Effects of Tyrosine, Phentermine, Caffeine d-amphetamine, and Placebo on Cognitive and Motor Performance Deficits During Sleep Deprivation

Summary
A 2003 Department of Defense sponsored experiment studied the effects of various drugs on analytic performance during the course of 40.5 hours of sleep deprivation found that all medication tested significantly improves performance in running memory, logical reasoning, mathematical processing, tracking and visual vigilance tasks during periods of continuous sleep deprivation. All the drugs tested improved some aspects of cognitive and motor performance during sleep deprivation compared to a placebo. The subjects realized the most significant effects during states of sleep deprivation for tasks requiring speed and accuracy.

The literature on the effects of sleep deprivation attributes performance failures to cognitive slowing, memory encoding problems, retrieval problems, reductions in vigilance, deterioration of response time, increased frequency of non-responses, and increased frequency of false responses.  

This experiment investigated and compared the effects of a placebo versus other treatment groups consisting of 20 mg of D-amphetamine, 300 mg/per 70 kg body weight of caffeine, 37.5 mg of phentermine, or 150 mg/per 1 kg of body weight of tyrosine after 32.5 hours without sleep on a series of eleven performance tests administered to 76 individuals in a laboratory set up for the experiment. 

The experiment took place over 5 days demarcated over four phases: Baseline (Days 1-3), Sleep Deprivation (Days 3-4), Medication (Day 4) and Recovery (Day 5). The researchers collected performance test data eight times during the Baseline period and again every 4 hours during the night of no sleep. After 32.5 hours of no sleep, the researchers administered the drug doses to the applicable treatment groups after which two further performance test batteries took place after 34 hours of no sleep and after 38 hours of no sleep. Four additional test sessions took place during the Recovery period. 

Outline of protocol from Figure 1.

The performance tests in the test battery were (in order administered): 

1. Visual Scanning Task: Subject required to scan a matrix of letters to locate the letter K. Subject performed 20 trials per session and performance measure was amount of time to locate the correct letter. 
2. Running Memory Task: Subject viewed series of 80 individually presented letters. When each letter was presented, subject indicated presented letter was same or different from the letter shown previously. Performance measures were percent correct and response delay time (RT). 
3. Logical Reasoning Task: Subject viewed statement in the form A is followed by B then a letter pair was presented and subject indicated whether or not the letter pair relationship was congruent with preceding statement. Subject performed 80 trials per session. Performance measures were response latency per response (RT) and number of errors per session. 
4. Mathematical Reasoning: Subjects solved addition or subtraction problem and indicated whether the answer is greater than or less than five. Subject performed 80 trials per session. Performance measures were percent correct and average response latency (RT) per correct response. 
5. Stroop Task: Subject viewed words RED, GREEN, AND BLUE one at a time. On each presentation, the letters could be red, blue, or green in color. Subject responded according to the color of the letters. Subject performed 80 trials per session. Performance measures were percent correct for congruent and incongruent word-color items and average response latency (RT). 
6. Four-choice Serial Reaction Time Task: Subject saw blinking + sign in one of four quadrants and responded as quickly as possible by pressing a corresponding keyboard key. The + remained visible until subject pressed a key and randomly appeared in one of four quadrants for next trial. Subject performed 75 trials per session. Performance measure was reaction time (RT) for correct responses. 
7. Time Wall Task: Subjects observed an object descend from the top of the monitor at a constant rate toward a target at the bottom of the monitor and the target disappeared after the object descended two-thirds of the way down the screen. Subject pressed a key at the estimated time that the object would contact the target, 20 trials per session. Performance measure was amount of timing error. 
8. Pursuit Tracking Task: Subject saw two cursors in the center of a monitor. Subject moved the mouse to make the top cursor follow the bottom target cursor as closely as possible as it moved at a constant rate across the screen for 3 minutes. Performance measure was amount of error per unit of time for subject cursor deviations from target cursor. 
9. Visual Vigilance Task: Subject observed darkened computer monitor for 40 minutes. At random intervals, a small dim light appeared somewhere on the monitor. The subject pressed an appropriate key when subject detected the dim light on monitor. Performance measures were number of correct responses (out of 40 possible) and the average response latency for correct responses.
10. Trails (B) Task: Subject given sheet of paper with a series of randomly arranged letters and numbers. Using a pencil and starting at number 1, subject traced a path between each succeeding number and letter (i.e. 1-A-2-B etc). Performance measure was time to completion. 
11. Long-term Memory Task: Subjects verbally given a sentence at the beginning of session. Included in sentence was 12 pieces of factual information. After 90 minutes, subject wrote down as much of the sentence as could be remembered. Performance measure was number of correct pieces of information recalled.

Interestingly enough, not every task showed performance deficits due to sleep deprivation. 

Results for tasks that showed performance deficits related to sleep deprivation from Table II.

Tasks involving performance measures related to time stress such as speed and accuracy showed more consistent performance deficits during sleep deprivation than performance measures related to accuracy alone. All four drugs had a primary performance benefit of an improved response delay time, with auxiliary benefits in reduction of error for visual vigilance and pursuit tracking tasks. 

Prior to this research, the performance improvements from D-amphetamine and caffeine were well known by the body of literature. In contrast, phentermine and tyrosine were not. The article indicates that phentermine has very low abuse potential and mimicked the performance affects of D-amphetamine. The effects of Tyrosine supplementation were delayed compared to the effects of other substances (effects on performance not realized until 5.5 hours after dose administration compared to 1.5 hours for other substances) but a perceived benefit is that Tyrosine is a naturally occurring, non-essential amino acid with no known potential for physiological addiction abuse.

Critique
An issue with performing the same type of tests repeatedly within the same treatment groups is improvement related to learning how to "game" a test rather than improvement related to the consumption of performing enhancing drugs. The researchers administered a freebie "pretest" on the first day of the experiment yet the researchers indicate that eight sessions during the Baseline period were needed to overcome learning effects based on pilot research findings. The statistical analysis assessed performance data for 10 of the 18 testing sessions. Only four sessions on Day 3 were considered as baseline performance. Day 5 sessions representing the recovery period after sleep deprivation were also excluded.

An organization-wide adoption of drugs to mitigate performance deficits due to sleep deprivation during critical time crunches must additionally factor tolerance and withdrawal effects. Even a psychoactive drug perceived as relatively benign like caffeine can induce symptoms of psychosis such as hallucinations and hearing voices at large enough doses in otherwise healthy individuals according to 2009 research at Durham University and consistent use of 300 mg per day of caffeine is enough to cause tolerance side effects. 


Sources

Richard A. Magill; William F. Waters; George A. Bray; Julia Volaufova; Steven R. Smith; Harris R. Lieberman; Nancy McNevin; Donna H. Ryan. "Effects of Tyrosine, Phentermine, Caffeine _d-amphetamine, and Placebo on Cognitive and Motor Performance Deficits During Sleep Deprivation." Nutritional Neuroscience. 2003  

Simon R. Jones; Charles Fernyhough. "Caffeine, stress, and proneness to psychosis-like experiences: A preliminary investigation." Personality and Individual Differences. 2009