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The Peptide That Binds: Overview of Human Research

UC Berkeley researchers just published a review of human oxytocin studies in the Harvard Review of Psychiatry. Behavioral Health Central has a brief report. In a nutshell:

The researchers concluded: "Key conclusions are (1) human research with intranasal oxytocin has uniquely enhanced our understanding of the microstructure and function of the human social brain, and (2) the oxytocin system is a promising target for therapeutic interventions in a variety of conditions, especially those characterized by anxiety and aberrations in social function."

The paper is called The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans.

New Oxytocin Trials Recruiting

Most of us should be able to increase our oxytocin by practicing comfortable behaviors, which may be as simple as calling a good friend or going to the dog park and scratching some ears. But I know that there's strong interest in some kind of drug we could take to either amplify our natural oxytocin or to experience the kind of oxytocin release that doesn't come naturally to us.

At this point in time, most researchers are focusing on using oxytocin to treat diagnosable disorders including social anxiety, autism and schizophrenia. While these studies test oxytocin's use in diagnosed disorders, if they result in marketable drugs, it's very likely that psychiatrists will begin to prescribe them off-label, that is, for other permissible treatments besides those for which the drug is sold.

UC San Diego is recruiting subjects for two studies of the effects of oxytocin on psychiatric disorders. One study will test whether an oxytocin inhalant can improve residual symptoms of schizophrenia. Another will look at oxytocin's effects on anxiety. If you have a diagnosis of SAD, GAD or PTSD and want to enroll, contact Angel Nguyen at 619-543-8296 or by email.

Meanwhile, if you're curious and live in the Boston area, Harvard is recruiting for a study of the connection between social support and oxytocin.  For more information or to enroll in the study, contact Laura D Kubzansky at 617-432-3589 or by email.

When I began researching my book four years ago, there were very few clinical studies of oxytocin. Now, there are lots, more than I want to mention in this newsletter. To find out about these -- or trials for other kinds of drugs -- search ClinicalTrials.gov.

WAY-267464: The Love and Connection Drug?

Jett asked me about WAY-267,464, after finding this Wikipedia entry on it. After looking through my archives, I found that I had discussed this potential drug that Wyeth is working on with Dr. Robert Ring, Head of Molecular Neurobiology, Depression & Anxiety Disorders, Discovery Neuroscience, Wyeth Research.

The original draft of my book, The Chemistry of Connection, contained a whole chapter about potential oxytocin therapies. Unfortunately, my publisher didn't want much of this in the book. But there's immense interest in oxytocin drugs, and I believe that oxytocin is going to be the wonder drug of this decade -- or maybe next decade.

In February 2007, I interviewed Wyeth's Robert Ring about the potential for oxytocin therapies. Below is the section of the chapter discussing WAY 267,464, with some additional comments.

The delivery method -- how to get a drug inside someone -- is a huge issue for oxytocin. The nasal spray stings and doesn't last very long; injections hurt; IVs are cumbersome and unpleasant; pills break down in the digestive system before they have a chance to work.

That's why pharmaceutical companies will likely produce drugs containing proprietary oxytocin-like molecules, instead of bio-identical oxytocin. These designer molecules will bind with oxytocin receptors, but they'll have other characteristics that make them more effective or limit what they do.

Robert Ring, head of molecular neurobiology, depression and anxiety disorders, discovery neuroscience for drug giant Wyeth Pharmaceuticals, is unusual among drug company executives for being willing to discuss oxytocin drug development.

"We're blown away at the various diverse range of functions oxytocin seems to be acting on," he says. "Working at a drug company, you can't ignore the fact that oxytocin seems to be a multifunctional anti-stress peptide -- and it seems to be a potent analgesic as well."

One hot prospect is Wyeth's WAY 267,464. It's not a peptide like oxytocin is, which means that it won't degrade into other neurologically active substances. Instead, it's an oxytocin agonist, that is, it increases the effects of oxytocin. The advantage of treating with an agonist instead of simply trying to supplement the brain's natural supply is that often, when docs dose someone with a hormone, it further inhibits the body from producing it. WAY 267,464 also is less likely to cross over and bind to vasopressin receptors. This is important because, while scientists haven't nailed down vasopressin's role in human bonding and social interaction, it definitely seems to be important. So, the less you get in there and muck with unknown systems, the better.

In animal studies, the substance, known as 464, behaves much like oxytocin in reducing anxiety, and it also has some promise as an anti-psychotic.

Eric Hollander of the The Seaver Center for Autism Research and Treatment, Mount Sinai Medical Center, would seem to have a patent lock on teating symptoms of autism spectrum disorder, or ASD, and other disorders using oxytocin. Wyeth isn't concerned about Hollander's patents; it hopes to develop a unique molecule that binds to oxytocin receptors but has better properties for a drug. Neither is it working on an autism drug -- at least, Ring wouldn't say it is.

He pointed out that, although there's intense interest in using oxytocin to treat ASD symptoms. Because oxytocin and oxytocin-like drugs are a novel category, the path to FDA approval isn't clear. It might not be easy to demonstrate positive outcomes using standard methodologies.

Oxytocin's broad reach, relieving pain, reducing stress and soothing anxiety, could be an extra benefit for conditions with complex pathologies. Depression, for example, may go along with anxiety, chronic pain or physical illness. Oxytocin could potentially relieve these "co-morbid" conditions, Ring says. Easing any one of them would be important. Anxiety itself, he adds, is "a huge market."

Another promising area for the industry might be an antidepressant without the sexual side effects of selective serotonin-reuptake inhibitors like Prozac and Paxil. Over time, as these drugs increase the level of serotonin in the brain, prolactin also rises. Among its many roles in the body, prolactin induces the feeling of sexual satiety after orgasm. Chronically high levels of prolactin therefore can make you feel you've had enough sex, even if you aren't having any at all. An apathetic sex life is a common complaint among people on SSRIs.

Although oxytocin release is often promoted by serotonin, oxytocin also helps regulate sexuality, and it seems to be involved in erections of the penis and, presumably, the clitoris. So, it's possible that an oxytocin-based antidepressant could actually improve someone's sex life, as well as his frame of mind. Dr. Ring told me, "It's one thing to treat male erectile dysfunction, but there's a much bigger market for therapeutics for female dysfunction." While lubrication or engorgement problems may be neurological, oxytocin might be important for the motivational side of things. For example, if some aspect of sexual dysfunction had to do with anxiety about interacting with your partner, anything that would lower that anxiety might help.

(My editorial comment: For most women, anxiety about potential sexual partners is protective and a good thing. Ideally, any of these potential drugs would only be given to women with anxiety disorders. We hope.)

But don't expect 464 to turn into a pharmacological silver bullet. While its action in the body is remarkably like oxytocin's, Ring cautioned that this molecule may lack some of the properties of a good medicine. A successful oxytocin mimic should be able to be taken orally, and ideally, just once a day.

Wyeth Research is, of course, focusing on developing drugs to treat psychiatric disorders. But if a drug like this comes out, it may, like SSRIs or Provigil, also be taken up by people who haven't been diagnosed with a disorder but are just hoping to warm up their lives a bit.

This July 2009 paper in Neuropharmacology details tests of WAY-267464 on mice.

Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin agonist. 

And here is the Wyeth patent application for using oxytocin receptor agonists to treat schizophrenia and anxiety disorders.

Joy Goes to an Oxytocin Party

My pal Joy Nordenstrom, CEO of JoyofRomance.com, hosts romantic dinner parties and coaches clients on how to be more romantic. She also produces IntelligentLove: 411 for Men. In this series, she uses scientific principles to help men get more real love and connection with women.

She went to an oxytocin party, where people took oxytocin lozenges. I had always thought that you could only get liquid oxytocin with a doctor's prescription, but I have since found that this is not true!

Watch the video here: Oxytocin Party Video

A couple of notes: As I said in the comments, it should be noted that these people are holding the lozenges under the tongue, not swallowing them. It's debatable whether sublingual drugs reach the brain, but, since intranasal drugs demonstrably do, I think it's possible.

Shameless self-promotion: If you want to find out everything that science knows about oxytocin's effects on the brain, including how to naturally experience an oxytocin release in the brain, please buy my book, The Chemistry of Connection: How the oxyotcin response can help you find trust, intimacy and love.

Ecstasy Drug Could be PTSD Breakthrough

Two researchers at the Norwegian University of Science and Technology propose that ecstasy, also known as MDMA, could be a valuable tool in therapy to treat post-traumatic stress disorder, or PTSD.

According to the article on EurekaAlert, Pål-Ørjan Johansen and Teri Krebs think that the recreational drug could be valuable for several reasons, including its ability to produce an oxytocin response.

According to Johansen and Krebs, "MDMA [ecstasy] has a combination of pharmacological effects that…could provide a balance of activating emotions while feeling safe and in control."

Psychiatrists are testing oxytocin inhalants to produce similar results. Oxytocin and/or ecstasy/MDMA might also be helpful for social anxiety disorder.

The entire journal article, How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale, in Psychopharmacology, is available for a little while for free; I've linked to the permanent abstract.

Actually, I covered this story back in February. Please see the earlier blog entry on oxytocin and PTSD.

Oxytocin Helps a Guy Ejaculate

One guy, okay? But this study points to still another potential therapeutic use for oxytocin, which sure seems like some kinda wonder drug.

A test published in April 2008)  at Cedars Sinai examined whether inhaling oxytocin would help a male patient who couldn't orgasm. The docs had ruled out medical conditions, drugs and  "psychological issues" as the cause of his inability to  ejaculate.  Yes, it did. He was able to ejaculate.

Why this worked is unclear from the abstract. My speculations:

Oxytocin relieves anxiety, and maybe this man had become so anxious about orgasm that he couldn't do it. (Although the researchers ruled out psychological issues, and I assume anxiety would classify.)

Oxytocin is responsible for erection and ejaculation (along with other chemicals). And a review of animal studies opined that the reason that SSRIs lower sexual desire and function could be because they decrease the sensitivity of oxytocin receptors. If this patient's oxytocin receptors had reduced sensitivity for some reason, the extra jolt of oxytocin could have been what was needed.

Ecstacy Helps PTSD Treatment

Two Norwegian scientists, Pål-Ørjan Johansen, a psychologist at the Norwegian University of Science and Technology, and  Teri Krebs, a neurobiologist at the university, have offered an explanation for how ecstasy aka MDMA might help people get over post-traumatic stress disorder.
They've analyzed a study by Michael Mithoefer that found ecstasy made treatment much more effective, as well as other studies. From Science Daily:

Mithoefer took 21 people with chronic PTSD, all of whom had been subjected to documented abuse. All had also been through six months of treatment with traditional therapy, in addition to a three-month treatment with drugs. None, however, had shown any improvement from the treatment.

Under Mithoefer’s treatment, the patients stopped their usual anxiety-reducing drugs, and began a new treatment with twelve sessions of psychotherapy. During two of these therapy sessions, some patients were given doses of MDMA, while the others were given a placebo (a fake pill).

Two months after the treatment, 92 percent of MDMA patients had clinically significant improvement in their conditions: They were more open to therapy and were able to process the trauma.

The researches propose that part of this effect is due to MDMA's increasing levels  of oxytocin in the brain, thereby making the person feel more trusting and open to the therapeutic relationship.  MDMA also reduces activity in the amygdala -- and this is likely also the result of the increase in oxytocin, because in other tests, inhaling oxytocin lowered activity in this part of the brain, which is responsible for pre-conscious emotional reactions such as fear.

The Norwegian University of Science and Technology (2009, January 8). Ecstasy For Treatment Of Traumatic Anxiety. ScienceDaily.

Finally! Massage Increases Oxytocin

UCLA scientists have confirmed something we feel intuitively must be true: Massage increases oxytocin.

Countless magazine and newspaper articles have said getting a massage is a good way to increase your oxytocin levels, and it sure makes sense. But there has been no scientific evidence that it was the case. According to this article in the Boston Globe, a new study included not only playing the Trust Game after getting a massage, but also drawing people's blood to measure the oxytocin levels. This study used men and women, too.

According to the article,

volunteers at UCLA were randomly assigned to be massaged or just wait in a room for 15 minutes and then play an anonymous, one-shot, money-giving game via computer. Those who were massaged returned 38 percent of the money that was given to them, compared with 11 percent for those who were not massaged. The researchers also drew blood from each person before and after the experiment to see if physiological changes - namely in the level of the hormone oxytocin, which is known to influence bonding behavior - could explain the effect. There was an increase in oxytocin only for those people who were massaged and then played the game.

Another way to describe the effect of oxytocin is to say that the well-kneaded group returned 243 percent more money than the stiffer bunch. The effect was stronger in women than in men, which also makes sense, given our greater sensitivity to oxytocin's effects.

They saw this effect not so much after the massage itself as after the trust game. Paul Zak, one of the researchers, thinks that the massage acts as a signal to the brain to be open to trusting interactions.

Another way of saying this is that massage makes us more relaxed, and when we're relaxed, we tend to be more open to others.

To get the most oxytocin-producing benefits, choose a gentle, soothing massage style. Avoid deep tissue work or acupressure; while these are valuable techniques for reducing muscle tension, their intensity may not allow for the right kind of relaxation. The Swedish or Esalen styles use gentler, rhythmic motions that have been shown to elevate oxytocin levels in animals. After the massage, you can test whether you feel more open to connection by calling or visiting with a friend.

"Monetary Sacrifice Among Strangers is Mediated by Endogenous Oxytocin Release after Physical Contact," is by Vera B. Morhenn, Jang Woo Park, Elisabeth Piper, Paul J. Zak, in Evolution and Human Behavior.

Oxytocin Hype and Backlash

I read New York magazine, and they have a regular item called something like "We ride the shifting curve of expectations." They chart where cultural events like books and films fall on the cycle from hype to backlash against the hype.

In the past couple of weeks, I've watched oxytocin follow a similar path. Because I look at every news article and study regarding oxytocin, as well as all the blog posts discovered by a couple blog search tools, I can see what studies spark news coverage, and what kinds of memes spread.

Oxytocin hype has been rampant for the past three weeks. As far as I can tell, it got started with study led by Thomas Baumgartner at the University of Zurich showing that inhaling oxytocin increased people's willingness to trust other players in an economic game, even after they'd been shafted once. This is the team at the University of Zurich that did the very first human oxytocin studies showing that oxytocin increased trust. (Read my blog post about the previous research here.)

In this study, "We find that subjects in the oxytocin group show no change in their trusting behavior after they learned that their trust had been breached several times while subjects receiving placebo decrease their trust."

Some genius copywriter translated this to, "Oxytocin Makes Us Trust after Betrayal," leading to a spate of stories about how "Spray Said to Turn People into Pushovers." And it also led to my appearance on the Fox Morning With Mike and Juliet show.

Not to be outdone, Markus Heinrichs, who leads the Zurich team, talked to reporters (but did not, I believe, actually publish anything new) about their work using oxytocin to treat social anxiety disorder, which has been under way for several years. That sparked another news rush.

They mostly followed the lines of this one, Scientists Find Childbirth Wonder Drug That Can Cure Shyness, kindly sent to me by Blaine. Is that a sexy headline or what? The articles finally recognized the work of Paul Zak, who has been giving oxytocin to humans for several years, without a lot of notice. I didn't blog all these articles, partly because they were so ubiquitous and partly because I was finishing the manuscript of my book, ta daaa!

Already, though, oxytocin hype has faded into the final cycle, backlash. In part this is simply because news reporters have to come up with new stories every day. Once you've written a story hyping the prospects of oxytocin -- or worse, when your competitors have and you haven't -- where do you go from there but to write another one decrying the first. Ideally, at least in the olden days when I started my career as a journalist, you were supposed to find naysayers to quote in every story. But that was then.

The Neurocritic links to an ABC News story now insisting, "Researchers Balk at Media Reports Hyping 'Love Drug' Hormone's Effects."

And Paul Zanucci of American Sentinel calls it, "The Oxytocin Nightmare to Come -- Drugging America." I agree with his premise, and have been saying for a while that oxytocin will be the next Prozac. That is, while oxytocin-based or oxytocin-like drugs will be developed for social anxiety disorder and ASD, it will eventually be prescribed for much milder psychological situations. Zanucci writes,

Every time someone blows their nose, there’s a new prescription written for nasal sprays and antihistamines even though products like Zyrtec can now be bought OTC in generic form.  Every time someone is stressed out by work, another prescription is written for anti-anxiety medication.  People are happy as clams to pay $30 to $50 for the latest in pharmaceutical living, not considering that their insurance is paying another $300 behind the scenes and that their cost for insurance is going to go up again next year.

Nevertheless, I think calling this a nightmare is way too anti-hyperbolic. I'd much rather we revise labor, birth and parenting practices to allow individuals to form a healthy oxytocin response naturally. But our society is probably too sick and mechanistic for that. In which case, a nation of loved-out citizens who inhale oxytocin several times a day would be preferable to our extant war-mongering, paranoid, crabby society.

At any rate, I think we can shortly expect oxytocin to fall off the news cycle for at least a few months.

Get Oxytocin Safely in Clinical Trials

In response to a recent comment, I took a new look at the database of clinical trials that are recruiting subjects for oxytocin studies, available at ClinicalTrials.gov. I see that Daniel Feifel of the University of California San Diego is recruiting subjects for two studies to test oxytocin on symptoms of schizophrenia.

And it looks like Evdokia Anagnostou of Eric Hollander's Mt. Sinai team is recruiting for a couple of studies of adults with ASD, although it's hard to tell if the database is current.

Meanwhile, the National Institutes of Mental Health is recruiting for a study of people without psychiatric diagnoses on "Identifying the Role of Oxytocin and Vasopressin in the Functioning of Neurocognitive Systems Involved in Mood Disorders."

We can expect more and more of these as #1 scientists strive to learn more and more about the neurochemical basis of emotion and #2 pharm companies look for new classes of drugs they can sell.