The effects of caffeine and d-amphetamine on spatial span task in healthy participants.

Studies that examined the effect of amphetamine or caffeine on spatial working memory (SWM) and verbal working memory (VWM) have used various tasks. However, there are no studies that have used spatial span tasks (SSTs) to assess the SWM effect of amphetamine and caffeine, although some studies have used digit span tasks (DST) to assess VWM. Previous reports also showed that increasing dopamine increases psychosis-like experiences (PLE, or schizotypy) scores which are in turn negatively associated with WM performance in people with high schizotypy and people with schizophrenia. Therefore, the present study aimed to examine the influence of d-amphetamine (0.45 mg/kg, PO), a dopamine releasing stimulant, on SST, DST, and on PLE in healthy volunteers. In a separate study, we examined the effect of caffeine, a nonspecific adenosine receptor antagonist with stimulant properties, on similar tasks. METHODS: Healthy participants (N = 40) took part in two randomized, double-blind, counter-balanced placebo-controlled cross-over pilot studies: The first group (N = 20) with d-amphetamine (0.45 mg/kg, PO) and the second group (N = 20) with caffeine (200 mg, PO). Spatial span and digit span were examined under four delay conditions (0, 2, 4, 8 s). PLE were assessed using several scales measuring various aspects of psychosis and schizotypy. RESULTS: We failed to find an effect of d-amphetamine or caffeine on SWM or VWM, relative to placebo. However, d-amphetamine increased a composite score of psychosis-like experiences (p = 0.0005), specifically: Scores on Brief Psychiatric Rating Scale, Perceptual Aberrations Scale, and Magical Ideation Scale were increased following d-amphetamine. The degree of change in PLE following d-amphetamine negatively and significantly correlated with changes in SWM, mainly at the longest delay condition of 8 s (r = -0.58, p = 0.006). CONCLUSION: The present results showed that moderate-high dose of d-amphetamine and moderate dose of caffeine do not directly affect performances on DST or SST. However, the results indicate that d-amphetamine indirectly influences SWM, through its effect on psychosis-like experiences. CLINICAL TRIAL REGISTRATION NUMBER: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry) for caffeine study, and ACTRN12608000610336 for d-amphetamine study.

Dexamphetamine widens temporal and spatial binding windows in healthy participants.

BACKGROUND: The pathophysiology of psychosis is complex, but a better understanding of stimulus binding windows (BWs) could help to improve our knowledge base. Previous studies have shown that dopamine release is associated with psychosis and widened BWs. We can probe BW mechanisms using drugs of specific interest to psychosis. Therefore, we were interested in understanding how manipulation of the dopamine or catecholamine systems affect psychosis and BWs. We aimed to investigate the effect of dexamphetamine, as a dopamine-releasing stimulant, on the BWs in a unimodal illusion: the tactile funneling illusion (TFI). METHODS: We conducted a randomized, double-blind, counterbalanced placebo-controlled crossover study to investigate funnelling and errors of localization. We administered dexamphetamine (0.45 mg/kg) to 46 participants. We manipulated 5 spatial (5-1 cm) and 3 temporal (0, 500 and 750 ms) conditions in the TFI. RESULTS: We found that dexamphetamine increased funnelling illusion (p = 0.009) and increased the error of localization in a delay-dependent manner (p = 0.03). We also found that dexamphetamine significantly increased the error of localization at 500 ms temporal separation and 4 cm spatial separation (p interaction = 0.009; p 500ms|4cm v. baseline = 0.01). LIMITATIONS: Although amphetamine-induced models of psychosis are a useful approach to understanding the physiology of psychosis related to dopamine hyperactivity, dexamphetamine is equally effective at releasing noradrenaline and dopamine, and, therefore, we were unable to tease apart the effects of the 2 systems on BWs in our study. CONCLUSION: We found that dexamphetamine increases illusory perception on the unimodal TFI in healthy participants, which suggests that dopamine or other catecholamines have a role in increasing tactile spatial and temporal BWs.

Dexamphetamine influences funneling illusion based on psychometric score.

OBJECTIVES: Our team previously showed that like the experience of the rubber hand illusion (RHI) in people with schizophrenia and their offspring¸ dexamphetamine administration to healthy volunteers increases the stimulus binding windows (BWs) in RHI. It is not clear if similar expansions of BWs are present for unimodal illusions. Studies have also shown that subjective or objective effects of amphetamine would be linked to between-person variations in personality measures. Therefore, we aimed to examine the effect of dexamphetamine (DEX), a dopamine-releasing stimulant, on illusory perception using unimodal sensory stimuli (Tactile Funneling Illusion [TFI]) across both temporal and spatial variables. We further examined the relationship between changes in psychometric scores and changes in illusion perception induced by dexamphetamine. METHODS: Healthy subjects (N = 20) participated in a randomized, double-blind, counter-balanced, placebo-controlled, cross-over study. The effects of dexamphetamine (0.45 mg/kg, PO, q.d.) on funneling and error of spatial localization (EL) were examined using TFI. Psychotomimetic effects were assessed using a battery of psychological measures. RESULTS: Dexamphetamine did not significantly increased the funneling illusion (p = 0.88) or EL (p = 0.5), relative to placebo. However, the degree of change in psychometric scores following dexamphetamine positively correlated with changes in funneling (ρ = 0.48, p = 0.03, n = 20), mainly at 0 ms delay condition (ρ = 0.6, p = 0.004, n = 20). CONCLUSION: Unlike multimodal illusions, alteration of BWs does not occur for unimodal illusions after administration of a dopamine-releasing agent. However, our findings indicate that moderate release of dopamine, through its psychotomimetic effect, indirectly influences unimodal illusion.

Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits.

OBJECTIVES: This research aimed to systematically review the acute effects of amphetamine (AMP), a dopamine-releasing agent, on working memory (WM) and other cognitive performances. The investigation also aimed to review the impact of personality traits on the subjective and objective effects of AMP and possible links between personality traits and effects of AMP. METHODS: Previous double-blind controlled studies assessing the main effects of AMP on WM and other cognitive performances in healthy volunteers were systematically reviewed. An electronic search was performed in the PUBMED and SCOPUS databases. Narrative reviews of the influence of personality traits on the subjective and objective effects of AMP were included. RESULTS: Nineteen WM studies were included in the current review. Seven studies found effects of AMP on spatial WM, but only one study found the effect of AMP on verbal WM. Thirty-seven independent studies on other aspects of cognitive performance were identified. Twenty-two reported effects of AMP on cognitive functions. Studies also showed that personality traits are associated with the subjective effects of AMP. However, few studies reported the impacts of personality traits on the objective (such as WM) effects of AMP. CONCLUSION: Overall, findings indicate that AMP has mixed-effects on spatial WM and other cognitive functions, but it lacks effects on verbal WM. Although there are insufficient studies on objective measures, studies also indicated that the subjective effects of AMP administration are linked to between-person variations in personality traits.

Nabilone Impairs Spatial and Verbal Working Memory in Healthy Volunteers.

Background: Memory impairments and psychosis-like experiences can be adverse effects of cannabis use. However, reports on the cognitive impact of cannabis use are not consistent. There are also limited studies on the psychotomimetic effects of cannabinoid compounds to reveal the association between cannabis and psychosis. Therefore, we investigated the effect of acute cannabinoid intoxication on verbal working memory (VWM) and spatial working memory (SWM) following oral doses of the synthetic cannabinoid agonist, nabilone (1-2 mg, oral). We further investigated the effect of nabilone on psychosis-like experiences (schizotypy scores) and associations of schizotypy with VWM and SWM. Methods: Healthy participants (n=28) completed spatial and digit span tasks across different delay conditions (0, 6, 12, and 18 sec) after receiving nabilone (1-2 mg, PO) or placebo in a randomized, double-blind, counterbalanced, crossover manner. A subset of participants completed a short battery of schizotypy measures (n=25). Results: Nabilone impaired VWM (p=0.03, weak effect size η2=0.02) and SWM (p=0.00016, η2=0.08). Nabilone did not significantly change overall schizotypy scores. Schizotypy scores were negatively correlated with working memory (WM) averaged across all delays and both modalities, under placebo (ρ=-0.41, p=0.04). In addition, there were significant negative correlations between occasions of cannabis use and overall WM averaged scores across drug treatments (ρ=-0.49, p=0.007) and under placebo (ρ=-0.45, p=0.004). The results showed that the drug effect in the less frequent cannabis users was more pronounced on the SWM (p<0.01) and VWM (p<0.01), whereas there appeared to be little drug effect in the frequent cannabis users. Conclusion: Low doses of synthetic cannabinoid impaired SWM and VWM, indicating that exogenous activation of the cannabinoid system influences cognitive performance. Further, the results replicated previous findings that schizotypy is correlated with deficits in WM. Clinical Trial Registry Name: Nabilone and caffeine effects on the perceptions of visually, auditory, tactile and multimodal illusions in healthy volunteers. Clinical Trial Registration Number: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry).