Varenicline improves motor and cognitive symptoms in early Huntington's disease.

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington's disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington's Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro®). Varenicline (1 mg twice daily) significantly improved performance in executive function and emotional recognition tasks. Our case reports describe no clinically significant adverse effects and suggest that varenicline improves aspects of cognitive function in patients with early HD. A randomized controlled study is now underway.

Investigation of the effects of 'piperazine-containing party pills' and dexamphetamine on interhemispheric communication using electroencephalography.

BACKGROUND: 'Piperazine-containing party pills' were marketed and sold as legal alternatives to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. The major constituents of these 'pills' were benzylphenylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). Despite their popularity, there is a paucity of knowledge about their central effects in humans. This study investigated their effects on human neural processing using electroencephalographic techniques. METHODS: A randomised, double-blind, placebo-controlled study investigated the effects of an acute dose of these compounds on the interhemispheric transfer of information (IHTT) using the Poffenberger task. Reaction time data were also collected. Healthy, right-handed males were given an oral dose of either BZP (n = 13) (200 mg), TFMPP (n = 15) (60 mg), a combination of BZP + TFMPP (n = 15) (100 mg/30 mg), dexamphetamine (n = 16) (20 mg), or placebo (n = 23) and tested both before and 120 min after drug administration. RESULTS: A mixed factorial repeated measures analysis of variance of absolute N160 latency and contrast analysis revealed that only TFMPP (F (1,77) = 17.30, p ≤ 0.001) significantly reduced the absolute N160 latency. Analysis of the IHTT revealed that only TFMPP (F (1,77) = 5.266, p ≤ 0.02) significantly reduced the IHTT, while BZP, BZP + TFMPP and dexamphetamine had no effect. Contrast analysis revealed that both TFMPP (F (1,77) = 17.30, p ≤ 0.001) and placebo (F (1,77) = 15.08, p ≤ 0.001) preserved the laterality of information transfer from one hemisphere to the other. Reaction time (p > 0.05) was not significantly affected by any of the drug treatments. CONCLUSIONS: The usual directional asymmetry (i.e. faster R-to-L transfer relative to L-to-R) observed in healthy control group was absent following the administration of either BZP, BZP + TFMPP or dexamphetamine. Surprisingly, lateralised hemispheric function was not affected by TFMPP. Our findings highlight how the administration of BZP, TFMPP and BZP + TFMPP leads to changes in the pattern of information transfer.

Acute effects of BZP, TFMPP and the combination of BZP and TFMPP in comparison to dexamphetamine on an auditory oddball task using electroencephalography: a single-dose study.

RATIONALE: Piperazine-based designer drugs such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been marketed and sold as legal alternatives to dexamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. When administered in combination, BZP + TFMPP have been reported to produce drug-drug synergism in rodents by stimulating the release of dopamine and serotonin. OBJECTIVES: This study was to evaluate the acute event-related potential effects of BZP, TFMPP or the combination of BZP + TFMPP compared with dexamphetamine in young healthy male adults. METHODS: A double-blind, randomised, placebo-controlled study investigated the effects of BZP, TFMPP, the combination of BZP + TFMPP, and dexamphetamine on the event-related potentials during an auditory oddball task. Healthy, right-handed males were given a single oral dose of either BZP (200 mg), TFMPP (60 mg), a combination of BZP + TFMPP (100/30 mg), dexamphetamine (20 mg) or placebo (lactose) and tested both before and 120 min after drug administration. RESULTS: A single dose of either TMFPP (t = -2.29, p = 0.03) or dexamphetamine (t = -2.33, p = 0.02) significantly reduced the P300 amplitude. A similar trend was also found in BZP. In contrast, BZP and TFMPP in combination has no effect. Neither P300 latency nor the mean reaction time was affected by any of the drug treatments. In addition, neither the P100 nor the P200 component was significantly affected following any of the drug treatments. CONCLUSIONS: A single oral dose of BZP or TFMPP, but not the combination of BZP/TFMPP, affected auditory sensory-evoked P300 potential in a manner similar to dexamphetamine.

Acute effects of the designer drugs benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) using functional magnetic resonance imaging (fMRI) and the Stroop task--a pilot study.

RATIONALE: A novel group of designer drugs containing benzylpiperazine (BZP) and/or trifluoromethylphenylpiperazine (TFMPP) have been available worldwide for more than a decade; however, their effects on human brain function have not been extensively described. OBJECTIVES: In a double-blind, placebo-controlled crossover study, the acute effects of BZP and TFMPP (alone and in combination) on the neural networks involved in executive function were investigated using an event-related Stroop functional magnetic resonance imaging (fMRI) paradigm. METHODS: Thirteen healthy participants aged 18-40 years undertook the Stroop task 90 min after taking an oral dose of either BZP (200 mg), TFMPP (either 50 or 60 mg), BZP + TFMPP (100 + 30 mg) or placebo. A change in activity in neural regions reflects an increase in local demand for oxygen, due to an increase in neuronal activity. RESULTS: Relative to placebo, an increase in neural activation was observed in the dorsal striatum following BZP, and in the thalamus following TFMPP, when performing the Stroop task. CONCLUSION: These data suggest that additional compensatory resources were recruited to maintain performance during the Stroop task. When BZP and TFMPP were administered together, both the dorsal striatum and thalamus were activated. However, the combination of BZP/TFMPP attenuated activation in the caudate, possibly due to TFMPP's indirect effects on dopamine release via 5HT2C receptors.

Investigating the microstructural and neurochemical environment within the basal ganglia of current methamphetamine abusers.

BACKGROUND: Methamphetamine is a highly addictive psychostimulant and the medical, social, and economic consequences associated with its use have become a major international problem. Current evidence has shown methamphetamine to be particularly neurotoxic to dopamine neurons and striatal structures within the basal ganglia. A previous study from our laboratory demonstrated larger putamen volumes in actively using methamphetamine-dependent participants. The purpose of this current study was to determine whether striatal structures in the same sample of participants also exhibit pathology on the microstructural and molecular level. METHODS: Diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were carried out in current methamphetamine users (n = 18) and healthy controls (n = 22) to investigate diffusion indices and neurometabolite levels in the basal ganglia. RESULTS: Contrary to findings from previous DTI and MRS studies, no significant differences in diffusion indices or metabolite levels were observed in the basal ganglia regions of current methamphetamine users. CONCLUSIONS: These findings differ from those reported in abstinent users and the absence of diffusion and neurochemical abnormalities may suggest that striatal enlargement in current methamphetamine use may be due to mechanisms other than edema and glial proliferation.

The effects of methylphenidate on cognitive control in active methamphetamine dependence using functional magnetic resonance imaging.

Methamphetamine (MA) dependence is associated with cognitive deficits. Methylphenidate (MPH) has been shown to improve inhibitory control in healthy and cocaine-dependent subjects. This study aimed to understand the neurophysiological effects before and after acute MPH administration in active MA-dependent and control subjects. Fifteen MA-dependent and 18 control subjects aged 18-46 years were scanned using functional magnetic resonance imaging before and after either a single oral dose of MPH (18 mg) or placebo while performing a color-word Stroop task. Baseline accuracy was lower (p = 0.026) and response time (RT) was longer (p < 0.0001) for the incongruent compared to congruent condition, demonstrating the task probed cognitive control. Increased activation of the dorsolateral prefrontal cortex (DLPFC) and parietal cortex during the incongruent and Stroop effect conditions, respectively was observed in MA-dependent compared to control subjects (p < 0.05), suggesting the need to recruit neural resources within these regions for conflict resolution. Post- compared to pre-MPH treatment, increased RT and DLPFC activation for the Stroop effect were observed in MA-dependent subjects (p < 0.05). In comparison to MPH-treated controls and placebo-treated MA-dependent subjects, MPH-treated MA-dependent subjects showed decreased activation of parietal and occipital regions during the incongruent and Stroop effect conditions (p < 0.05). These findings suggest that in MA-dependent subjects, MPH facilitated increased recruitment of the DLPFC for Stroop conflict resolution, and a decreased need for recruitment of neural resources in parietal and occipital regions compared to the other groups, while maintaining a comparable level of task performance to that achieved pre-drug administration. Due to the small sample size, the results from this study are preliminary; however, they inform us about the effects of MPH on the neural correlates of cognitive control in active MA-dependent subjects.

Functional and structural brain changes associated with methamphetamine abuse.

Methamphetamine (MA) is a potent psychostimulant drug whose abuse has become a global epidemic in recent years. Firstly, this review article briefly discusses the epidemiology and clinical pharmacology of methamphetamine dependence. Secondly, the article reviews relevant animal literature modeling methamphetamine dependence and discusses possible mechanisms of methamphetamine-induced neurotoxicity. Thirdly, it provides a critical review of functional and structural neuroimaging studies in human MA abusers; including positron emission tomography (PET) and functional and structural magnetic resonance imaging (MRI). The effect of abstinence from methamphetamine, both short- and long-term within the context of these studies is also reviewed.

Striatal volume increases in active methamphetamine-dependent individuals and correlation with cognitive performance.

The effect of methamphetamine (MA) dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM) volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18-46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores) on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more substantial cortical and subcortical GM changes amongst MA-dependent participants, including variability in MA exposure variables and difference in abstinence status from previous studies.

Subjective effects in humans following administration of party pill drugs BZP and TFMPP alone and in combination.

The use of piperazine derivatives, colloquially named 'party pills', has been escalating in New Zealand and worldwide since their introduction in the 1990s. Benzylpiperazine (BZP) is often used alone, or can be combined with trifluoromethylphenylpiperazine (TFMPP). Taken together as an oral dose, they have been reported to produce effects similar to 3, 4-methylenedioxymethamphetamine (MDMA). While the pharmacokinetic data have recently been published, little research has been conducted on the subjective effects of these piperazines on humans. This paper outlines the subjective effects observed following oral doses of BZP (200 mg) and TFMPP (60 mg) alone, or in combination (100/30 mg) compared to placebo. Participants were asked to comment on the subjective effects of each drug using three subjective rating scales-the Addiction Center Research Inventory (ARCI), the Profile of Mood States (POMS), and the Visual Analog Scales (VAS)-before and approximately 120 min after a single dose. BZP showed significant dexamphetamine-like stimulant effects, inducing euphoria, sociability, and drug liking, whereas TFMPP induced fewer stimulant-like effects and increased anxiety, via its serotonergic effects. The combination of BZP and TFMPP induced similar subjective effects, along with well-characterized dexamphetamine- and MDMA-like effects. These subjective data allow for obvious comparisons to be made between party pill drugs and other commonly known stimulants. However, despite estimates of over 20 million doses sold in New Zealand alone and increasing seizures by the Drug Enforcement Administration in the USA, there are no published cases of dependence worldwide. The long-term effects of regular party pill use are also unknown, and create the potential for future research.

Determining the subjective and physiological effects of BZP combined with TFMPP in human males.

RATIONALE: 'Party Pills' containing benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been used in a recreational context since the 1990s and, prior to April 2008, were legally available in New Zealand. Taken together, they have been reported to produce a 'high' similar to that produced by 3,4-methylenedioxymethamphetamine (MDMA). OBJECTIVES: There has been little research on the subjective effects of piperazines in humans. The purpose of this study is to further investigate the subjective and physiological responses following an oral dose of BZP combined with TFMPP in males. METHODS: In a randomised, double-blind, placebo-controlled study the subjective and physiological effects of BZP/TFMPP were investigated in 36 healthy, non-smoking males (mean age 22 ± 4 years). Participants were tested before and approximately 120 min after administration of a single dose of placebo (n = 16) or 100/30 mg BZP/TFMPP (n = 20). Participants were required to comment on the subjective effects using three rating scales­the Addiction Research Centre Inventory (ARCI), the Visual Analogue Scale (VAS) and the Profile of Mood States (POMS). Participants' blood pressure, heart rate and body temperature were also measured. RESULTS: Statistical analysis using repeated-measures analysis of variance (ANOVA) and planned comparisons revealed that BZP/TFMPP significantly increases blood pressure and heart rate (p < 0.05). Likewise, the subjective rating scales revealed that BZP/TFMPP has significant dexamphetamine-like effects, increases dysphoria and feelings of self-confidence (p < 0.05). CONCLUSION: These physiological and subjective data reflect clear similarities between the effects of BZP/TFMPP and commonly known stimulants such as dexamphetamine and MDMA.

Effects of trifluoromethylphenylpiperazine (TFMPP) on interhemispheric communication.

BACKGROUND: 'Party Pills' containing trifluoromethylphenylpiperazine (TFMPP) and benzylpiperazine are legally available in many countries and marketed as safe alternatives to other illicit substances such as methamphetamine and methylenedioxymethamphetamine (or Ecstasy). They have gained huge popularity around the world, especially amongst young adults. However, there is no information currently available describing the acute neurophysiological effects of these psychoactive drugs in humans. The purpose of this study is to investigate the effects of TFMPP on central information processing speed in humans. METHODS: A randomised, double blind, placebo-controlled study using electroencephalography (EEG) was carried out to investigate the effects of TFMPP on interhemispheric transfer time (IHTT). Healthy, right-handed males (age: 25 ± 5.6 years) were given placebo (n = 15) or TFMPP (0.94 mg/kg, oral, n = 15) and tested both pre- and 2 h post-drug administration. High-density EEG recordings (128 channels which were re-referenced using an average reference to make 129 electrodes) were used to record event-related potentials. The N160 component was defined as the biggest negative peak in the range between 140 and 220 ms after the event. The IHHTs were analysed by deducting the N160 latency obtained in the contralateral hemisphere from the N160 latency obtained in the hemisphere ipsilateral to stimulus signal. RESULTS: Statistical analysis using a split-plot design analysis of variance revealed that TFMPP significantly reduced the IHTT but did not affect reaction time. No statistically significant changes were observed in the placebo group. CONCLUSIONS: This study is the first to report the neurophysiological effects of TFMPP in humans and suggests that TFMPP may affect transmitter systems involved in speeding of interhemispheric communication in the male brain.

Determining the subjective effects of TFMPP in human males.

RATIONALE: Trifluoromethylphenyl piperazine (TFMPP) is an active constituent of a relatively new group of recreational drugs known as 'party pills'. TFMPP has been anecdotally reported to induce mild psychedelic effects similar to lysergic acid diethylamide and psilocybin. There has been no research about the subjective effects of TFMPP in humans. OBJECTIVES: This study aimed to investigate the subjective effects of TFMPP in human males. METHODS: A randomised, double-blind, placebo-controlled trial design was used to investigate the subjective effects of TFMPP in 30 healthy, non-smoking male volunteers (mean age 24 +/- 4 years). Participants were randomised into two groups and given either TFMPP 60 mg (n = 15) or placebo (n = 15). Each participant completed three rating scales, the Addiction Research Centre Inventory (ARCI), the Profile of Mood States (POMS) and the Visual Analogue Scales (VAS), both before and 120 min after drug administration. RESULTS: Results from the ARCI indicated that TFMPP produced increases in 'dysphoria' and 'dexamphetamine-like effects'. TFMPP also increased ratings of 'tension/anxiety' and 'confusion/bewilderment' as rated on the POMS. Results from the VAS indicated increases in 'drug liking', 'high' and 'stimulated' ratings relevant to placebo. CONCLUSIONS: Increased ratings of 'dexamphetamine-like effects', 'tension/anxiety', 'stimulated' and 'high' following TFMPP administration resemble the subjective effects of common amphetamine-type stimulants. However, increases in 'dysphoria' and 'confusion/bewilderment' ratings following TFMPP are more commonly associated with drugs that have greater effects on serotonin release, binding and reuptake such as 1-[3-chlorophenyl]-piperazine, fenfluramine and lysergic acid diethylamide.

Determining the subjective and physiological effects of BZP on human females.

BACKGROUND: "Party pills" containing benzylpiperazine (BZP) used to be widely and legally available as recreational drugs in New Zealand. There are only two published trials on human subjects (1973), which suggested that 100 mg of BZP produced subjective and physiological effects similar to 10 mg of dexamphetamine. The purpose of this study is to further investigate the subjective and physiological responses to BZP in females. METHODS/STUDY DESIGN: In a randomised, double blind, placebo-controlled study, the subjective and physiological effects of BZP were investigated in 27 healthy, right-handed non-smoking females (mean age 22 +/- 3 years). Two groups were tested before and approximately 120 minutes after administration of a single oral dose of either 200 mg BZP (n = 14) or placebo (n = 13). Participants were required to comment on the subjective effects of BZP using three rating scales-the Addiction Centre for Research Inventory, the Profile of Mood States and the Visual Analogue Scale. Participants' blood pressure, heart rate and temperature were also measured. RESULTS/FINDINGS: Statistical analysis using a split-plot analysis of variance and t tests revealed that BZP significantly increases blood pressure and heart rate (p < 0.05) Likewise, the subjective reports revealed that BZP has significant stimulant effects, increases euphoria and dysphoria and increases sociability and drug liking (p < 0.05). DISCUSSION/INTERPRETATION: Physiological and subjective data reflected a clear similarity between the effects of BZP and those of other commonly known stimulants such as amphetamine and 3,4-methylenedioxymethamphetamine.