Psychedelics Back in the Spotlight

But will it be any different this time?

Two papers on the use of psychedelics for the treatment of mood disorders surfaced last week in the prestigious journals Science and Nature. The articles have garnered a great deal of publicity, especially the results having to do with the effect of ketamine on depression. I cannot pretend to offer more insightful coverage than the posts and articles listed below have already done, but I do think it’s profitable to take a closer look at the Nature piece by Franz X. Vollenweider and Michael Kometer. This paper looked at both dissociative anesthetics, like PCP and ketamine, AND “classical hallucinogens,” like psilocybin and LSD.

Traditionally, LSD has been thought of as a relentlessly serotonin-active drug, while ketamine was more actively involved with NMDA and other glutamate receptors. There is accumulating evidence, the researchers believe, that a common mechanism undergirds the operations of both kinds of psychedelics. “Despite their different primary modes of action,” they write, “classical hallucinogens and dissociative anesthetics both modulate glutamatergic neurotransmission in the prefrontal-limbic circuitry that is implicated in the pathophysiology of mood disorders.”

It’s worth noting that Vollenweider and Kometer maintain that almost all depressed patients relapse within two weeks after a single dose of ketamine. In studies of patients with advanced cancer, say the authors, psilocybin improves mood just as effectively, and lasts longer, than ketamine.

While there are significant differences between the subjective effects of ketamine and LSD, there is also “a set of overlapping psychological experiences.” The two trips are different, but not completely different—they share effects such as distortion of perception, visual and auditory hallucinations, a sense that the boundaries of self have softened, and often an ecstatic experience or sense of profound unity. The serotonin-glutamate connection leads the authors to assert that “classical hallucinogens are potent modulators of prefrontal network activity that involves a complex interaction between the serotonin and glutamate systems in prefrontal circuits.”

Alternately, these drugs can trigger a classic “bad trip” in certain users--time, place, circumstance, and innate biology depending.  As the authors put it: “The same hallucinogen might produce a pleasurable loss of ego boundaries combined with feelings of oneness or might lead to a more psychotic ego dissolution that involves fear and paranoid ideation.”

And there you have it: In the case of psychedelics, there are certain extenuating factors which may forever limit the use of these substances for therapeutic purposes. The primary problem is that the drugs are clinically unreliable. With psychedelics, it is always, in a sense, the Lady or the Tiger.  “The strongly dissociative effects of ketamine may limit clinical use despite its reported efficacy,” the researchers conclude. Which is, I think, putting it mildly--and which brings the authors to suggest that pharmacology-assisted psychotherapy might require some tweaks.

Specifically, the hunt is now on for psychedelics that are, well, less psychedelic. In the same way that pharmacologists seek to dial down the euphoric effects of pain medication to lessen the chances for black market abuse, researchers are now looking for ways to tone down the mental fireworks often associated with the use of ketamine, LSD, or psilocybin, on the assumption that these represent nothing but unwanted side effects, rather than the core of the experience that alleviates depression, OCD, and addiction—at least for awhile. These drugs are among the most powerful mind-altering compounds on the planet. So good luck with that project. Studying the behavioral effects of these drugs in the first place is a bit like trying to pin down a writhing fire hose with a pair of tweezers.

Curing or successfully treating chronic ailments like depression and addiction with a power psychoactive medication is both an old and an exciting idea. The Nature opinion piece also documents studies, beginning in the 1960s, which showed that psilocybin and LSD were effective treatments for Obsessive-Compulsive Disorder (OCD).  Other studies have shown alleged successes using low-dose ketamine for heroin addiction. And some of the earliest LSD studies of all showed impressive results when LSD and psychotherapy were combined as a treatment for alcoholism.

 By 1965, the authors claim, there were more than 1,000 published clinical studies on the therapeutic effects of psychedelics.  But many, if not most, of the early studies were marred by procedural problems, lack of control groups, and the fact that researchers from a dozen different disciplines, representing a dozen different experimental methods, predictably emphasized different kinds of experiential results.  The authors suggest that novel neuroimaging techniques combined with an increased understanding of molecular mechanisms of action mean that it will be different this time. If the only real result of the ketamine studies is increased funding for research on psychedelic drugs after a long hiatus, that is still progress, and it’s long overdue.

Resources

David Biello, Scientific American

Maia Szalavitz, New Scientist

and MSN Health and Fitness

Scicurious at Neurotic Physiology

Neuroskeptic at Neuroskeptic

Eugene Rubin, Psychology Today

Jonah Lehrer at Frontal Cortex

Photo Credit: http://cherished79.wordpress.com/

Shining New Light on Addiction

SAD phototherapy may help with alcoholism

It’s that time of the year again.

For many people, autumn is a bracing and enjoyable time of the year. But for an unlucky minority of people, the advent of seasonal affective disorder, or SAD, is only, and literally, a matter of time. Since the autumnal equinox at 9.51 a.m. GMT on September 23, when daytime lost its annual circadian struggle with nighttime, the amount of daily sunlight slowly but surely diminishes by as much as several minutes a day. And for a few months, it will only get worse. For dwellers in the northern latitudes, the long dark has begun.

To be precise, seasonal affective disorder is not typically considered to be a separate or unique disorder, but rather a symptom of unipolar or general depression, the “garden-variety” form of depression. Both general depression and its seasonal variant involve symptoms such as lethargy, weight gain, carbohydrate craving, oversleeping and joylessness.

The addition of strong light in certain frequencies—a form of phototherapy—helps some people combat this seasonal form of depression. The so-called SAD lights have become a fixture in homes, offices, and mail-order catalogs. The evidence for effectiveness is somewhat controversial, but generally accepted.

Recently, Science magazine has spotlighted work being done on other conditions that may respond to SAD phototherapy. Citing the work of Alfred Lewy and Thomas Wehr at the National Institute of Mental Health (NIMH), who showed that phototherapy worked by decreasing the production of melatonin through a complicated set of reactions leading to an increase in blood levels of serotonin, the article summarizes the evidence showing that many people suffering from either seasonal depression or general depression benefited from spending 30 minutes each morning sitting three feet away from bright white fluorescent lighting--light banks very much like the indoor “grow lights” people often purchase for their house plants.

However unorthodox it may sound, recent studies strongly suggest that phototherapy might also aid people suffering from bipolar disorder, commonly called “manic-depression.” This is a striking possibility, since bipolar depression is distinct from general depression, and rarely responds to the same therapies and medications used for that condition.

This development has led researchers to wonder whether other mental or behavioral disorders partially mediated by fluctuations in serotonin might also respond to light therapy. Last year, writing in the American Family Physician, Stephen J. Lurie and coworkers pointed out that “SAD is associated with serotonergic dysregulation and… may overlap with other diagnoses that share similar mechanisms.”

One diagnosis that shares similar mechanisms is alcoholism. The neurological connection between alcoholism and major depression is well documented by now, and involves serotonin, among other neurotransmitters and neurotransporters that ferry molecules around the brain and the rest of the central nervous system. Brain imaging studies of alcoholics do indeed show a marked reduction in serotonin transporter availability in cases of accompanying depression.

According to Lurie, a summary of recent research findings reveals that “some patients with alcoholism may be self-medicating an underlying depression with alcohol or manifesting a seasonal pattern to alcohol-induced depression.” Such patterns also show genetic underpinnings—SAD often runs in families with a strong history of alcoholism and general depression. All of this, the paper states, “may be related to serotonergic functioning.”

Dr. Leo Sher of the Department of Psychiatry at Columbia University believes that “Family and molecular genetic studies suggest that there may be a genetic link between seasonality and alcoholism.” In an article for the January 2004 issue of Comprehensive Psychiatry, Sher writes:

“The fact that SAD and alcoholism may be comorbid [occur together] shows the importance of a thorough diagnostic interview. Both mental health and drug and alcohol professionals should be provided with education to assist with appropriate identification, management and referral of patients presenting with comorbid alcoholism and SAD.”

For alcoholics who also suffer from seasonal affective disorder, a therapy regimen that includes exposure to bright lights in the morning could do more than boost their moods. It might also help them drink less. Much more research is needed, but the possibility that SAD phototherapy might help curb alcohol cravings or prevent relapse is a hypothesis worthy of further investigation.

Sources:

Bhattacharjee, Yudhijit, “Is Internal Timing Key to Mental Health?” Science, 317 14 September 2007. (Subscription).

“Alcohol and Seasonal Affective Disorder.” Comprehensive Psychiatry.

“Serotonergic dysfunction, negative mood states, and response to alcohol.” Alcoholism, Clinical and Experimental Research.

"Circadian Phase Variation in Bipolar I Disorder." Chronobiology International

"Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression." Journal of Clinical Psychiatry.

“Seasonal Affective Disorder.” American Family Physician

“Shedding Some Light on Bipolar Disorder.” Living the Scientific Life (Scientist, Interrupted).