Such Stuff As Dreams Are Made On: Marijuana and Sleeping

Study sheds potential light on indica vs. sativa debate.

[Thanks to Ivan Oransky (@ivanoransky) for alerting me to this study.]

Anyone who has smoked marijuana more than a couple of times knows that cannabis can alter how you sleep. The effect of cannabis on sleep is even part of the never-ending debate over Cannabis indica vs. Cannabis sativa, the two major species of the marijuana plant. Indica smokers typically report a marijuana high that is body-intensive and often soporific, sometimes leading to the condition aptly known as “couch lock.” Whereas sativa smokers, according to marijuana lore, experience a more cerebral, energetic “head high,” with fewer somatic effects. Not surprisingly, hybrid strains incorporating the alleged characteristics of both indica and sativa strains are popular in the medical marijuana community.

Although there is no official sanction for it in the medical community, marijuana is often dispensed medically for sleep problems. One piece of common wisdom holds that the higher the THC content of marijuana, the more helpful it will be in promoting sleep and improving poor sleep. The stronger the better, in other words. Similarly, indica strains are assumed to promote sleep more than sativa strains.

In an effort to clear the air, so to speak, a group of researchers, writing in Addictive Behaviors, sought to “document naturalistic choice of particular medical cannabis types among individuals who self-report using cannabis for the treatment of sleep problems…. Little research has documented species or cannabinoid concentration preferences among individuals who use medical cannabis for particular conditions…. We also evaluated the interaction between the type of cannabis used and diagnosis of cannabis use disorder among study participants.”

The researchers recruited participants from a medical cannabis dispensary in California under procedures approved by the VA and Stanford University review boards. 163 people with a mean age of 40, who used cannabis twice a day on average, provided self-reported information on their cannabis use for the study. 81 participants reported using cannabis for the management of insomnia, and another 14 reported using cannabis to reduce nightmares. (Frequent smokers insist they dream less. THC does appear to decrease the density of REM cycles, leading to more restful, dream-free sleep, according to some studies. )

So what did they find?

—“Individuals who reported using cannabis for nightmares, compared to those who did not, preferred sativa to indica.” (Small effect.)

Indica, considered the “heavier” high, might have seemed the likely choice here.

—"Individuals who self-report using cannabis to treat symptoms of insomnia and those with greater self-reported sleep latency reported using cannabis with significantly higher concentrations of CBD.” (Large effect.)

Again, a somewhat counterintuitive finding, since it is widely believed that CBD conduces toward a more wakeful state than THC alone.

—“Individuals who used sleep medication less than once/week used cannabis with higher THC concentrations than those who used sleep medication at least once a week.” (Large effect.) “There were no differences in THC concentration as a function of self-reported sleep quality, or use for insomnia or nightmares.”

Pretty straightforward finding: THC makes you sleepy. It is not clear, however, that above a certain threshold, more THC makes you even sleepier. In fact, some researchers would consider this finding unexpected, given that high THC concentrations have been shown to have a stimulating effect.

—“Older individuals were less likely to have cannabis use disorder compared to those younger….

No surprise about the older folks, since prior studies show a decrease in the prevalence of cannabis use disorders with age.

—“Individuals who preferred sativa or primary sativa hybrid strains were less likely to have cannabis use disorder compared to those who preferred indica or primary indica hybrid strains.” (Small effect.)

If replicated, this finding could have significant implications; both in strengthening programs to reduce marijuana smoking among the very young, and it warning consumers that some evidence suggests indica strains may be more addictive than sativa strains in plants with similar THC/CBD levels and ratios.

—“Neither concentration of THC nor CBD were associated with cannabis use disorder.”

Common sense, but useful to remember. In other addictive behaviors, such as heroin and alcohol abuse, the relative strength of the drug is not the primary determinant of its addictive potential.

Caveats and design limitations: The survey relied on retrospective reports of sleep quality and pot preferences. Also lacking is an examination of additional variables such as PTSD and co-occurring substance abuse.

Orexin and Insomnia

If Valium makes you groggy, and Ambien makes you sleepwalk…

A compound that blocks a brain receptor you probably have never heard of may hold the key to the next generation of sleeping pills—and there is always a next generation of sleeping pills.

A new class of hypnotic compounds that serve as antagonists for the neurotransmitter orexin may combat insomnia without the “confusional arousals” that have come to plague some users of zolpidem, otherwise known as Ambien. Sleepwalking, sleep driving, and sleep sex are common among the reports. Orexin is involved in central nervous system arousal. So-called DORAs, or dual orexin receptor antagonists, discovered in 1998, are being seen as potential therapies for insomnia, without the daytime drowsiness and rebound insomnia typical of existing treatments. The sleep disorder narcolepsy, which is in many ways the exact opposite of insomnia, is caused by “an autoimmune attack against neurons that express orexin,” according to Emmanuel Mignot of Stanford’s Center for Sleep Sciences, in an article for Science magazine.

 If these drugs are already being thought of as potential insomnia therapies, their addiction potential will have to be much lower than that of earlier generations of sleep medications. But that just might be the case, since DORA-style drugs don’t appear to promote sleep by inhibiting brain activity through neurotransmitter systems for GABA, as most existing treatments do. A study last month in Science Translational Medicine by J.M. Uslaner and coworkers asserted that DORA-type drugs caused less cognition and memory impairment in rats than Valium or Ambien, and are effective at lower doses.  With drugs that modulate the orexin system, the hope is that there would be less rebound insomnia, less memory loss, less addiction, and less weird wandering around like a zombie in the middle of the night.

The search for safer sleep drugs was recently given a shot in the arm by a disturbing report from the U.S. Substance Abuse & Mental Health Services Administration (SAMHSA). Emergency room visits caused by Ambien more than doubled from 2005 to 2010, and patients 45 years and up accounted for 74% of adverse zolpidem reactions. Overall, male ER visits went up by 144%, whereas female ER visits went up almost twice as much. Overall, women made up two-thirds of all Ambien-related emergency visits—a bald fact that led the Food & Drug Administration (FDA) in January 2013 to cut the recommended dose for females in half. Lower doses were also recommended for men as well.

But a closer look at the report shows the typical confusion of polydrug use: 50% of emergency department visits for Ambien involved its use in combination with other drugs. And in 37% of cases, Ambien was used specifically in combination with other central nervous system depressants. “Although short-term medications can help patients,” SAMSHA Administrator Pamela Hyde said in a prepared statement, “it is exceedingly important that they be carefully used and monitored.”

A new class of medications based on orexin-active drugs would follow three earlier generations of sleeping pills. And each new generation of sleeping pills seems to bring its own history of unintended consequences.

In the beginning, there was meprobamate, the postwar tranquilizer known as Miltown. In additional, powerful barbiturates like phenobarbital were marketed as miracle drugs for the anxious insomniac. By the 1950s, it had become clear that these drugs were seriously addictive, and dangerous in overdose. Emmanuel Mignot noted that in high doses, barbiturates “lead to pulmonary arrest and death, outcomes that gained further notoriety with the deaths of celebrities Marilyn Monroe and Jimi Hendrix.” Barbiturates do their work by activating chloride channel receptors for the inhibitory neurotransmitter GABA. In addition, strong sedatives were increasingly being used on psychotic patients in the 1950s, and found their way into the treatment of insomnia.

The continued promise of a safe and effective hypnotic for insomnia drove research that led to the development of the first benzodiazepines, and eventually to Valium. The benzodiazepines like Valium were safer in overdose, came in a bewildering variety of flavors, and found widespread use for sleep induction—but also as anticonvulsants, anti-anxiety agents, and muscle relaxers. The benzos bound to GABA receptor sites just like the barbiturates, but the effects were less extensive. Still, it was not long before Valium, another “perfect” drug, showed it’s adverse side, in the form of sedation, memory problems, and addiction.

Then, in 2007 came the 3rd generation, in the form of the now wildly popular “Z-drugs”—zolpidem, (Ambien) zopiclone (used overseas), and zaleplon (Sonata). And again, the side effect profiles looked better in testing, the effective dose was lower, and the binding site—GABA again—looked like the right place to bring on slower brain activity and more inclination toward sleep without the “knockout effect” of earlier barbiturates and benzos. These drugs are now the default treatment for insomnia. But over time, predictably, problems revealed themselves: “Occasional problems with dependence, tolerance, and ‘confusional arousals’ are still reported with Z-drugs…. And viewed with some suspicion by doctors and patients,” writes Mignot.

Put simply, any sleep treatment that relies on the broad-brush inhibition of GABA will likely produce a range of unwelcome side effects. There are only about 70,000 orexin-producing neurons in the hypothalamus, researchers have found. But this small band of neurons has projections to histamine systems, as well as “the adrenergic locus coeruleus, and various cholinergic and aminergic cell groups,” as Mignot sums up the research. “Blocking orexin may thus be closer to treating the underlying issue of excess alertness in insomnia compared to promoting sleep by inhibiting brain activity.”

That’s the idea, at least. And it may represent a change in thinking. Researchers are no longer looking for a better knockout drug by bludgeoning the brain into inactivity. Instead, they are looking for ways to combat hyper-alertness as a key component of insomnia.

Uslaner J.M., Tye S.J., Eddins D.M., Wang X., Fox S.V., Savitz A.T., Binns J., Cannon C.E., Garson S.L. & Yao L. &  (2013). Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition, Science Translational Medicine, 5 (179) 179ra44-179ra44. DOI: 10.1126/scitranslmed.3005213

Photo Credit: F Delventhal under license from Creative Commons.