Archive for the ‘serotonin’ Category

Humans have been ingesting mind-altering substances for a very long time. Hallucinogen-huffing bowls 2,500 years old (http://www.livescience.com/5240-ancient-family-heirlooms-snort-hallucinogens.html) have been found on islands in the Lesser Antilles, and traditional cultures from the Americas to Africa use hallucinogenic substances for spiritual purposes. Here are some notable substances that send the mind tripping.

LSD is commonly known as “acid,” but its scientific name is a mouthful: lysergic acid diethylamaide. The drug was first synthesized in 1938 from a chemical called ergotamine. Ergotamine, in turn, is produced by a grain fungus that grow on rye.

LSD was originally produced by a pharmaceutical company under the name Delysid, but it got a bad reputation in the 1950s when the CIA decided to research its effects on mind control. The test subjects of the CIA project MKULTRA proved very difficult to control indeed, and many, like counter-culture writer Ken Kesey, started taking the drug for fun (and for their own form of 1960s enlightenment).

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Ayahuasca is a hallucinatory mixture of Amazonian infusions centered around the Banisteriopsis caapi vine. The brew has long been used by native South American tribes for spiritual rituals and healing, and like other hallucinogens, ayahuasca often triggers very intense emotional experiences (vomiting is also common). In 2006, National Geographic writer Kira Salak described her experience with ayahuasca in Peru for the magazine.

” I will never forget what it was like. The overwhelming misery. The certainty of never-ending suffering. No one to help you, no way to escape. Everywhere I looked: darkness so thick that the idea of light seemed inconceivable,” Salak wrote. “Suddenly, I swirled down a tunnel of fire, wailing figures calling out to me in agony, begging me to save them. Others tried to terrorize me. ‘You will never leave here,’ they said. ‘Never. Never.'”

Nonetheless, Salak wrote, when she broke free of her hallucinations, her crippling depression was alleviated. It’s anecdotal experiences like this that have led researchers to investigate the uses of hallucinogens as therapy for mental disorders such as anxiety, depression and post-traumatic stress disorder.

Peyote is a cactus that gets its hallucinatory power from mescaline. Like most hallucinogens, mescaline binds to serotonin receptors in the brain, producing heightened sensations and kaleidoscopic visions.

Native groups in Mexico have used peyote in ceremonies for thousands of years, and other mescaline-producing cacti have long been used by South American tribes for their rituals. Peyote has been the subject of many a court battle because of its role in religious practice; currently, Arizona, Colorado, New Mexico, Nevada and Oregon allow some peyote possession, but only if linked to religious ceremonies, according to Arizona’s Peyote Way Church of God.

The “magic” ingredient in hallucinogenic mushrooms is psilocybin, a compound that breaks down into psilocin in the body. Psilocin bonds to serotonin receptors all over the brain, and can cause hallucinations as well as synesthesia, or the mixture of two senses. Under the influence, for example, a person might feel that they can smell colors.

In keeping with the human tradition of eating anything that might alter your mind, people have been ingesting psilocybin-continuing mushrooms for thousands of years. Synthetic psilocybin is now under study as a potential treatment for anxiety, depression and addiction.

Best known by its street name, “angel dust,” PCP stands for phencyclidine. The drug blocks receptors in the brain for the neurotransmitter glutamate. It’s more dangerous than other hallucinogens, with schizophrenia-like symptoms and nasty side effects.

Those side effects are why PCP has no medical uses. The drug was tested as an anesthetic in the 1950s and used briefly to knock out animals during veterinary surgeries. But by the 1960s, PCP had hit the streets and was being used as a recreation drug, famous for the feelings of euphoria and invincibility it bestowed on the user. Unfortunately, a side effect of all that euphoria is sometimes truly destructive behavior, including users trying to jump out of windows or otherwise self-mutilating. Not to mention that high enough doses can cause convulsions.

Derived from the African iboga plant, ibogaine is another hallucinogen with a long history of tribal use. More recently, the drug has shown promise in treating addiction, although mostly in Mexico and Europe where ibogaine treatment is not prohibited as it is in the U.S.

Using ibogaine as therapy is tricky, however. The drug can cause heart rhythm problems, and vomiting is a common side effect. The Massachusetts-based Multidisciplinary Association for Psychedelic Research (MAPS) reports that an estimated 1 in 300 ibogaine users die due to the drug. The group is studying the long-term effects of ibogaine on patients in drug treatment programs in New Zealand and Mexico.

Salvia divinorum, also known as seer’s or diviner’s sage, grows in the cloud forest of Oaxaca, Mexico. The native Mazatec people have long used tea made out of the leaves in spiritual ceremonies, but the plant can also be smoked or chewed for its hallucinogenic effects.

Salvia is not currently a controlled substance, according to the National Institute on Drug Abuse, but it is under consideration to be made illegal and placed in the same drug class as marijuana.

Ecstasy, “E” or “X” are the street names for MDMA, or (get ready for a long one) 3,4-methylenedioxymethamphetamine. The drug acts on serotonin in the brain, causing feelings of euphoria, energy and distortions of perception. It can also nudge body temperatures up, raising the risk of heat stroke. Animal studies suggest that MDMA causes long-term and potentially dangerous changes in the brain, according to the National Institute on Drug Abuse.

MDMA was first synthesized by a chemist looking for substances to stop bleeding in 1912. No one paid the compound much mind for the next half-decade, but by the 1970s, MDMA had hit the streets. It was popular at raves and nightclubs and among those who liked their music psychedelic. Today, ecstasy is still a common street drug, but researchers are investigating whether MDMA could be used to treat post-traumatic stress disorder and cancer-related anxiety.

http://www.livescience.com/16286-hallucinogens-lsd-mushrooms-ecstasy-history.html

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As a teenager growing up in New Mexico, Zach Weinberg had the same thing for breakfast every day of high school. Next to his tortilla and cream cheese, which he insists is delicious, was a small, round, yellow pill – an antidepressant called Lexapro. By his senior year, the only thing different was the color of his pill, now a shiny white. This one was Wellbutrin. He’d traded one antidepressant for another. If the pills work, they certainly don’t work for long. Now, at age 23, he’s frustrated at still having to play around with different drug combinations and doses.

The odds are that you know someone in the same situation. According to the National Institutes of Health, approximately one in 10 men and one in four women in the U.S. will suffer from depression at some point in their lives. Clinical depression can come at any time, lasting anywhere from months to years, and is characterized by low self-esteem and a loss of interest in things that were once enjoyable.

Along with various forms of therapy, antidepressant drugs are the most effective treatment. But even when they work, they come with side effects – such as weight gain and trouble sleeping – that can make the symptoms of depression worse. So for people like Weinberg, choosing between one kind of antidepressant and another isn’t really much of a choice.

But that may be changing. New insights into how traditional antidepressants – including the wildly popular SSRIs, or selective serotonin reuptake inhibitor, drugs like Prozac, Paxil and Lexapro – work inside the brain are stimulating the development of a new generation of medications that may work faster and more effectively.

Contrary to what their developers originally thought, many antidepressants have a surprising, indirect way of altering brain chemistry: by stimulating the growth of new neurons and protecting those neurons from dying. “The SSRI hypothesis is really falling apart,” says Paul Currie, a neuroscientist at Reed College in Portland, Ore. He explains that these new ideas have researchers trying something a little different to treat depression.

SSRIs work by manipulating serotonin, one of the most important chemical messengers in the brain. Serotonin is at least partly responsible for everything from eating disorders to the pretty colors and patterns people see while on psychedelic drugs.

When serotonin is released from one neuron and picked up by another in the course of transmitting a message between them, some is taken back up into the original neuron. By blocking this mechanism, SSRIs force more serotonin to circulate in the system, supposedly reducing feelings of depression.

Similar drugs use the same reuptake-blocking technique with other neurotransmitters, usually dopamine and norepinephrine. The success of drugs that target this system provides the basis of the monoamine hypothesis of depression – the idea that depression is a result of a chemical imbalance. That’s why decades of research have been aimed at balancing out our monoamine neurotransmitters, including serotonin.

But it takes a week or two for antidepressants to have any noticeable effect, suggesting that it’s not that immediate boost in serotonin that’s making people feel better. Recently, studies have suggested a different explanation: using antidepressants seems to correlate with having more new neurons in the hippocampus, an area of the brain responsible for many memory processes. Those suffering from depression tend to lose neurons in their hippocampi, so researchers have started to think that the effectiveness of monoamine drugs actually comes from their repairing of damaged brain areas.

Rene Hen is one of those curious researchers. A neuroscientist at Columbia University, Hen used radiation to block neurogenesis – the process of growing, repairing, and protecting new neurons – in mice. Later, when given antidepressants, these mice still showed signs of anxiety and depression, unlike the mice that were generating new neurons. This suggested that neurogenesis is actually essential for antidepressants to have any effect. Instead of waiting for the slower, indirect effect on neurogenesis patients get from SSRIs, researchers are now experimenting with drugs that take more direct routes to stimulate neuron growth.

“If you don’t have to do it through the back door, then absolutely that’s the way to go,” says Reed’s Currie. The aim now is to nail down the indirect effect that Hen identified and make it as direct as possible.

And the first drugs specifically targeting neurogenesis for all sorts of disorders, including depression, are starting to appear. In 2010, Andrew Pieper, a psychiatrist at the University of Iowa, ran a massive screening test on 1,000 small molecules. He discovered eight that had positive effects on neurogenesis in the hippocampus. He picked one, called P7C3, and ran with it. When given to mice that lacked a gene necessary for neurogenesis, P7C3 helped them create new neurons and keep them alive.

“There’s a huge unmet need for treatments that block cell death,” Pieper says. And the hope is that treatments for depression derived from P7C3 will work faster, better, and with fewer side effects than SSRIs. Although Peiper and his team have only tested P7C3 on mice, he’s optimistic about its effects in humans and is on the hunt for a commercial partner to develop it.

Neuralstem Inc., a Maryland-based pharmaceutical company, has just announced that their first round of human clinical testing on a similar drug was successful. Their drug, NSI-189, targets neurogenesis in the hippocampus by actually creating new neurons and has been successful in animal models, but these are the first tests in humans.

Despite the early success of these treatments, other scientists are concerned that a drug targeting neurogenesis might be meddling with that system prematurely. “I’m a little worried that, again, we have an oversimplified model,” Currie says. It’s like stirring up a bowl of soup, he continues, “without any thought as to what makes it taste good.”

Brian Luikart at Dartmouth College’s Geisel School of Medicine agrees. “One possibility,” he says, “is that there are global changes in the brain that enhance neurogenesis in the hippocampus.” If that’s true, then more neurogenesis could just be one of many effects of SSRIs without being the key to their success. Although the links between neurogenesis and antidepressants are well established, there is still no evidence to suggest that solely enhancing neurogenesis can help fight depression in humans. “Increasing neurogenesis does not increase happiness,” he says.

Luikart also worries that, while a neurogenesis drug may have fewer side effects, the ones it does have could be even more damaging – especially for cancer patients. A drug that keeps neurons alive could potentially do the same to tumor cells.

But Pieper says he hasn’t seen any negative effects. Neuralstem also says there haven’t been any health concerns in their trials. And even if there are side effects like those Luikart is worried about, it might be worth the risk for those with severe depression.

Neurogenesis drugs are still years from being commercially available, however. Pieper’s is still in pre-clinical testing, and Neuralstem’s, while farther along, is still years away from patients. Until then, Zach Weinberg and the rest of us are just going to have to stick with our reuptake inhibitors and cream cheese tortillas.

http://scienceline.org/2013/01/shiny-happy-neurons/

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Over the last half decade, it has become increasingly clear that the normal gastrointestinal (GI) bacteria play a variety of very important roles in the biology of human and animals. Now Vic Norris of the University of Rouen, France, and coauthors propose yet another role for GI bacteria: that they exert some control over their hosts’ appetites. Their review was published online ahead of print in the Journal of Bacteriology.

This hypothesis is based in large part on observations of the number of roles bacteria are already known to play in host biology, as well as their relationship to the host system. “Bacteria both recognize and synthesize neuroendocrine hormones,” Norris et al. write. “This has led to the hypothesis that microbes within the gut comprise a community that forms a microbial organ interfacing with the mammalian nervous system that innervates the gastrointestinal tract.” (That nervous system innervating the GI tract is called the “enteric nervous system.” It contains roughly half a billion neurons, compared with 85 billion neurons in the central nervous system.)

“The gut microbiota respond both to both the nutrients consumed by their hosts and to the state of their hosts as signaled by various hormones,” write Norris et al. That communication presumably goes both ways: they also generate compounds that are used for signaling within the human system, “including neurotransmitters such as GABA, amino acids such as tyrosine and tryptophan — which can be converted into the mood-determining molecules, dopamine and serotonin” — and much else, says Norris.

Furthermore, it is becoming increasingly clear that gut bacteria may play a role in diseases such as cancer, metabolic syndrome, and thyroid disease, through their influence on host signaling pathways. They may even influence mood disorders, according to recent, pioneering studies, via actions on dopamine and peptides involved in appetite. The gut bacterium, Campilobacter jejuni, has been implicated in the induction of anxiety in mice, says Norris.

But do the gut flora in fact use their abilities to influence choice of food? The investigators propose a variety of experiments that could help answer this question, including epidemiological studies, and “experiments correlating the presence of particular bacterial metabolites with images of the activity of regions of the brain associated with appetite and pleasure.”

1.V. Norris, F. Molina, A. T. Gewirtz. Hypothesis: bacteria control host appetites. Journal of Bacteriology, 2012; DOI: 10.1128/JB.01384-12

http://www.sciencedaily.com/releases/2012/12/121219142301.htm

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A recent study by a researcher at the Centre for Studies on Human Stress (CSHS) at the Hôpital Louis-H. Lafontaine and professor at the Université de Montréal suggests that bullying by peers changes the structure surrounding a gene involved in regulating mood, making victims more vulnerable to mental health problems as they age.

The study published in the journal Psychological Medicine seeks to better understand the mechanisms that explain how difficult experiences disrupt our response to stressful situations. “Many people think that our genes are immutable; however this study suggests that environment, even the social environment, can affect their functioning. This is particularly the case for victimization experiences in childhood, which change not only our stress response but also the functioning of genes involved in mood regulation,” says Isabelle Ouellet-Morin, lead author of the study.

A previous study by Ouellet-Morin, conducted at the Institute of Psychiatry in London (UK), showed that bullied children secrete less cortisol — the stress hormone — but had more problems with social interaction and aggressive behaviour. The present study indicates that the reduction of cortisol, which occurs around the age of 12, is preceded two years earlier by a change in the structure surrounding a gene (SERT) that regulates serotonin, a neurotransmitter involved in mood regulation and depression.

To achieve these results, 28 pairs of identical twins with a mean age of 10 years were analyzed separately according to their experiences of bullying by peers: one twin had been bullied at school while the other had not. “Since they were identical twins living in the same conditions, changes in the chemical structure surrounding the gene cannot be explained by genetics or family environment. Our results suggest that victimization experiences are the source of these changes,” says Ouellet-Morin. According to the author, it would now be worthwhile to evaluate the possibility of reversing these psychological effects, in particular, through interventions at school and support for victims.

Journal Reference:

1.I. Ouellet-Morin, C. C. Y. Wong, A. Danese, C. M. Pariante, A. S. Papadopoulos, J. Mill, L. Arseneault. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychological Medicine, 2012; DOI: 10.1017/S0033291712002784

http://www.sciencedaily.com/releases/2012/12/121218081615.htm