Animal study highlights potential new target for treating anxiety disorders
Increasing acidity in the brain’s emotional control center reduces anxiety, according to an animal study published February 26 in The Journal of Neuroscience. The findings suggest a new mechanism for the body’s control of fear and anxiety, and point to a new target for the treatment of anxiety disorders.
Anxiety disorders, which are characterized by an inability to control feelings of fear and uncertainty, are the most prevalent group of psychiatric diseases. At the cellular level, these disorders are associated with heightened activity in the basolateral amygdala (BLA), which is known to play a central role in emotional behavior.
Many cells in the BLA possess acid-sensing ion channels called ASIC1a, which respond to pH changes in the environment outside of the cell. Maria Braga, DDS, PhD, and colleagues at the Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, found that activating ASIC1a decreased the activity of nearby cells and reduced anxiety-like behavior in animals. These findings add to previous evidence implicating the role of ASIC1a in anxiety.
“These findings suggest that activating these channels, specifically in fear-related areas such as the amygdala, may be a key to regulating anxiety,” explained Anantha Shekhar, MD, PhD, who studies panic disorders at Indiana University and was not involved in this study. “Developing specific drugs that can stimulate these channels could provide a new way to treat anxiety and fear disorders such a post-traumatic stress and panic disorders.”
To determine the effect ASIC1a activation has on neighboring cells, Braga’s group bathed BLA cells in an acidic solution in the laboratory and measured the signals sent to nearby cells. Lowering the pH of the solution decreased the activity of cells in the BLA.
Activating ASIC1a also affected animal behavior. When the researchers administered a drug that blocks ASIC1a directly into the BLA of rats, the rats displayed more anxiety-like behavior than animals that did not receive the drug. In contrast, when rats received a drug designed to increase the activity of ASIC1a channels in the BLA, the animals displayed less anxiety-like behavior.
“Our study emphasizes the importance of identifying and elucidating mechanisms involved in the regulation of brain function for the development of more efficacious therapies for treating psychiatric and neurological illnesses,” Braga said. While the findings suggest that drugs targeting ASICs may one day lead to novel therapies for anxiety disorders, Braga noted that “more research is needed to understand the roles that ASIC1a channels play in the brain.”
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Why the Thrill is Gone: Scientists Identify Potential Target for Treating Major Symptom of Depression
Stanford University School of Medicine scientists have laid bare a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While their study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.
Additionally, opinion leaders hailed the study’s inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers.
While as many as one in six Americans is likely to suffer a major depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of those for whom they’re prescribed.
“This may be because all current medications for depression work via the same mechanisms,” said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. “They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms.” The study’s first author is Byung Kook Lim, PhD, a postdoctoral scholar in Malenka’s laboratory.
Malenka is senior author of the new study, published July 12 in Nature, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain’s ability to experience pleasure when an animal is stressed. This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviors and environments — such as food, sex and warmth — that enhance their prospects for survival.
Scientists found that both chronic stress and the direct administration of melanocortin diminished the signaling strength of some synapses in the nucleus accumbens that contain receptors for melanocortin. The nucleus accumbens is labeled in this drawing of a human brain cross section. (up)
“This is the first study to suggest that we should look at the role of melanocortin in depression-related syndromes,” said Eric Nestler, MD, PhD, professor and chair of neuroscience and director of the Friedman Brain Institute at Mount Sinai School of Medicine in New York. Nestler was not involved in the study but is familiar with its contents. Read more…
On August 15th, 1951, an outbreak of hallucinations, panic attacks and psychotic episodes swept through the town of Pont-Saint-Esprit in southern France, hospitalizing dozens of its inhabitants and leaving five people dead. Doctors concluded that the incident occurred because bread in one of the town’s bakeries had been contaminated with ergot, a toxic fungus that grows on rye. But according to investigative journalist Hank Albarelli, the CIA had actually dosed the bread with d-lysergic acid diethylamide-25 (LSD), an extremely potent hallucinogenic drug derived from ergot, as part of a mind control research project.
Although we may never learn the truth behind the events at Pont-Saint-Esprit, it is now well known that the United States Army experimented with LSD on willing and unwilling military personnel and civilians. Less well known is the work of a group of psychiatrists working in the Canadian province of Saskatchewan, who pioneered the use of LSD as a treatment for alcoholism, and claimed that it produced unprecedented rates of recovery. Their findings were soon brushed under the carpet, however, and research into the potential therapeutic effects of psychedelics was abruptly halted in the late 1960s, leaving a promising avenue of research unexplored for some 40 years.
The secret history of psychedelic psychiatry began in the early 1950s, about 10 years after Albert Hofmann discovered the hallucinogenic properties of LSD, and lasted until 1970. It was uncovered by medical historian Erika Dyck, who examined the archives from Canadian mental health researchers and conducted interviews with some of the psychiatrists, patients and nurses involved in the early LSD trials. Dyck’s work shows early LSD experimentation in a new light, as a fruitful branch of mainstream psychiatric research: it redefined alcoholism as a disease that could be cured and played a role in the psychopharmacological revolution which radically transformed psychiatry. But, despite some encouraging results, it was cut short prematurely.
At the forefront of early psychedelic research was a British psychiatrist by the name of Humphry Osmond (1917-2004), a senior registrar at St. George’s Hospital in South London, who began investigating the chemical properties of mescaline, the psychoactive ingredient of the peyote cactus, during the late 1940s. After experimenting with the drug for nearly two years, Osmond and his colleagues concluded that it “caused symptoms in normal people that were similar to the symptoms of schizophrenia.” Further investigation led them to believe that the chemical structure of mescaline closely resembled that of adrenaline. As a consequence, they came to regard schizophrenia as being caused by an overproduction of adrenaline. In doing so, they had formulated what Osmond believed to be the first biochemical theory of mental illness.
In 1951, Osmond moved to Canada to take the position of deputy director of psychiatry at the Weyburn Mental Hospital in Saskatchewan and, with funding from the government and the Rockefeller Foundation, established a biochemistry research program. The following year, he met another psychiatrist by the name of Abram Hoffer, and the two embarked on a long-term collaboration. Osmond expanded his research program, and started using LSD instead of mescaline, because it was readily available from the Sandoz Pharmaceutical Company’s Canadian branch in Toronto.
The pair hit upon the idea of using LSD to treat alcoholism in 1953, at a conference in Ottawa. After arriving at their hotel, they were unable to sleep, and stayed up late discussing problems in psychiatry. In the small hours of the morning the conversation moved on to the similarities between the effects of LSD and the delirium tremens often experienced by alcoholics during withdrawal, and they began to wonder whether LSD could be effective in treating alcoholism. Hoffer recalls that the idea “seemed so bizarre that we laughed uproariously. But when our laughter subsided, the question seemed less comical and we formed our hypothesis: Would a controlled LSD-produced delirium help alcoholics stay sober?”
On their return to Saskatchewan, Osmond and Hoffer decided to test their hypothesis, and treated two chronic alcoholics who had been admitted to the Saskatchewan Mental Hospital with a single 200 microgram dose of LSD. Osmond knew from earlier self-experimentation that much smaller amounts were sufficient to produce profound changes in consciousness, but used very large doses for a stronger effect, the idea being that it would induce a terrifying artificial delirium that might frighten the patient into changing their drinking behaviour. One of the patients stopped drinking immediately after the treatment and remained sober for the entire six month period of the follow-up study. The other continued to drink after the experiment, but stopped after six months. Osmond and Hoffer found these results somewhat confusing, but concluded that LSD had a 50% chance of helping alcoholics.
The next Saskatchewan LSD trial was conducted several years later by Colin Smith, who treated 24 patients and reported that 12 of them were “improved” or “much improved” afterwards. Encouraged by these initial results, others began using the drug to treat alcoholics. Meanwhile, Osmond and Hoffer continued with their own research. By 1960, they had treated some 2,000 alcoholic patients with LSD, and claimed that their results were very similar to those obtained in the first experiment. Their treatment was endorsed by Bill W., a co-founder of Alcoholics Anonymous who was given several sessions of LSD therapy himself, and Jace Colder, director of Saskatchewan’s Bureau on Alcoholism, who believed it to be the best treatment available for alcoholics.
Osmond also “turned on” Aldous Huxley to mescaline, by giving the novelist his first dose of the drug in 1953, which inspired him to write the classic book The Doors of Perception. The two eventually became friends, and Osmond consulted Huxley when trying to find a word to describe the effects of LSD. Huxley suggested phanerothyme, from the Greek words meaning “to show” and “spirit”, telling Osmond: “To make this mundane world sublime/ Take half a gram of phanerothyme.” But Osmond decided instead on the term psychedelic, from the Greek words psyche, meaning “mind”, and deloun, meaning “to manifest”, and countered Huxley’s rhyme with his own: “To fathom Hell or soar angelic/Just take a pinch of psychedelic.” The term he had coined was announced at the meeting of the New York Academy of Sciences in 1957.
LSD therapy peaked in the 1950s, during which time it was even used to treat Hollywood film stars, including luminaries such as Cary Grant. By then, two forms of therapy had emerged. Psychedelic (“mind-manifesting”) therapy was practised mostly in North America and involved intensive psychotherapy followed by a single megadose of LSD. It was thought that the transcendental experiences induced by such large doses, as well as heightened self-awareness, would enable the patient to reflect on their condition with greater clarity. Psycholytic (“mind-loosening”) therapy, on the other hand, was practised mostly in Europe, and involved regular low to moderate doses of the drug in conjunction with psychoanalysis, in order to release long-lost memories and reveal the unconscious mind.
The early LSD studies took place alongside trials of newly developed drugs such as the antipsychotic chlorpromazine and the tricyclic antidepressant imipramine. Together, these drug trials led to the emergence of the new field of psychopharmacology, and so caused a major paradigm shift that revolutionized psychiatry and “dragged it into the modern world”. The finding that psychedelics can induce schizophrenia-like symptoms bolstered the notion that psychiatric conditions are caused by chemical imbalances in the brain. And psychiatrists, faced with new evidence that mental disorders can be effectively treated with drugs, began to abandon the psychoanalytical approach in favour of new disease models based on brain chemistry.
LSD hit the streets in the early 1960s, by which time more than 1,000 scientific research papers had been published about the drug, describing promising results in some 40,000 patients. Shortly afterwards, however, the investigations of LSD as a therapeutic agent came to an end for two reasons. Firstly, some researchers pointed at the flawed methodology of the studies. Most lacked proper controls, so that the patients involved were not randomly assigned into groups that received the real treatment or a placebo. Today, the randomized, placebo-controlled double blind study is the gold standard for clinical trials. The patient does not know whether they have been given the treatment or the placebo. The researcher should not know either, so that she does not bias the results with her expectations. Back then, though, this experimental design still had not been universally accepted as the best method for evaluating the efficacy of new drug treatments.
The second – and more important – reason was the cultural and political climate of the time. By the mid-1960s, LSD had became a popular recreational drug, and was closely linked to the hippie counterculture and related phenomena – student riots and anti-war demonstrations, non-conformity and social disobedience. The mass media increasingly portrayed LSD as a dangerous drug of abuse that could cause, among other things, chromosomal damage and foetal abnormalities. Sandoz voluntarily stopped making and supplying the drug in 1966, and the American, British and Canadian governments first placed severe restrictions on its use in research, then banned its use altogether in 1970. The documents pertaining to the Saskatchewan LSD trials were locked away, and gathered dust in the archives until they were re-discovered by Dyck five years ago.
The mid-1990s saw renewed interest in the potential therapeutic benefits of psychedelics, a key figure being Franz Vollenweider, who co-authored the new Nature Reviews Neuroscience paper. As the article explains, the new research confirms that psychedelics are indeed effective therapeutic agents, at least when given in combination with behavioural therapy, and can alleviate the symptoms of various psychiatric disorders. Sophisticated new techniques such as functional magnetic resonance imaging (fMRI) are providing fresh insights into how they affect the brain, and revealing the brain mechanisms that might underly their therapeutic effects.
We now know, for example, that the classical hallucinogens (LSD, psilocybin and mescaline) exert their effects by activating the 5-HT2A serotonin receptor subtype expressed by pyramidal cells in the deep layers of the prefrontal cortex. Serotonin is involved in signalling within a widely distributed neural circuit that is implicated in mood and affective disorders. Activation of the serotonin receptors in turn alters signalling mediated by glutamate and dopamine, and may also induce synaptic plasticity, modifying the strength of the long-range connections between the circuit components. The therapeutic effects of psychedelics may therefore be due to their ability to modulate the neuronal activity within these circuits.
Other new research shows that ketamine, a dissociative anaesthetic with hallucinogenic properties that acts primarily on the glutamatergic transmitter system, can effectively alleviate depression, and can also reduce the frequency of suicidal thoughts in depressed patients. A recent clinical trial showed MDMA (‘Ecstasy’) is beneficial for patients suffering from post-traumatic stress disorder. And some of Vollenwieder’s own research shows that psilocybin can alleviate anxiety and pain in terminally ill cancer patients. Remarkably, this recent work shows that some psychedelics are effective after just one dose; this has obvious advantages over other drug treatments, which can take many months or even years. But despite these advances, much remains to be discovered about how the psychedelics act on the brain and why they are of therapeutic value.
The history of LSD experimentation could be of use to those who make decisions about drug policy, too. The criminalization of LSD in 1970 was evidently a knee-jerk reaction by governments to the sensationalist media reports about the dangers of the drug that occurred without proper debate. A similar situation arose earlier this year, when the British government banned mephedrone. Examination of the reasons why the early LSD trials were brought to an end so abruptly could therefore provide valuable lessons about how controversial drugs could be effectively incorporated into modern medicine.
Vollenweider F. X. & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat. Rev. Neurosci. 11: 642-651. doi: 10.1038/nrn2884
Dyck, E. (2006). ‘Hitting Highs at Rock Bottom’: LSD Treatment for Alcoholism, 1950-1970. Soc. Hist. Med. 19: 313-219. [PDF]
Dyck, E. (2005). Flashback: Psychiatric Experimentation With LSD in Historical Perspective. Can. J. Psychiatry 50: 381-388. [PDF]
Smart, R. G. & Storm, T. (1966). The Efficacy of LSD in the Treatment of Alcoholism. Quart. J. Stud. Alcohol 25: 333-338. [PDF]