[Buprenorphine depot in opiate use disorder]. / Buprenorfinedepot bij een stoornis in het gebruik van opiaten.

BACKGROUND: Patients with opiate use disorder may be treated medicamentally with methadone and sublingual buprenorphine. However, also two forms of subcutaneous buprenorphine that can be administered weekly or monthly are available. AIM: To describe the effectiveness and the side effects of the buprenorphine depot. METHOD: Embase was searched and cross-references were sought in the included studies and previous reviews. RESULTS: Nine articles were included. One randomized study (n = 428) compared buprenorphine depot to the sublingual form, with the depot being more effective after 12-24 weeks. The other randomized study (n = 504) compared the depot with placebo. The depot was found to be effective. In two comparative non-blinded studies, no significant difference in abstinence was reported between the depot and sublingual administration. Medium-term effectiveness (16-52 weeks) was confirmed in five follow-up studies, in which the depot preparation proved both effective and well tolerated. CONCLUSION: The buprenorphine depot is described as promising in the international literature. However, there are still several uncertainties that make its prescription should be done with great caution.

[Cognitive behavioral therapy in combination with pharmacotherapy for adults with ADHD]. / Cognitieve gedragstherapie bij medica-menteuze behandeling van ADHD bij volwassenen.

BACKGROUND: Treatment options for attention deficit hyperactivity disorder (ADHD) in adults consist of psycho-education, cognitive behavioral therapy (CBT), pharmacotherapy or a combination thereof. AIM: To investigate the effect of CBT combined with pharmacotherapy on the quality of life in adults with ADHD compared to medication alone. METHOD: In this multicenter prospective cohort study a total of 627 patients were included, 305 where included in the medication only group and 322 in de combination group (CBT and medication). The Adult ADHD Quality-of-Life scale (AAQoL) was conducted at baseline and at the end of treatment. RESULTS: The quality of life as measured by the AAQoL increased significantly in both groups but was not significantly different between the two groups (p = 0.33). CONCLUSION: To our knowledge, this is the first study to describe the effect of CBT as an addition to ADHD drug therapy on the quality of life in adults. Contrary to our expectations, there was no significant effect of CBT as an addition to drug therapy on the quality of life.

[Nabiximols as a substitute for cannabis]. / Nabiximols als substituut voor cannabis?

Cannabis addiction is worldwide one of the most prevalent addictions, without any effective pharmacotherapeutic options. Nabiximols spray, consisting of 2.7 mg tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD), could serve as an effective substitution therapy for cannabis addiction. Researchers reported that patients who were treated for 12 weeks with nabiximols significantly reduced the number of days on which they used cannabis (18.6 days less compared to placebo users; 95% CI: 3.5-33.7). There was no difference between groups regarding general health, the use of other substances, cannabis craving, withdrawal symptoms or achieving abstinence.

[The efficacy of baclofen in alcohol dependence]. / De effectiviteit van baclofen bij de stoornis in alcoholgebruik.

BACKGROUND: In the past years numerous studies have investigated the efficacy of baclofen for alcohol dependence. After publication of several reviews a number of new randomized controlled trials have been published. Two recent meta-analyses, based on largely the same studies, reported contrary results. One meta-analysis showed a positive effect on time to relapse and abstinence at endpoint. The other meta-analysis did not show an effect on the primary outcome measures.
AIM: To clarify the clinical relevance of the effect of baclofen on alcohol use in patients with a disorder in the use of alcohol, in the light of the positive and the negative meta-analysis.
METHOD: A systematic literature search using Medline, Embase and PsycINFO (Prisma guideline).
RESULTS: We found 16 randomized controlled trials in which the effect of baclofen was studied. Seven of them showed a significant positive effect of baclofen on (one or more of the) primary outcome measures.

Essential diseases in prescribing: A national Delphi study towards a core curriculum in pharmacotherapy education.

AIMS: Prescribing is a core skill for junior doctors, yet 8-10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors. METHODS: A two-round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five-point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases. RESULTS: Sixty-two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases. CONCLUSION: This is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence.

The acute effects of MDMA and ethanol administration on electrophysiological correlates of performance monitoring in healthy volunteers.

RATIONALE: Knowing how commonly used drugs affect performance monitoring is of great importance, because drug use is often associated with compromised behavioral control. Two of the most commonly used recreational drugs in the western world, 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and ethanol (alcohol), are also often used in combination. The error-related negativity (ERN), correct-related negativity (CRN), and N2 are electrophysiological indices of performance monitoring. OBJECTIVES: The present study aimed to investigate how ethanol, MDMA, and their co-administration affect performance monitoring as indexed by the electrophysiological correlates. METHODS: Behavioral and EEG data were obtained from 14 healthy volunteers during execution of a speeded choice-reaction-time task after administration of ethanol, MDMA, and combined ethanol and MDMA, in a double-blind, placebo-controlled, randomized crossover design. RESULTS: Ethanol significantly reduced ERN amplitudes, while administration of MDMA did not affect the ERN. Co-administration of MDMA and ethanol did not further impair nor ameliorate the effect of ethanol alone. No drug effects on CRN nor N2 were observed. DISCUSSION: A decreased ERN following ethanol administration is in line with previous work and offers further support for the impairing effects of alcohol intoxication on performance monitoring. This impairment may underlie maladaptive behavior in people who are under influence. Moreover, these data demonstrate for the first time that MDMA does not affect performance monitoring nor does it interact with ethanol in this process. These findings corroborate the notion that MDMA leaves central executive functions relatively unaffected.

Acute psychomotor, memory and subjective effects of MDMA and THC co-administration over time in healthy volunteers.

In Western societies a considerable percentage of young people expose themselves to the combination of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') and cannabis. The aim of the present study was to assess the acute effects of co-administration of MDMA and THC (the main psychoactive compound of cannabis) on pharmacokinetics, psychomotor performance, memory and subjective experience over time. We performed a four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (12 male, four female) between the ages of 18 and 27. MDMA (100 mg) was given orally, THC (4, 6, and 6 mg, interval of 90 min) was vaporized and inhaled. THC induced more robust cognitive impairment compared with MDMA, and co-administration did not exacerbate single drug effects on cognitive function. However, co-administration of THC with MDMA increased desired subjective drug effects and drug strength compared with the MDMA condition, which may explain the widespread use of this combination.

Ethanol co-administration moderates 3,4-methylenedioxymethamphetamine effects on human physiology.

Alcohol is frequently used in combination with 3,4-methylenedioxymethamphetamine (MDMA). Both drugs affect cardiovascular function, hydration and temperature regulation, but may have partly opposing effects. The present study aims to assess the acute physiologic effects of (co-) administration of MDMA and ethanol over time. A four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (9 male and 7 female) between the ages of 18 and 29. MDMA (100 mg) was given orally and blood ethanol concentration was maintained at pseudo-steady state levels of 0.6 per thousand by a three-hour 10% intravenous ethanol clamp. Cardiovascular function, temperature and hydration measures were recorded throughout the study days. Ethanol did not significantly affect physiologic function, with the exception of a short lasting increase in heart rate. MDMA potently increased heart rate and blood pressure and induced fluid retention as well as an increase in temperature. Co-administration of ethanol with MDMA did not affect cardiovascular function compared to the MDMA alone condition, but attenuated the effects of MDMA on fluid retention and showed a trend for attenuation of MDMA-induced temperature increase. In conclusion, co-administration of ethanol and MDMA did not exacerbate physiologic effects compared to all other drug conditions, and moderated some effects of MDMA alone.

Acute psychomotor effects of MDMA and ethanol (co-) administration over time in healthy volunteers.

In Western societies, a considerable percentage of young people use 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). The use of alcohol (ethanol) in combination with ecstasy is common. The aim of the present study was to assess the acute psychomotor and subjective effects of (co-) administration of MDMA and ethanol over time and in relation to the pharmacokinetics. We performed a four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (nine men, seven women) between the ages of 18 and 29. MDMA (100 mg) was given orally while blood alcohol concentration was maintained at pseudo-steady state levels of approximately 0.6 per thousand for 3 h by a 10% intravenous ethanol clamp. MDMA significantly increased psychomotor speed but did not affect psychomotor accuracy and induced subjective arousal. Ethanol impaired both psychomotor speed and accuracy and induced sedation. Coadministration of ethanol and MDMA improved psychomotor speed but impaired psychomotor accuracy compared with placebo and reversed ethanol-induced sedation. Pharmacokinetics and pharmacodynamics showed maximal effects at 90-150 min after MDMA administration after which drug effects declined in spite of persisting MDMA plasma concentration, with the exception of ethanol-induced sedation, which manifested itself fully only after the infusion was stopped. In conclusion, results show that subjects were more aroused when intoxicated with both substances combined compared with placebo, but psychomotor accuracy was significantly impaired. These findings may have implications for general neuropsychological functioning as this may provide a sense of adequate performance that does not agree with a significant reduction in psychomotor accuracy.

Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration.

MDMA (3,4-methylenedioxymethamphetamine or "ecstasy") is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.

Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers.

RATIONALE: In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. OBJECTIVE: The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. MATERIALS AND METHODS: We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime. RESULTS: Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. CONCLUSIONS: Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function.

A review of acute effects of 3,4-methylenedioxymethamphetamine in healthy volunteers.

This review of the literature aims to identify the acute effects of MDMA (ecstasy) in healthy volunteers. The wide range of relevant but methodologically diverse tests was .rst grouped into clusters to allow an evaluation of tests that would otherwise have been excluded due to their low frequency of utilization. The following three types of tests were evaluated: (1) functional tests quantifying executive, attention, visual, motor, visuomotor and auditory functions, (2) phenomenological tests assessing personal, subjective experiences, and (3) physiological measures reflecting neurophysiological, endocrine and physiological parameters. MDMA showed robust effects on most of the phenomenological and physiological tests. Functional tests were scarce, preventing any meaningful conclusions to be drawn from their evaluation other than that these tests should be incorporated into future acute-effect studies. A striking doseñresponse relationship appeared for cardiovascular effects. At doses below 1.0 mg/kg MDMA no change was observed relative to placebo while above this dose all studies reported significant increases. Furthermore, pupil size, plasma cortisol and plasma prolactin levels proved responsive to MDMA administration. The reported subjective effects of MDMA matched the entactogenic profile. Although interest in the action of MDMA is considerable, the existing knowledge about the cognitive effects of MDMA in humans is still rather limited and further research into the drug's effects is recommended, also in view of potential therapeutic uses of the drug.

Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects.

AIMS: Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. METHODS: These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (-), improvement/increase (+) or no change (=) relative to placebo. RESULTS: 56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration. CONCLUSIONS: SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review.