A second block using the same standardized protocol was carried out 12 weeks later. Alcoholics entered block I 8 days after the last ethanol ingestion. Up to block II, they were strictly controlled for abstinence. On each experimental day, subjects remained supine from 0700h until 1500h. Stimuli were applied alternatively at 1030h each day. Fourteen blood samples were drawn per day with simultaneous fluid substitution. There were no significant changes in plasma AVP as an acute response to any of the stimuli in either group or block. However, unexpectedly, controls had significantly higher basal AVP levels throughout block I as compared with block II without concomitant changes in plasma osmolality or blood pressure. Further analysis of the data revealed that the dramatically increased AVP levels of the five younger control subjects accounted for this difference. In fact, AVP levels in the five older healthy subjects and in all alcoholics remained low throughout the two blocks. Our data suggest that plasma AVP is continuously elevated in healthy young men upon anticipation of novelty. In contrast, healthy men of the older age group and early abstinent alcoholics seem to lack such a sustained AVP response.

Effects of chronic treatment with methadone and naltrexone on sleep in addicts.

Previous studies have described sleep disturbance secondary to chronic opiate use and abuse. Drug-dependency insomnia is of interest because chronic sleep disturbances can promote depressive symptoms which could lead to a drug relapse. For the first time we compared the polysomnographic parameters of 10 methadone-substituted outpatients and 10 naltrexone-treated outpatients. Methadone (mu-opioid agonist) produced a marked fragmentation of the sleep architecture with frequent awakenings and a decrease in EEG arousals. In comparison with methadone and controls, the naltrexone (mu-opioid antagonist) group showed the shortest sleep latency and the longest total sleep time. These data indicate that mu-agonists and mu-antagonists have different effects on sleep. The implications, especially the involvement of opioid-dopamine interactions on sleep and movements during sleep, are discussed.

Mortality in patients with dependence on prescription drugs.

In 1974 we started a follow-up of patients with different psychoactive substance use disorders (PSUD) according to DSM-III; 2082 cases out of 2127 were analyzed; 1370 patients had taken legal drugs (i.e. prescription drugs and/or over-the-counter drugs); 444 patients suffered from abuse or dependence of legal drugs alone; 678 combined legal drugs and ethanol, and 248 cases combined legal and illegal drugs, often together with ethanol. A group of 712 alcoholics were included for comparison. Mean time under observation was 6.5 +/- 5.4 years, and 269 patients died. Mortality and survival were calculated and compared with expected survival from the normal population of the former Federal Republic of Germany. Mortality in all subgroups of PSUD was increased, the standardized mortality ratio (SMR) for patients on legal drugs alone being 2.1. Patients with legal plus illegal drugs had a SMR as high as 20.7; those with legal drugs plus ethanol 3.4; and alcoholics 4.2. The increased mortality seemed to be constant over the years. Mortality decreased in patients with stable abstinence. There was no clear sex difference. Abuse had a better prognosis than dependence. An estimation of potential life lost by the different PSUDs was attempted. Patients on legal drugs died from suicides, malignancies or accidents (including intoxication). In alcoholics or patients on legal drugs plus ethanol malignoma, liver cirrhosis, accident and suicide were the most prominent causes of death.

Auditory and visual influences on phonemic restoration.

Phonemic restoration was studied using a version of Samuel's (1981a) psychophysical paradigm. We examined the influence of specific acoustic correlates of voicing and place of articulation on phonemic restoration (d') and response bias (Beta). The influence of a higher-level, phonotactic constraint was also examined. All of the stimuli were presented in both auditory-only and auditory-visual conditions, allowing the investigation of potential benefits of vision on phonemic restoration. The results support the predictions of an interactive-activation model, combining both top-down and bottom-up factors. As predicted, voicing and place of articulation significantly affected d': Voiceless stop consonants received greater restoration than voiced stops, and alveolar stops were less restorable than bilabial and velar stops. The phonotactic, top-down constraint affected neither d' nor Beta. Visual information, however, appeared to reduce the bias to report an item as intact.