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Atomoxetine Versus Placebo for Cognitive Deficits in Stimulant Use Disorder: A Systematic Review.

BACKGROUND: Stimulant use disorder (StUD), particularly involving cocaine and amphetamines, is associated with significant cognitive impairments that impede recovery and increase relapse risk. Atomoxetine, a selective norepinephrine reuptake inhibitor, has been proposed as a potential treatment given its role in enhancing executive function and its established efficacy in attention-deficit/hyperactivity disorder (ADHD). This systematic review aimed to evaluate the efficacy, cognitive, and mood effects of atomoxetine compared with placebo in individuals with StUD. METHODS: A comprehensive literature search of PubMed, Cochrane CENTRAL, and Embase databases was conducted to identify randomized controlled trials (RCTs) evaluating atomoxetine for StUD. Eligible studies compared atomoxetine with placebo and assessed outcomes related to cognition (attention and response inhibition), stimulant use or abstinence, mood symptoms, and safety. Data were extracted and synthesized qualitatively due to methodological heterogeneity across studies. RESULTS: Nine RCTs met the inclusion criteria. Findings on cognitive outcomes were inconsistent: Some studies reported improvements in attentional bias and inhibitory control, while others showed no significant effects. Atomoxetine did not significantly reduce stimulant use, craving, or sustain abstinence compared with placebo. Limited mood-related benefits were observed, particularly among male participants, although results were variable. Across studies, atomoxetine was well tolerated, with most adverse events mild and transient. CONCLUSION: Despite a compelling neurobiological rationale and evidence of modest cognitive and mood benefits, atomoxetine has not demonstrated consistent efficacy as a monotherapy for StUD. Its favorable safety profile may warrant further investigation in carefully defined populations, such as individuals with comorbid ADHD or in combination with behavioral interventions.

Atomoxetine Hydrochloride

Assessing the potential of wastewater-based epidemiology to evaluate the impact of COVID-19 policy changes on stimulant use across 17 countries.

BACKGROUND AND AIMS: A limited number of studies have employed wastewater-based epidemiology (WBE) to assess the impact of specific COVID-19 public health directives on stimulant consumption. This study investigates the potential of WBE as a complementary information source to support decision-making, by examining drug use changes during the pandemic. METHODS: WBE data on stimulant use from 2019 through 2022 was obtained from 17 countries covering a total of 47 wastewater treatment plants worldwide. The Oxford Coronavirus Government Response Tracker stringency index was used to standardize the severity of the COVID-19 interventions across different countries. A multiple linear regression model was fitted for the population-normalized mass loads of amphetamine, cocaine (through its metabolite benzoylecgonine), MDMA, and methamphetamine to investigate whether changes in COVID-19 restrictions influenced stimulant use, controlling for possible week-weekend and spatial effects. RESULTS: In most locations, WBE suggests that stimulant use was not significantly affected by the COVID-19 interventions, or even increased under the stricter measures. Methamphetamine use showed the largest decrease with increasing policy stringency, with a negative linear relationship found in 19% of cities, followed by MDMA (18%), cocaine (15%) and amphetamine (6%). Social gathering restrictions mainly impacted cocaine and MDMA use, while methamphetamine consumption declined most under stringent travel restrictions. CONCLUSIONS: This study highlights the heterogeneous effects of the COVID-19 policy changes on stimulant use, even within countries. The ability of WBE to compile consecutive daily estimates proves to be particularly useful to assess the direct effect of specific policy changes on the consumption of different stimulants.

COVID-19 interventions

Fundamental studies on electric stimulator used for acupuncture analgesia.

In order to perform safe and effective electric stimulation in acupuncture analgesia or therapy, basic knowledge concerning the electric stimulator is required. If direct current is used, a negative square wave with a pulse duration of 0.5 approximately 1.5 msec should be applied to the needle electrode to perform effective stimulation. Negative current is more effective at lower amperage than positive current and the possible corrosion hazard by the positive current can be avoided.

Acupuncture Therapy

[Anterior and posterior medullary analgesic stimulation, using a percutaneous implantation technic].

The technique of percutaneous implantation of a pain-relieving stimulator reduces the surgical procedure considerably. This advantage is, however, lessened by the absence of precision in placing epidural electrodes, and by the risk of their later displacement leading to inadequate stimulation. To reduce this disadvantage the authors suggest a technique that is a modification of the classical open procedure: it is particularly suitable for implantation at the cervico-dorsal junction. In 12 patients treated by percutaneous implantation, 5 received, from epidural electrodes, an anterior medullary electrical stimulation which caused analgesia without paraesthesiae in the painful ares. The results, however, do not justify a conclusion that anterior medullary stimulation is better than posterior column stimulation.

Adult

Long-term maintenance in vitro of human T cells by repeated exposure to the same stimulator cells. Differences when using repeated stimulation in allogeneic mixed leukocyte culture and when using stimulation with autologous lymphoblastoid cells.

Cells from one-way human mixed leukocyte cultures (MLC) which had reverted to small lymphocytes after 2 weeks' incubation responded with accelerated kinetics and higher thymidine incorporation on restimulation with lymphocytes or lymphoblastoid cell line (LCL) cells having relevant antigens. In contrast to fresh lymphocytes, they did not respond to autologous LCL cells. Cultures could be restimulated every second week with relevant allogeneic lymphocytes and could thus be maintained for periods of up to 4 months. Almost all these cultured cells had T-cell characteristics, during stimulation as well as in their reverted phase. The response to phytohemagglutinin (PHA) successively disappeared with repeated allogeneic restimulation, whereas the response to the relevant lymphocytes and cells of related donors was maintained. When lymphocytes had been stimulated with autologous LCL cells, the restimulation response was accelerated, although lower than after the primary stimulation. Restimulated cultures could not be maintained by further restimulation. Allogeneic and autologous LCL were equally efficient restumulators. A low level of stimulation was also achieved with allogeneic lymphocytes. The PHA response was usually reduced.

Cell Line

Chronic dopamine receptor stimulation using bromocriptine: failure to modify thyroid function.

Administration of 2.5 mg bromocriptine (Parlodel), a dopamine agonist, on two occasions to six normal volunteers did not alter the plasma TSH response to an i.v. injection of 100 micrograms TRH, but significantly (P less than 0.01) blunted it after 200 micrograms. Chronic bromocriptine treatment (7.5--50 mg/day) of fifteen acromegalic subjects failed to influence basal plasma TSH or the response pattern to 200 micrograms TRH. The thyroxine Binding Index (TBI) and the levels of T3 and T4 were not modified by treatment. These results indicate that chronic dopaminergic therapy with bromocriptine does not alter thyroid function.

Acromegaly

Hyperkinetic children: the use of stimulant drugs evaluated.

Use of stimulant drugs in the treatment of hyperkinetic children is reviewed briefly. While drugs appear to be effective in "normalizing" behavior, too little attention has been paid to potential side effects. There is need for a broader program of clinical evaluation, assessing drug effects not only on behavior, but on appetite and the cardiovascular system, and taking into account the sociological impact of drug use by children.

Achievement

Cutaneous and muscular rasodilation in the canine hindlimb evoked by central stimulation.

Using stereotaxic procedures, we electrically stimulated specific sites in the hypothalamus and midbrain of anesthetized dogs pretreated with guanethidine and atropine methonitrate. A tract in which stimulation caused noncholinergic dilator responses in the hindlimbs was identified. The course of this trace was different from that subserving cholinergic vasodilation in the hindlimb musculature. In a number of experiments we studied the proportional distribution of blood flow to leg and paw. Responses restricted to the paw were regarded as occurring mainly in cutaneous vessels; those restricted to the leg were regarded as occurring mainly in the skeletal muscle vessels. Some dilator responses in both beds were abolished by intra-arterial administration of antihistamines: other dilator responses were abolished by intra-arterial injections of dopamine antagonists. Centrally evoked dilation of leg and paw vessels by noncholinergic pathways suggests physiological roles for these fibers in the regulation of cardiovascular function.

Animals

[Value of visual evoked potentials in multiple sclerosis (MS). Comparative study of results obtained by light flash and checkerboard reversal stimulation].

Evoked visual potentials were studied in 12 subjects diagnosed or suspected of having MS. A comparison was made between these subjects and results obtained with single eye stimulation using a flash of light (101 subjects) or by using a reversible checker-board pattern (58 subjects). Reversible checker-board pattern simulation showed pathological unilateral or bilateral increase in the latency of the main positive spike in the response of 80% of the verified MS cases and 50% of the probable or possible MS cases. These percentages were 25% lower when flashes of light were used as stimulation. 58% of those patients who have never presented ophtalmological symptoms have abnormal latency in responses invoked by the reversible checker-board pattern, as opposed to 20% using flashes of light for stimulation. Study of E.V.P. in normal subjects indicates that the better results obtained with reversible checker-board stimulation can be attributed to greater reproductibility of the response. Analysis of the overall morphology of the responses significantly increases E.V.P. examination efficiency when using flashes of light as stimulation. However, in our series, it does not change the results obtained by only calculating the latency of response to reversal of a checker-board pattern.

Adult

Blood pressure changes when uterine stimulants are used after normal delivery.

Use of an automatic sphygmomanometer showed that intravenous ergometrine given immediately after delivery caused significant elevation of diastolic blood pressure in all 10 normotensive women studied. Blood pressure was also raised in some patients following the use of intramuscular oxytocin and ergometrine (Syntometrine). Uterine stimulants for use after delivery must be chosen with care.

Blood Pressure

Typing for HLA-D determinants. comparison of typing results using homozygous stimulating cells and primed cultures.

Typing for HLA-D determinants, using primed lymphocyte typing (PLT), has been compared to the results obtained using conventional homozygous stimulating cell primary MLC tests. The HLA-Dwl, -Dw2 and -Dw3 specificities were studied. Preliminary results indicate that these two methods essentially type for the HLA-D determinants and that reproducible results can be obtained employing the PLT technique after 24 hours of incubation in the secondary cultures.

Epitopes

An analgesic action of intranvenously administered lidocaine on dorsal-horn neurons responding to noxious thermal stimulation.

Using extracellular single-unit recording techniques, effects of intravenously administered lidocaine on dorsal-horn nociceptive neurons were studied in cats made decerebrate whose spinal cords had been transected. Thirty-seven neurons in Rexed lamina V responding to high-threshold mechanical and noxious thermal stimuli (radiant heat, using Hardy-Wolff-Goodell dolorimeter) were studied. Lidocaine hydrochloride, 2.5, 5, and 10 mg/kg, iv, produced dose-related suppression of both spontaneous activity and responses of these neurons to noxious thermal stimulation. Spontaneous discharge frequencies at maximum suppression, observed 3--7 min after administration of each of the three doses of lidocaine were 64 +/- 14 (mean +/- 1 SE), 32 +/- 8, and 25 +/- 9 per cent of control values, respectively; responses to noxious thermal stimuli were 83 +/- 5, 52 +/- 8, and 39 +/- 7 per cent of the control values, respectively. Threshold skin temperature to noxious thermal stimulation increased from 44.7 +/- 0.4 C (control) to 46.3 +/- 0.7 C with lidocaine, 5 mg/kg (P less than 0.05), to 47.8 +/- 0.8 C with lidocaine, 10 mg/kg (P less than 0.01). The times necessary for recovery varied in a dose-related fashion. Plasma lidocaine concentrations 5 min after lidocaine, 5 mg/kg, averaged 3.6 +/- 0.7 microgram/ml. These data support the clinical impression that intravenously administered lidocaine produces analgesia at plasma concentrations of 3--10 microgram/ml. It is suggested that lidocaine may block conduction of nociceptive impulses, at least in part, by suppression of spinal-cord nociceptive neurons.

Analgesics

Increased release of lymphokines by allografted mouse spleen cells following concanavalin A stimulation.

Using a test proposed in this laboratory for following macrophage "activation" (intracellular beta-glucuronidase content) and quantitative dilution studies, we have shown that lymphocytes from mice presensitized by a skin allograft release far more macrophage activating lympholines than do normal lymphocytes when non-specifically stimulated by concanavalin A. This difference may be due to latent metabolic changes of sensitized lymphocytes, but it may also express a modified balance among the various lymphocyte subpopulations within the spleen of grafted mice.

Animals

Clinical assessment of analgesics using ultrasonic stimulation. A new method.

A quantitative method for measuring pain threshold by the use of ultrasonic stimulation in man was designed and the possibility of clinical application in assessing analgesics was investigated. Ultrasonic stimulus was given to Japanese subjects on the palmer distal part of the 2nd, 3rd and 4th fingers of both hands. The latent time between start of the stimulation and withdrawal of the hand when perceiving pain was considered the pain threshold. The ultrasonic evoked pain was a sharp pin-prick type, without sensations such as thermal and mechanical. The pain threshold lowered with increasing either stimulus intensity or water bath temperature when the hand of the subject was immersed during measurement. Normal threshold to ultrasonic stimulation measured in both 50 men and 50 women gave nearly normal distribution curves; women being more sensitive to ultrasonics than men. Analgesia with codeine phosphate (20 mg p.o.), aspirin (1.5, 1.0, 0.5 g p.o.), aminopyrine (100 mg p.o.) and mefenamic acid (500 mg p.o.) in volunteers of both sexes was demonstrated significantly using this method under double blind circumstances. Pentobarbital, diazepam, butylscopolamine, bromelain and placebo each in the usual dose used clinically failed to alter the pain threshold. Humans were at least 25 fold more sensitive than mice to the analgesics used herein.

Adolescent

Cortical slow negative waves following non-paired stimuli: effects of modality, intensity and rate of stimulation.

Using a simple stimulus counting task, negative after-waves following single (unpaired) stimuli were investigated under a variety of stimulus conditions. Responses were obtained to tones at 3 intensities, to light flashes at 3 intensities, and to tones at 3 rates of presentation. The acoustic stimuli led to a negative after-wave that peaked at frontal sites around 500 or 600 msec, and then trailed off to a more central scalp representation. This negative after-wave was increased in amplitude by slowing the rate of stimulus presentation. In comparison, no appreciable or sustained after-wave was elicited by visual stimuli. No significant effects in the negative after-wave were associated with intensity, either for visual or for acoustic stimuli. When analyzed by Principal Components Analysis, the negative after-waves were shown to comprise in all cases two underlying factors, although the factors contributed less to the total wave form for visual stimuli than for acoustic stimuli. Two interpretations for the negative after-wave were contrasted, one considering it to be an integral feature of the auditory evoked potential. A second interpretation, more compatible with the data obtained here, links the negative after-wave with non-specific activation processes.

Acoustic Stimulation