Cognitive enhancement: Effects of methylphenidate, modafinil, and caffeine on latent memory and resting state functional connectivity in healthy adults.

Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.

Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study.

Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults. In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (N = 13) or 200 mg modafinil (N = 12) or 200 mg caffeine (N = 14) were administrated to in total 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition compared to task-related activation under placebo. While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show any BOLD signal alterations at all. These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group. However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.

Doxazosin, an α-1-adrenergic-receptor Antagonist, for Nightmares in Patients with Posttraumatic Stress Disorder and/or Borderline Personality Disorder: a Chart Review.

Objective: Centrally active α-1-adrenergic-receptor antagonists such as prazosin are effective in the treatment of nightmares in patients with posttraumatic stress disorder (PTSD). A pharmacological alternative is doxazosin, which has a longer half-life and fewer side effects. However, doxazosin is currently being used without solid empirical evidence. Furthermore, no study so far has assessed the effects of α-1-antagonists on nightmares in patients with borderline personality disorder (BPD). We retrospectively assessed the effectiveness of doxazosin on nightmares in PTSD and BPD. Method: A retrospective chart review of patients treated with doxazosin for trauma-associated nightmares in our clinic was performed. As in previous prazosin studies, the B2 score of the Clinician-Administered PTSD Scale (CAPS) was used as the primary outcome measure. Furthermore, the Pittsburgh Sleep Quality Index-Addendum for PTSD (PSQI-A) and sleep logs were analyzed. Results: We identified 51 patients with PTSD and/or BPD (mean age 35.7 years, 92.3% women) who received doxazosin for nightmares. Of these, 46 patients continued doxazosin over a 4-week period and 31 patients over a 12-week period. Within the 12-week period, doxazosin treatment significantly reduced nightmares regardless of PTSD/BPD. 25 percent of patients treated for 12 weeks had full remission of nightmares. PSQI-A scores indicated that additional trauma-associated sleep symptoms improved over 12 weeks. Furthermore, recuperation of sleep improved with doxazosin within the first 4 weeks of treatment. Conclusion: Doxazosin might improve trauma associated nightmares and more general sleep parameters in patients with PTSD and BPD. Randomized controlled trials are warranted.

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

Study protocol for "MDMA-assisted therapy as a treatment for major depressive disorder: A proof of principle study".

Background: Major depressive disorder (MDD) is a world-leading cause of disability. The available treatments are not effective in all patients, and there is a significant need for more effective treatment options. Here we present the protocol for an investigator-initiated and publicly funded trial of MDMA-assisted therapy (MDMA-AT) for MDD. This single-site, open-label study investigates the proof of principle and safety of MDMA-AT in participants with MDD and provides an initial impression of treatment effectiveness. Methods: A total of 12 participants [>18 years] with DSM-5 diagnosis of MDD will receive a flexible dose of MDMA in a therapeutic setting on two dosing days over a 4 week period preceded by three preparatory sessions. Each MDMA dosing session will be followed by three integration sessions. The primary outcome is change in MDD symptom severity, as measured by the mean change in MADRS scores from Baseline to 8 weeks after the second MDMA session. The secondary outcome is change in functional impairment, as evaluated by the mean change in Sheehan Disability Scale scores from Baseline to 8 weeks after the second MDMA session. Safety measures include vital signs, the incidence of Adverse Events and suicidality as measured by the Colombia-Suicide Severity Rating Scale. Discussion: This proof of principle trial will inform the development of fully powered clinical trials, optimize the protocol for the administration of MDMA-AT in participants with MDD and explore uncertainties including barriers to recruitment, retention and acceptability of MDMA-AT as a treatment for MDD. Clinical trial identification: EudraCT number 2021-000805-26.

Moral Psychopharmacology Needs Moral Inquiry: The Case of Psychedelics.

The revival of psychedelic research coincided and more recently conjoined with psychopharmacological research on how drugs affect moral judgments and behaviors. This article makes the case for a moral psychopharmacology of psychedelics that examines whether psychedelics serve as non-specific amplifiers that enable subjects to (re-)connect with their values, or whether they promote specific moral-political orientations such as liberal and anti-authoritarian views, as recent psychopharmacological studies suggest. This question gains urgency from the fact that the return of psychedelics from counterculture and underground laboratories to mainstream science and society has been accompanied by a diversification of their users and uses. We propose bringing the pharmacological and neuroscientific literature into a conversation with historical and anthropological scholarship documenting the full spectrum of moral and political views associated with the uses of psychedelics. This paper sheds new light on the cultural plasticity of drug action and has implications for the design of psychedelic pharmacopsychotherapies. It also raises the question of whether other classes of psychoactive drugs have an equally rich moral and political life.

Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine.

RATIONAL: At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants such as caffeine, but also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance. OBJECTIVES: There is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals (as compared with patients) and especially on the effects of different substances across different cognitive domains. METHODS: We conducted a pilot study with three arms in which male participants received placebo and one of three stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive domains. RESULTS: Our study showed some moderate effects of the three stimulants tested. Methylphenidate had positive effects on self-reported fatigue as well as on declarative memory 24 hours after learning; caffeine had a positive effect on sustained attention; there was no significant effect of modafinil in any of the instruments of our test battery. All stimulants were well tolerated, and no trade-off negative effects on other cognitive domains were found. CONCLUSIONS: The few observed significant positive effects of the tested stimulants were domain-specific and of rather low magnitude. The results can inform the use of stimulants for cognitive enhancement purposes as well as direct further research to investigate the effects of stimulants on specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.

A Central Clearing Clinic to Provide Mental Health Services for Refugees in Germany.

Objective: To determine migration related distress pattern in refugees and feasibility of a de novo established, central low-threshold outpatient clinic serving more than 80,000 newly arrived refugees in the metropole of Berlin. Methods: In an observational cohort study the relative prevalence of major psychiatric disorders by age, place of living within berlin, language and region of origin were assessed in a refugee cohort from 63 nationalities speaking 36 languages. Findings: Within 18 months, a total of 3,096 cases with a mean age of 29.7 years (11.7) have been referred from all 12 districts and 165 of 182 subdistricts of Berlin to the CCC. 33.7% of the patients were female. The three most frequent diagnoses were unipolar depression (40.4%), posttraumatic stress disorder (24.3%), and adjustment disorder (19.6%). Conclusion: The present data gives insight into the distribution of mental disorders in a large sample of refugees and provides evidence that a CCC is an effective service to quickly and broadly provide psychiatric consultations and thus to overcome classical barriers refugees usually experience in the host communities. In Berlin, Germany, and Europe treatment resources for this population should focus on stress and trauma related disorders.

Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review.

The term neuroenhancement refers to improvement in the cognitive, emotional and motivational functions of healthy individuals through, inter alia, the use of drugs. Of known interventions, psychopharmacology provides readily available options, such as the anti-dementia drugs, e.g. acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Based on a systematic review we found that expectations about the potential of these drugs exceed their actual effects, as has been demonstrated in randomised controlled trials. Both single and repeated dose trials were included in the systematic review, however repeated dose trials have only been conducted for donepezil. In six small trials lasting 14-42 days, the following results emerged: donepezil improved the retention of training on complex aviation tasks and verbal memory for semantically processed words. In one study episodic memory was improved, whereas in others it remained unaffected by donepezil. In a sleep deprivation trial, donepezil reduced the memory and attention deficits resulting from 24h of sleep deprivation. Two studies reported even transient negative effects. Regarding the safety profile of donepezil, these studies found that it was rather well tolerated. In any case, since large longitudinal studies are not available no conclusions can be drawn. Seven small studies about the effects of a single dose of memantine, and one study with a single dose of rivastigmine have been reported. Again, these studies are not adequate to answer our research question. If, as here and elsewhere suggested, the concept of pharmaceutical neuroenhancement is not to be rejected in principle, the decision of healthy individuals to take drugs for the purpose of neuroenhancement should be based on exhaustive information. At the moment, the research that would support or oppose the use of acetylcholinesterase inhibitors and memantine for neuroenhancement by healthy individuals has not yet been performed.

Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review.

The term neuroenhancement refers to improvement in the cognitive, emotional and motivational functions of healthy individuals through, inter alia, the use of drugs. Of known interventions, psychopharmacology provides readily available options, such as methylphenidate and modafinil. Both drugs are presumed to be in widespread use as cognitive enhancers for non-medical reasons. Based on a systematic review and meta-analysis we show that expectations regarding the effectiveness of these drugs exceed their actual effects, as has been demonstrated in single- or double-blind randomised controlled trials. Only studies with sufficient extractable data were included in the statistical analyses. For methylphenidate an improvement of memory was found, but no consistent evidence for other enhancing effects was uncovered. Modafinil on the other hand, was found to improve attention for well-rested individuals, while maintaining wakefulness, memory and executive functions to a significantly higher degree in sleep deprived individuals than did a placebo. However, repeated doses of modafinil were unable to prevent deterioration of cognitive performance over a longer period of sleep deprivation though maintaining wakefulness and possibly even inducing overconfidence in a person's own cognitive performance.

REM sleep in acutely traumatized individuals and interventions for the secondary prevention of post-traumatic stress disorder.

Increasing evidence supports a close link between REM sleep and the consolidation of emotionally toned memories such as traumatic experiences. In order to investigate the role of sleep for the development of symptoms related to traumatic experiences, beyond experimental models in the laboratory, sleep of acutely traumatised individuals may be examined on the first night after trauma. This might allow us to identify EEG variables predicting the development of posttraumatic stress disorder (PTSD) symptoms, and guide the way to novel sleep interventions to prevent PTSD. Based on our experience, patients' acceptance of polysomnography in the first hours after treatment in an emergency room poses obstacles to such a strategy. Wearable, self-applicable sleep recorders might be an option for the investigation of sleep in the aftermath of trauma. They would considerably decrease the perceived burden for patients and thus increase the likelihood of successful patient recruitment. As one potential sleep intervention, sleep deprivation directly after trauma has been suggested to reduce the consolidation of traumatic memories and hence act as a secondary preventive measure. However, experimental data from sleep deprivation studies in healthy volunteers with the trauma film paradigm have been inconclusive regarding the beneficial or detrimental effects of sleep on traumatic memory processing. Depending on further insights into the role of sleep in traumatic memory consolidation through observational and experimental studies, several options for therapeutic sleep interventions are conceivable: besides behavioural sleep deprivation, selective REM sleep suppression or enhancement by a pharmacological intervention into the serotonergic, noradrenergic or cholinergic systems might provide novel therapeutic options. While REM-modulating drugs have been used with some success for the prevention of PTSD after trauma, they have never been tried before the first night of sleep. In conclusion, more experimental and observational research is needed before sleep interventions are performed in actual trauma victims.

La evidencia creciente respalda un vínculo cercano entre el sueño REM y la consolidación de recuerdos emocionalmente teñidos tales como las experiencias traumáticas. Con el fin de investigar el papel del sueño REM para el desarrollo de síntomas clínicos relacionados con experiencias traumáticas, más allá de los modelos experimentales en el laboratorio, se examinó el sueño de individuos traumatizados de forma aguda la primera noche después del evento traumático. Esto nos permitiría identificar las variables de EEG que predicen el desarrollo de los síntomas del trastorno de estrés postraumático (TEPT) y guiar el camino hacia nuevas intervenciones del sueño para prevenir el TEPT. Basado en nuestra experiencia, la aceptación de los pacientes de la polisomnografía completa en las primeras horas después de su tratamiento en una sala de emergencias plantea obstáculos para dicha estrategia. Sistemas de registro de sueño que sean portables y autoinstalables podrían ser una opción para la investigación del sueño en las secuelas del trauma. Disminuirían considerablemente la carga percibida para los pacientes y, por lo tanto, aumentarían la probabilidad de un reclutamiento exitoso de pacientes. Como una posible intervención del sueño, se ha sugerido que la privación total del sueño posterior al trauma reduce la consolidación de los recuerdos traumáticos y, por lo tanto, actúa como una medida preventiva secundaria.Sin embargo, los datos experimentales de estudios de privación del sueño en voluntarios sanos con el 'trauma film paradigm' no han sido concluyentes con respecto a los efectos beneficiosos o perjudiciales del sueño en el procesamiento de la memoria traumática.Dado que la privación del sueño en la primera noche después de la traumatización podría no ser aceptable para muchas personas traumatizadas, la supresión selectiva del sueño REM, por ejemplo, mediante una intervención farmacológica, podría ser una alternativa dado el papel del sueño REM en la consolidación de la memoria emocional. Si bien los antidepresivos supresores de REM ya se han utilizado con cierto éxito para la prevención del TEPT, hasta ahora no se han probado antes de la primera noche de sueño después de un trauma. En conclusión, se necesita más investigación experimental y observacional antes de que se realicen intervenciones de sueño en víctimas de trauma reales.

Hacking the Brain: Dimensions of Cognitive Enhancement.

In an increasingly complex information society, demands for cognitive functioning are growing steadily. In recent years, numerous strategies to augment brain function have been proposed. Evidence for their efficacy (or lack thereof) and side effects has prompted discussions about ethical, societal, and medical implications. In the public debate, cognitive enhancement is often seen as a monolithic phenomenon. On a closer look, however, cognitive enhancement turns out to be a multifaceted concept: There is not one cognitive enhancer that augments brain function per se, but a great variety of interventions that can be clustered into biochemical, physical, and behavioral enhancement strategies. These cognitive enhancers differ in their mode of action, the cognitive domain they target, the time scale they work on, their availability and side effects, and how they differentially affect different groups of subjects. Here we disentangle the dimensions of cognitive enhancement, review prominent examples of cognitive enhancers that differ across these dimensions, and thereby provide a framework for both theoretical discussions and empirical research.

Feeling smart: Effects of caffeine and glucose on cognition, mood and self-judgment.

During education and early career, young adults often face examinations and assessment centers. Coffee and energy drinks are convenient and commonly used to enhance or maintain performance in these situations. Whether these macronutrients improve performance in a demanding and drawn-out multi-task situation is not clear. Using double-blind, placebo-controlled studies, we set out to examine the effects of caffeine and glucose in an assessment center-like situation, under natural consumption conditions, in a group of young adults who were heterogeneous with respect to consumption patterns. We measured multi-task performance including logical thinking, processing speed, numeric and verbal memory, attention and the ability to concentrate, and mood over a two-hour period. Caffeine and glucose were administered in common beverages with appropriate placebo controls allowing the assessment of psychological effects of expectancy. Importantly, and in contrast to most previous studies, participants retained their habitual caffeine and sugar intake (studies 1 and 2) as this represents common behavior. Based on the bulk of literature, we hypothesized that (i) caffeine enhances attentional performance and mood, while performance in more complex tasks will remain unchanged, and that (ii) glucose enhances performance on memory tasks accompanied with negative mood. Our results provide evidence that neither caffeine nor glucose significantly influence cognitive performance when compared with placebo, water, or no treatment controls in a multi-task setting. Yet, caffeine and, by trend, placebo improve dispositions such that participants perceive preserved mental energy throughout the test procedure. These subjective effects were stronger after 24 h caffeine abstinence (study 3). Future studies will have to address whether these mood changes actually result in increased motivation during a challenging task.

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review.

Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant's action, whose potential effectiveness was assessed in randomized placebo-controlled trials (RCTs). A systematic review was carried out, using the words "attention", "memory", "learning", "executive functions", and "vigilance/wakefulness" combined to "cognitive enhancer" or "smart drug". Methylphenidate, amphetamines, modafinil, nicotine, acetylcholine esterase inhibitors and antidepressants were extensively studied in previous meta-analyses and were not included in the present work. Drugs were classified according to their primary mode of action, namely catecholaminergic drugs (tolcapone, pramipexole, guanfacine), cholinergic drugs (anticholinergics), glutamatergic drugs (ampakines), histaminergic drugs, and non-specified (glucocorticoids). Overall, 50 RCTs were included in the present review. In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However the number of RCTs was limited, and most of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). One explanation for the limited number of recent RCTs with new psychostimulants seems to be the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

Non-pharmacological cognitive enhancement.

The term "cognitive enhancement" usually characterizes interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health. While the current bioethical debate mainly concentrates on pharmaceuticals, according to the given characterization, cognitive enhancement also by non-pharmacological means has to be regarded as enhancement proper. Here we summarize empirical data on approaches using nutrition, physical exercise, sleep, meditation, mnemonic strategies, computer training, and brain stimulation for enhancing cognitive capabilities. Several of these non-pharmacological enhancement strategies seem to be more efficacious compared to currently available pharmaceuticals usually coined as cognitive enhancers. While many ethical arguments of the cognitive enhancement debate apply to both pharmacological and non-pharmacological enhancers, some of them appear in new light when considered on the background of non-pharmacological enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'.