Acute effects of methylphenidate, modafinil and MDMA on negative emotion processing

This double-blind, placebo-controlled study (n=22) only used MDMA as a control condition and found that modafinil, although often used as a cognitive enhancer, may show some adverse effects regarding emotion processing.

Abstract

“Background: Stimulants such as methylphenidate and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of methylphenidate and modafinil on negative emotions in healthy subjects have been partially missing. The aim of this study was to compare the acute effects of methylphenidate and modafinil on the neural correlates of fearful face processing using 3,4-methylenedioxymethamphetamine as a positive control.

Methods: Using a double-blind, within-subject, placebo-controlled, cross-over design, 60 mg methylphenidate, 600 mg modafinil, and 125 mg 3,4-methylenedioxymethamphetamine were administrated to 22 healthy subjects while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings.

Results: Relative to placebo, modafinil, but not methylphenidate or 3,4-methylenedioxymethamphetamine, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not methylphenidate also increased amygdala responses to fearful faces compared with 3,4-methylenedioxymethamphetamine. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration.

Conclusions: Despite the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.”

Authors: André Schmidt, Felix Müller, Patrick C. Dolder, Yasmin Schmid, Davide Zanchi, Laura Egloff, Matthias E. Liechti & Stefan Borgwardt

Summary

Introduction

LSD and psilocybin induce agitation, anxiety, visual hallucinations and illusion, which are reminiscent of the first episode of psychosis. 5-HT2ARs are predominantly mediated by LSD and psilocybin, and the 5-HT2AR inverse agonist pimavanserin is effective for treatment of visual hallucinations in patients with Parkinson’s disease psychosis.

Recent studies demonstrated that LSD administration to healthy subjects produces visual pseudo-hallucinations, impaired inhibitory processes, and induced cognitive disorganization. 5-HT2ARs are indeed critically involved in different cognitive functions, and abnormal 5-HT2AR activity is associated with cognitive impairments in a number of psychiatric disorders.

Cognitive impairments and visual hallucinations often co-exist. Patients with Parkinson’s disease and Alzheimer’s disease who experience visual hallucinations have impaired inhibitory ability and score lower on tests evaluating prefrontal-executive functions such as inhibition.

In this study, we first explored the relationship between subjective LSD-induced cognitive impairments and visual imageries in healthy subjects, and then explored the relationship between acute LSD effects on response inhibition neural networks and subjective feelings of impaired cognitive control and visual imageries.

Participants

24 subjects were recruited from the University of Basel campus by online advertisement and word of mouth. Exclusion criteria were age 25 or >65 years, physical illness, pregnancy, nursing, use of medication that could interfere with effects of the study medication, and smoking of >10 cigarettes/day.

Three participants were excluded due to too much movement in preceding functional magnetic resonance imaging tasks, leaving 18 subjects (nine men, nine women; mean age: 31 9 years, range: 25 – 58).

Drug administration

A placebo-controlled, double-blind, cross-over design was used to administer LSD to participants 2.5 hours before an MRI scan.

Subjective LSD effects on cognitive control and visual perception

We used the 5D-ASC scale to assess effects of LSD on cognitive control and visual perception 3 h after intake. Impaired cognition and control comprised items such as ‘I felt like a marionette’, ‘I had difficulty making even the smallest decision’, ‘I had difficulty in distinguishing important from unimportant things’, ‘I felt isolated from everything and everyone’.

Analysis of LSD plasma concentration

We measured the plasma concentrations of LSD 0, 1, 2 and 3 h after administration and tested the relationship between LSD plasma concentrations and impaired cognition and control and elemental/complex imagery.

The Go/No-Go task

Approximately 200 min after drug administration, all patients underwent an event-related Go/No-Go fMRI paradigm. This paradigm requires either the execution or the inhibition of a motor response. The basic Go task is a choice reaction time paradigm in which subjects press a left or right response button according to the direction of the arrow. In 12% of the trials, arrows pointed upward, and in 12% of the trials arrows pointed at a 22.5° angle.

fMRI data acquisition and analysis

Scanning was performed on a 3 T scanner using an echo planar imaging (EPI) sequence with 2.5 s repetition time, 28 ms echo time, a matrix size of 76 x 76 and 38 slices with 0.5-mm interslice gap. 160 volumes were acquired, and three subjects were excluded.

Voxel-wise maximum likelihood parameter estimates were calculated during the first-level analysis using the general linear model, and subject-specific condition effects during response inhibition were computed using t-contrasts. A one-sample t test was performed to examine whole brain activation during response inhibition across all treatments.

Relationship between brain activation, plasma concentration, cognitive impairments and visual perception

We used a SPM one-sample test design to test if LSD-induced brain activation during response inhibition was related to subjective feelings of cognitive impairments and visual hallucinations.

Subjective LSD effects on cognitive control and visual perception

LSD produced significantly higher scores than placebo for cognitive impairments and visual hallucination, and there was a significant positive correlation between impaired control/cognition and elementary but not complex imagery.

LSD plasma concentrations

LSD plasma concentrations increased rapidly to 1.29 and 1.33 ng/mL 1 and 2 h after administration, and then decreased to 1.15 ng/mL 3 h after intake. The concentration was positively related to subjectively experienced visual imagery.

Behavioural task performance

Acute LSD administration significantly reduced the probability of inhibition, reduced the number of responses to Go trials, and prolonged reaction times to Go trials relative to placebo.

Relationship between brain activation and task performance

The relationship between right parahippocampal activation during response inhibition and the probability of inhibition was different under placebo and LSD exposure.

Relationship between brain activation, plasma concentration, cognitive impairments and visual perception

We found that there was a significant negative relationship between subjectively experienced cognitive impairments and activation in the right middle frontal gyrus and right and left superior frontal gyrus.

Discussion

Our study showed that subjective feelings of impaired cognitive control and visual imageries are positively correlated with LSD effects, and that LSD administration impairs inhibitory performance and reduces activation in the middle temporal gyrus.

Acute LSD administration significantly increased subjective feelings of impaired cognitive control and visual imageries, and both of them were positively related to each other. This suggests that impaired reality monitoring after LSD intake disrupts the ability to update internal representations and might thereby promote to the formation of visual imageries.

LSD impaired motor response inhibition during the Go/No-Go task, and this impairment was inversely related to the degree of subjective cognitive impairments after LSD administration.

LSD reduced activation in key regions mediating response inhibition in rats, and this reduced activation was also evident in schizophrenia patients. Furthermore, visual hallucinations were also found to be negatively related to grey matter volumes in the right dorsolateral prefrontal cortex in Parkinson’s disease patients.

The anterior cingulate cortex signals to the right dorsolateral prefrontal cortex to adapt goal-directed behaviour when erroneous or conflicting behaviour is detected, and the LSD-induced reduction in anterior cingulate cortex activation reflects impaired error processing.

We found that the right parahippocampus correlated positively with inhibitory performance after placebo treatment, whereas no such relationship was evident after LSD administration. This suggests that LSD impaired the error-related activation in the anterior cingulate cortex and parahippocampus and thereby prevented further improvement of task performance.

A negative relationship was found between left superior frontal gyrus activation during response inhibition and subjective feelings of impaired cognitive control and visual hallucinations after LSD administration. This result suggests that LSD-induced impairments in cognitive control might have contributed to visual imageries.

LSD reduced activation in regions responsible for error detection, which might have led to an impaired learning from errors and a shift in focus towards internally generated representation and the formation of visual hallucinations.

The present study used a well-established paradigm from previous fMRI studies, but we were not able to disentangle neural activation in response to successful v. failed inhibitions due to the modest number of No-Go trials. LSD intake was associated with cognitive impairments and visual hallucinations. Further studies are warranted to understand the causality of this relationship, and a broad cognitive test battery might help to explore if LSD specifically impairs response inhibition or rather cognitive processes in general.

LSD-induced deficits in inhibitory processing were mediated via reduced parahippocampal – prefrontal activation in healthy volunteers. This study helps to better understand visual hallucinations.