Effects of Acute Drug Administration on Emotion: a Review of Pharmacological MRI Studies

This review (2021) examined the effects of different drugs on neural responses to emotional stimuli and found that alcohol, analgesics, and psychedelics reduce neural reactivity to negative emotional stimuli in the amygdala and other brain regions and MDMA decreases activation during the presentation of negative images. In contrast, stimulants such as caffeine and modafinil increase brain activation while viewing emotional stimuli, and the effects of cannabinoids (cannabidiol and THC) are mixed.

Abstract

“Purpose of Review: Many drug users claim to use drugs to cope with negative emotions, which may, in turn, result in persistent emotional blunting or anhedonia even when they are not using drugs. The purpose of this review is to describe the ways acute administration of psychoactive drugs impacts brain regions during emotion-related tasks, as a first step in understanding how drugs influence emotion processing in the brain.

Recent Findings: Drugs have varying effects on neural responses to emotional stimuli. In general, alcohol, analgesics, and psychedelics reduce neural reactivity to negative emotional stimuli in the amygdala and other brain regions. Other drugs produce mixed effects: Stimulants such as caffeine and modafinil increase brain activation while viewing emotional stimuli, whereas MDMA decreases activation during presentation of negative images. The effects of cannabinoids (cannabidiol and THC) are mixed. There are also inconsistent findings on the associations between neural responses to emotional stimuli and subjective drug effects.

Summary: Consistent with the notion that individuals might use drugs non-medically to diminish the experience of negative emotions, several drugs of abuse decrease neural responses to negative stimuli in limbic brain regions. These neural actions may underlie the reported “emotional blunting” of drugs, which may contribute to drug-seeking behavior. Future work is needed to examine these limbic responses in relation to self-reports of changes in affect, both during acute administration and after extended drug use.”

Authors: Kathryne Van Hedger, Leah M. Mayo, Anya K. Bershad, Racheal Madray & Harriet de Wit

Summary

Many drug users claim to use drugs to cope with negative emotions, but little is known about how drugs influence emotion processing in the brain.

Alcohol, analgesics, and psychedelics reduce neural reactivity to negative emotional stimuli, whereas stimulants increase brain activation.

Drugs decrease activation in limbic brain regions during presentation of negative images, which may contribute to drug-seeking behavior.

Keywords: phMRI, emotion, alcohol, cannabinoids, analgesics, stimulants

Introduction

Emotional blunting is a common symptom in many psychiatric disorders, including substance use disorders. Studies have shown that drugs dampen responses to negative emotional stimuli and enhance responses to positive emotional stimuli, affecting the motivation to continue taking the drug.

PhMRI is a powerful translational tool that can be used to address both basic science and clinical questions. It allows researchers to simultaneously study drug effects on neural circuits and on emotional and cognitive experiences.

For this review, we included articles published within the past 15 years that examined the neural responses to emotional stimuli under the influence of commonly used recreational drugs in healthy human participants.

Alcohol

Several phMRI studies have found that alcohol decreases neural responses to negative emotional stimuli. Heavy drinkers exhibit a dampened response to fearful faces, and may have long-term blunted emotional responses.

Alcohol increases activity in the nucleus accumbens in healthy social drinkers while viewing neutral faces, and this activation is positively correlated with subjective ratings of intoxication. In heavy drinkers, alcohol fails to activate these brain regions or produce subjective reports of intoxication.

Some studies suggest that alcohol may affect responses to emotional stimuli regardless of valence, while others fail to detect effects of alcohol on amygdala activation during presentation of negative emotional faces.

Alcohol can blunt responses to negative stimuli and enhance responses to neutral stimuli in reward-associated brain regions, but these effects are susceptible to change depending on frequency of alcohol use.

Cannabinoids

Most studies on cannabinoids in healthy human participants focus on actions of the primary active constituent of cannabis, 9-tetrahydrocannabinol (THC). Based on the phMRI studies reviewed here, THC has inconsistent effects on neural responses to emotional stimuli. It attenuates amygdala reactivity to fearful and angry faces, and attenuates subgenual anterior cingulate cortex activation while viewing negative pictures.

Several studies found that THC increased functional connectivity between amygdala and frontal brain regions while subjects viewed emotional stimuli, but did not alter functional connectivity between these regions when viewing happy faces.

Fusar-Poli and colleagues examined effects of CBD on the anterior cingulate and amygdala while participants viewed fearful faces. CBD decreased activity in the anterior cingulate and amygdala, while THC increased activity in the precuneus.

Cannabinoids appear to have some efficacy in attenuating amygdala reactivity to negative emotional faces. However, more recent work shows that THC can also increase activation in posterior brains regions and increase functional connectivity between basolateral amygdala and frontal regions while processing negative emotional stimuli.

There is little information linking the subjective effects of cannabinoid drugs with their neural effects, and more work is needed to understand the acute and chronic effects of cannabinoid drugs on emotion processing.

Analgesics

Acute doses of pain-relieving medications can blunt emotional reactivity to stimuli, and long-term use of these medications can alter emotional responses as well. Few studies have examined the effects of opioids and other analgesics on neural circuitry during emotion processing in healthy participants.

One study using phMRI to examine an opioid drug (oxycodone) found no differences in amygdala or nucleus accumbens activity between oxycodone and placebo while viewing emotional stimuli, but a higher dose of oxycodone reduced activity in medial orbitofrontal cortex.

There have been mixed results regarding the effects of acetaminophen on emotion processing, but it has been shown to reduce neural responses to social rejection.

Ketamine, a dissociative anesthetic drug, has been used to study emotion processing with phMRI. The drug reduced brain activity to negative and neutral stimuli in amygdala and hippocampus, and decreased activation in right insula to negative affective words.

Ketamine attenuates brain activation to negative emotional stimuli, and increases activation in visual processing regions and areas of the striatum when viewing neutral faces compared to fearful faces.

Stimulants

Stimulant drugs produce inconsistent effects on emotional reactivity and its neural correlates. Acute administration of stimulants can alter amygdala activation in response to fearful faces, but chronic use of stimulants can affect amygdala activation in response to fearful faces. Researchers have examined the acute effects of stimulants, including modafinil, caffeine, and 3,4 methylenedioxymethamphetamine (MDMA), using phMRI. Results suggest that some stimulants increase neural reactivity to negative emotional stimuli, while others enhance reactivity to positive emotional stimuli.

Psychedelics

Several studies have examined the effects of psychedelic drugs on neural responses to emotional stimuli. Psilocybin reduced amygdala reactivity to negative and neutral pictures and increased subjective reports of positive mood.

Dolder et al. found that 100-g and 200-g doses of LSD impaired participants’ abilities to identify fear on the facial emotion recognition task, and Mueller and colleagues found that even 13ugof LSD affected amygdala seed – based functional connectivity during resting state.

Conclusions

This review of the current literature finds that many psychoactive drugs reduce neural responses to emotional stimuli in limbic brain areas like the amygdala. Alcohol, cannabinoids, CBD, ketamine, and psychedelics all appear to reduce amygdala activation to negative emotional stimuli.

Further insights in this area will likely be driven by modifications to phMRI methodologies, including more sensitive instruments and declining costs. Additionally, additional scanning procedures may help disentangle the physiological effects of some drugs on BOLD response.

The studies reviewed here have several limitations, including that reduced neural response is not necessarily indicative of diminished subjective experiences of emotion. In addition, the studies focused on acute drug effects, and did not include emotion-related experiences like receiving a monetary reward.

Future Directions

Studies have shown that drugs affect neural responses to emotional stimuli. Future work will help to optimize drug administration.

This review identified several gaps and inconsistencies in the current literature, and revealed that phMRI studies with drugs such as opioids and methamphetamine are urgently needed to understand the sources of variability in responses to this category of drugs.

Future phMRI studies will likely use more immersive and ecologically valid tasks to capture a more nuanced understanding of emotion processing, such as by using dynamic emotional stimuli such as faces that morph into an emotion.