Evening caffeine use changes circadian rhythm

By MANISH PARANJPE

Millions of Americans start their days with caffeine. While drinking a cup of morning joe may seem innocuous, a new study published in Science Translational Medicine found that caffeine may actually be altering our body’s internal circadian clock.

Caffeine is the most widely consumed neuropsychotic drug in the world. Prolonged wakefulness, in the absence of caffeine, causes adenosine, a neurotransmitter, to build up in neuronal synapses, or the extracellular space between two neurons. In time, adenosine binds to and activates adenosine receptors found on neurons in the brain and spinal cord, activating a host of cellular processes and ultimately leading to a decrease in cellular metabolism. This decreased metabolism causes us to feel drowsy.

The caffeine that almost 54 percent of American adults consume on a daily basis works by binding to the adenosine receptor, preventing adenosine from binding to the receptor. As a result, adenosine can no longer promote drowsiness. Caffeine can also inhibit phosphodiesterase, the enzyme that degrades cAMP, resulting in an increase in cAMP and a host of metabolic changes.

For their study, researchers at the University of Colorado Boulder kept five individuals under controlled conditions. Each subject was placed in either a dimly lit or a brightly lit environment three hours before his or her habitual bedtime. Before bedtime, each participant received either a placebo pill or 2.9 mg/kg of caffeine — approximately equal to a double-shot espresso. The study lasted for 49 days.

The researchers then measured the melatonin levels in each participant. Melatonin, a hormone that induces sleep and regulates our day-night cycle, is a well-characterized readout for circadian rhythm. By measuring melatonin levels in the participants’ saliva, the researchers were able to study shifts in circadian rhythm as a result of caffeine use.

In an interview with The News-Letter last year, Vsevolod Y. Polotsky, associate professor in the Department of Pulmonary and Critical Medicine at The Johns Hopkins University School of Medicine explained the mechanisms behind a circadian rhythm.

“Circadian rhythm is regulated by the light-sensitive melanopsin receptor in the retina, which transmits information to the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the whole body circadian pacemaker. SCN regulates the pineal gland, which secretes melatonin, which [then] regulates sleep onset,” Polotsky said.

All of our tissues have their own circadian clocks, which, Polotsky explained, are genetically regulated by what is known as the CLOCK gene. In addition to this genetic regulation, our circadian rhythms can also be influenced by several environmental factors, including stress, caffeine and lighting conditions.

The study found that subjects who were given the bright light placebo and bright light caffeine treatment, on average, experienced a shift of 80 and 103 minutes, respectively, in their circadian rhythms as compared with the dim light placebo controls.

The team then set out to elucidate the mechanism of this caffeine-induced dysregulation in circadian rhythm. The researchers began with two mechanistic hypotheses:

1) Caffeine competitively inhibits phosphodiesterase, the enzyme that is responsible for cAMP.

2) Caffeine blocks the adenosine receptor and causes an increase in cAMP production. After using drugs that selectively block either phosphodiesterase or the adenosine receptor but not both, the researchers were able to identify that caffeine acts by blocking the adenosine receptor.

Heroin, LSD, methamphetamine and now caffeine are all psychoactive drugs capable of causing long-term changes in the brain, resulting in alterations in perception and mood. And while caffeine will likely not lead to extreme addiction or hallucinations, the study does implicate that caffeine causes changes in our body’s internal clock or circadian rhythm. The results of the study may have implications in helping us better address sleep-related problems.

“[There is a] long-standing pattern of metabolic change due to a daily mismatch [of circadian rhythm],” Dr. Jonathan Jun, associate professor of Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine, told The News-Letter last year.

A better understanding of the molecular pathways underlying circadian rhythm may one day enable us to work to correct these metabolic deficits.