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NIDA. (2005, August 1). Cocaine-Related Environmental Cues Elicit Physiological Stress Responses. Retrieved from

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August 01, 2005
Lori Whitten
Drug Cues Induce Physiological Stress Responses in Cocaine-Addicted PatientsDrug Cues Induce Physiological Stress Responses in Cocaine-Addicted Patients. Cortisol levels, which normally decline in the morning, remain relatively high in cocaine-addicted patients after they listen to a five-minute tape of a stressful or drug-related experience, but not after they listen to a relaxing tape. Cue-induced elevations in cortisol and other stress hormones persisted for up to 30 minutes.

Overcoming addiction is in part a learning process, and people in recovery work to make and maintain healthy changes. In behavioral therapy, clinicians help patients learn techniques to avoid or navigate safely through experiences that evoke powerful urges to consume drugs: stressful situations and the people, places, and things the patient associates with past drug-taking experiences. Recent NIDA-funded research has demonstrated that cocaine-addicted patients respond to these drug-associated features in the environment as if they were stressful situations, with the release of adrenaline and other hormones that increase pulse rate and blood pressure, among other effects. The investigators also found that these responses of cocaine abusers take a long time to normalize, perhaps indicating that the drug heightens sensitivity to stress.

Dr. Rajita Sinha and colleagues at the Yale University School of Medicine in New Haven, Connecticut, conducted their study with 54 cocaine-addicted men and women, aged 21 to 50, at an inpatient research facility. Before entering treatment, the patients had abused cocaine for an average of 9 years; immediately prior to treatment, they had, on average, consumed the drug 3 or more times per week and spent $224 weekly to buy the drug. Almost all (94 percent) consumed cocaine in its smoked form (crack). Each patient had been abstinent for 2 weeks prior to the laboratory sessions.

Drug and Stress Cues Induce Arousal, Craving, and Anxiety in Cocaine-Addicted PatientsDrug and Stress Cues Induce Arousal, Craving, and Anxiety in Cocaine-Addicted Patients. Cocaine-addicted patients showed greater arousal and increased pulse and biochemical stress response, as well as increased craving and anxiety, when they mentally relived a 5-minute stressful or drug-related personal experience than when they listened to relaxation tapes. Arousal persisted for up to 30 minutes after the imagery stopped.

To study physiological and emotional responses to stress and cocaine-related cues in the laboratory, the investigators drew on the patients' individual experiences. They elicited from each patient detailed accounts of three past personal experiences: one very stressful, one relaxing, and one specifically related to taking cocaine. From each patient's stories, the researchers created three tape recordings that would, when played back, rekindle his or her feelings of stress, relaxation, and cue-induced craving (see "Reliving A Stressful Situation: Excerpt From a Guided Imagery Tape"). To enhance the strength of the responses, the researchers trained the patients in guided imagery—how to relive a scene mentally while listening to a tape, as if it were happening at that moment.

Each patient participated in three 3-hour testing sessions. Throughout each session, the patient sat on a hospital bed wearing headphones, an intravenous catheter in one arm for drawing blood, a blood pressure monitor on the other arm, and a pulse sensor on one finger. For the first hour, an adaptation period, the patient practiced tape-guided progressive relaxation while periodically reporting anxiety and craving levels. Next, the patient heard one of the 5-minute tapes based on his or her own experiences, introduced with a message to "Close your eyes and imagine yourself in the following situation." Over the three testing sessions, conducted on different days, the patient relived all three of his or her stressful, drug-related, and relaxing experiences. When the tape finished, the patient rated the vividness of the scenes and his or her cocaine craving and anxiety. A nurse monitored the patient's pulse and blood pressure and drew blood samples periodically during the testing and for 75 minutes after the tape ended.

The researchers found similar responses to the stressful and drug-related tapes. Patients' pulses increased and their blood pressure rose while they listened to both. Blood levels of biochemicals involved in the stress response—including noradrenaline, cortisol, prolactin, adrenocorticotropic hormone, and adrenaline—were elevated when participants listened to stressful and drug-related tapes compared with when they listened to the relaxing tapes. Stressful and drug-related tapes also increased participants' subjective responses—craving and anxiety— compared with the relaxing tapes.

The stress responses generated in the study were in keeping with previous laboratory studies with cocaine abusers, says Dr. Sinha. "Stress reactions after both the stressful and drug-related tapes in this study were similar to or higher than those observed when researchers have used other techniques to induce stress—for example, requiring participants to prepare and give a speech in 5 minutes."

Stress Response Persists

Normally the stress response, including the adrenaline rush and increased heart rate, breathing, and blood pressure, returns quickly to normal once a threat has passed. "What was different and striking in our patients was that they continued to show stress after the tape was over—up to 30 minutes longer than would be expected," says Dr. Sinha. The results suggest that cocaine abusers' stress responses may take longer to normalize, perhaps indicating a heightened reactivity to stress.

Dr. Sinha and her colleagues are following up with patients in this study to determine whether those with more intense biological reactions and craving in response to the tapes are more likely to relapse. Similarly, they are using brain-imaging technology to determine whether neural activation after patients listen to stressful and cocaine-related tapes predicts relapse. In addition, to determine whether drug abuse is related to a heightened stress response, Dr. Sinha is planning studies that compare the stress reactivity of addicted and nonaddicted people.

"Understanding the effects of chronic drug use on how people handle stress—particularly the craving and biological responses that occur after stressful situations—will allow us to develop medications that are effective against craving induced by drug and stressful environmental cues," says Dr. Harold Gordon of NIDA's Division of Clinical Neuroscience, Development and Behavioral Treatment.


  • Sinha, R., et al. Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology 170(1):62-72, 2003. [Abstract]

Reliving a Stressful Situation: Excerpt From a Guided Imagery Tape

There is a knock on the door. You feel tense all over your arms, legs, back, and forehead. "You are going to get evicted," he says. Your heart beats faster. You had been paying rent to your boyfriend, but he never gave it to them. You feel the butterflies in your stomach. You have no place to go. "The second notice will be here in a couple of days," he is saying, but your mind is racing. You feel shaky all over. "What am I going to do? Where will I go?" you say. You have cramps in your stomach. You grit your teeth and call your mother. She has no money to help you. You've run out of options. There is a deep intense pain inside you and tears come to your eyes.