杏吧原创

JOSEPH SHARP remembers the first time he injected methamphetamine. 鈥淚t shot up like a geyser into my brain and I actually spluttered aloud, involuntarily, 鈥業 want to do this every day for the rest of my life鈥�,鈥� he says. 鈥淚t was like the euphoric feeling of being madly in love.鈥�

Sharp first used the drug 鈥� also known as crystal meth or ice 鈥� to lower his inhibitions and make him 鈥渟uper social鈥�. Having recently moved to Los Angeles to become a screenwriter, he was eager to make friends. But as addiction took hold, he gradually withdrew from those close to him. 鈥淚n the end, it was just me alone in a room with a needle in my arm,鈥� Sharp says. 鈥淭alk about social.鈥�

This story sounds familiar to at the University of Sydney, who has been studying substance abuse for over 25 years. One of the hallmarks of addiction is a waning interest in human contact and a growing fixation on seeking out the vice 鈥� be it alcohol, amphetamines, cocaine, heroin, prescription opioids, nicotine or any other addictive substance.

A decade ago, this observation gave McGregor an idea. Would it be possible to reverse substance addiction by switching the brain back from drug-chasing mode to social mode? If McGregor鈥檚 hunch was right, this could be the silver bullet 鈥� a universal treatment for all addictions at once.

It was worth a shot. Alcohol, tobacco and illicit substances are . Prescription opioids are adding to this crisis. In 2016, in the US alone, .

But even though addictive substances claim almost as many lives as cancer each year, no cures are available and few drug firms are interested in developing them. 鈥淪ubstance users are not a very popular population for health funding and not many pharmaceutical companies want to associate with them,鈥� says at the University of Adelaide in Australia. Existing treatments for substance addictions have had limited success.

To try to restore the social behaviour of drug users, McGregor set his sights on oxytocin, known as the love hormone or cuddle chemical. Naturally released during social interactions, sex and when women give birth, it helps to strengthen human bonds.

As a starting point, McGregor tried injecting oxytocin into rats that were so heavily addicted to methamphetamine that they would push a lever hundreds of times just to get one hit. 鈥淲e actually had to limit their intake or they鈥檇 overdose and die,鈥� he says. The results were astounding: the oxytocin-treated rats , a sign they had lost interest in the drug.

Next he tried it with alcohol. Along with , who was then his student but is now a colleague, McGregor showed that alcoholic rats if they were given an oxytocin injection directly beforehand. Other research groups found that oxytocin and in rats.

Following these promising findings, several small clinical trials were set up in the US to test the potential of oxytocin for , , , , and . Unlike in rat studies, the hormone couldn鈥檛 be injected in large doses into peoples鈥� bloodstreams or directly into their brains due to safety issues. So to get the oxytocin into the brain, they sprayed it up the nose.

However, the results from these trials so far have been disappointing: intranasal oxytocin relieves drug cravings only slightly, if at all. This is probably because . The large molecule has trouble crossing the blood-brain barrier and is known to break down easily in the circulation.

To overcome this problem, McGregor and Bowen teamed up with and his then student William Jorgensen, medicinal chemists at the University of Sydney, to help develop an oxytocin mimic that was small enough to cross the blood-brain barrier, but still had similar actions. They came up with an idea, but it was a tricky molecule to make, and Kassiou鈥檚 team ran into problems trying to put its three individual parts together.

Growing impatient, McGregor suggested to Jorgensen that they test these three precursor fragments in rats 鈥渏ust for the hell of it鈥�, says Bowen. The first two fragments did nothing. But after they injected the third one, they found the rats became more social, showing an increased preference for spending time with other rats rather than objects, and even cuddling up to rats they had never met before. 鈥淏ingo. That was when we thought it must be activating the oxytocin system,鈥� says Bowen.

To confirm this, they looked at what was happening in the rats鈥� brains. Sure enough, they found the fragment was strongly activating the brain鈥檚 two major oxytocin-producing factories.

鈥淭he drug seems to prevent relapse, one of the biggest barriers to recovery鈥�

Since then, the team 鈥� named synthetic oxytocin-like compound 1 (SOC-1) 鈥� in rats addicted to methamphetamine, rhesus monkeys hooked on cocaine and baboons with an alcohol habit. The results have been 鈥渘othing short of incredible鈥�, says Bowen.

For example, when SOC-1 was injected into the rats, their motivation to consume methamphetamine 鈥� measured by how many times they pressed a lever to get a hit 鈥� dropped by more than 85 per cent. Similarly, with the rhesus monkeys, their interest in self-administering cocaine fell by 90 per cent. In other words, instead of pressing a lever almost 350 times to get one intravenous shot of cocaine, the monkeys gave up after 35 goes.

Impressively, the molecule also seemed to prevent relapse, one of the biggest barriers to recovery in those with substance use disorders. Research shows that within the first year of leaving rehab. 鈥淭he biggest problem is not quitting, but staying quit,鈥� says Sharp, who relapsed after four years, then took two years of stopping and starting to get clean again.

There are three common triggers for relapse. The first is stress 鈥� for Sharp, it was breaking up with his boyfriend. The second is a cue 鈥� for example, walking past your drug dealer on the street. And the third is a prime 鈥� 鈥渓ike one sip of beer that turns into 20 beers and half a bottle of vodka鈥�, says Bowen.

SOC-1 seems to weaken the power of these triggers. In one experiment, rats were trained to push a lever to self-administer methamphetamine. Once they were addicted, the set-up was changed so the lever no longer released any drug. Eventually, the rats gave up pressing it 鈥� this was the 鈥渞ehab鈥� phase. But then they were given one tiny dose of methamphetamine. Immediately, they switched into a frenzied state, hammering the lever over 120 times during a 2-hour period to try to get another hit. In contrast, those treated with SOC-1 just before receiving this prime barely touched the lever.

According to McGregor, the effects of SOC-1 could be long-lasting. 鈥淲e know that oxytocin brings about what psychologists call a state change,鈥� he says. 鈥淔or example, in childbirth, mothers don鈥檛 want to be in love with their babies just for a few minutes. The initial oxytocin surge needs to have an enduring effect.鈥� This idea is borne out by his and Bowen鈥檚 research. They showed, for example, that alcoholic rats given a single dose of oxytocin across the full six weeks of the experiment. They also found that administering a short course of oxytocin to adolescent rats and in adulthood.

The big question the team is now trying to answer is: how exactly does SOC-1 work? Their research so far suggests it stimulates a rush of oxytocin that recalibrates the brain鈥檚 focus towards social engagement.

We have known for a long time that pleasurable sensations are orchestrated by dopamine 鈥� the 鈥渇eel-good chemical鈥� 鈥� in a part of the brain called the nucleus accumbens. But over the past two decades, we have discovered that in this area. D1 dopamine receptors are activated by stimulation from objects like and , but can also be powerfully hijacked by drugs. D2 dopamine receptors, in contrast, . And it seems that oxytocin has a double whammy effect: , while at the same time , which increases social behaviour.

This fits with several lines of evidence. Research shows that people with fewer D2 dopamine receptors , perhaps because they try to compensate by stimulating their D1 dopamine receptors with drugs.

Moreover, chronic substance use is known to reduce levels of D2 dopamine receptors and oxytocin, making it increasingly difficult to get satisfaction from social interactions. In prairie voles addicted to amphetamine 鈥� also known as speed 鈥� this has the striking effect of breaking up their normally monogamous relationships. But an oxytocin hit can restore the bond, probably by reinvigorating the social dopamine pathway, according to research by at Florida State University and his colleagues, who .

Phase I clinical trials with a pill version of SOC-1 are planned for 2019. First, they will look at treating people who have drug addictions, but one day it might be possible to inoculate teenagers against future drug addictions.

They are hopeful that SOC-1 will work as well in people as it did in the lab animals, since the basic reward pathways in the brain that are hijacked by drugs are similar across species. They also believe it could work for addictions to all drugs of abuse, since they operate on the same dopamine pathways. This would be particularly helpful for people with methamphetamine and marijuana dependency, for which there are no current treatments available, says Buisman-Pijlman. 鈥淚t would be a really big step forward.鈥�

But will it have side effects? In lab animals, SOC-1 didn鈥檛 show any signs of toxicity and didn鈥檛 cause weight changes or problematic behaviour. Importantly, SOC-1 isn鈥檛 addictive itself: rats given the opportunity to self-administer showed no interest in doing so. And in human studies of intranasal oxytocin, participants can鈥檛 tell if they have been given the active agent or a placebo. 鈥淥xytocin doesn鈥檛 seem to be rewarding in and of itself,鈥� says Bowen. 鈥淚t鈥檚 more subtle. It might just make you want to hang out with your friends instead of pursuing a drug.鈥� This makes SOC-1 different to replacement therapies like methadone, which can help people get off heroin and other opioids, but is addictive itself.

鈥淭oo much of an oxytocin boost could have unintended social effects鈥�

Buisman-Pijlman says SOC-1 is promising, but cautions that drug addiction is far more difficult to treat in humans than in lab animals. People with substance use disorders often have other psychological issues, such as post-traumatic stress disorder, depression or schizophrenia, which can affect their response to treatment. Sharp agrees that it鈥檚 complex. 鈥淚鈥檝e yet to meet an addict who isn鈥檛, in some manner, self-medicating a mental health issue with the drug,鈥� he says.

And too much of an oxytocin boost could have unintended effects. 鈥淥ne of the problems is that we don鈥檛 know a lot yet about our normal oxytocin system,鈥� says Buisman-Pijlman. 鈥淪o if you cause a big increase, then what? More is not necessarily better.鈥�

Studies of intranasal oxytocin have already pointed to a possible dark side of the hormone. Growing evidence suggests that by making us feel more connected with our loved ones, oxytocin can also foster hostility towards other groups.

For example, at Leiden University in the Netherlands showed that oxytocin-sniffers playing a game seemed to display , but greater defensiveness towards a competing out-group. Dutch students given intranasal oxytocin were than a Dutch name in a hypothetical life-or-death scenario. And chimpanzees were found to get an oxytocin rush before going into battle with rival clans. Although the amount of oxytocin that crosses the blood-brain barrier from a nasal spray isn鈥檛 enough to help with addiction, it seems to be enough to elicit behaviour change.

Worth a gamble

Then again, in the context of substance addiction, SOC-1 may simply return oxytocin levels to normal rather than pushing them too far, says Buisman-Pijlman. Moreover, if it is life-saving, it won鈥檛 matter if it has some small side effects, she says. 鈥淭here鈥檚 not a lot of new stuff coming out for treating substance addiction,鈥� she says. 鈥淧eople are trying things, but often it鈥檚 a case of making a small tweak to a drug we already have that doesn鈥檛 work very well. Maybe SOC-1 will not be perfect, but it鈥檚 something new and it could be a big improvement.鈥�

McGregor and Bowen are now looking into other possible applications of SOC-1, like treating social anxiety. It might also work for other types of addiction, like gambling, which has a similar effect on the brain to drugs.

But for the time being, their main focus is tackling drug addiction. 鈥淔or the millions of people who are really struggling with these disorders, I hold great hope that SOC-1 will provide the breakthrough they are waiting for,鈥� says Bowen.

Sharp, who has been clean for over a year with the help of Crystal Meth Anonymous meetings and psychotherapy, says that anything that could alleviate drug cravings would be an enormous boon. 鈥淥ur disease is cunning, baffling and powerful, and the journey of recovery is much bigger than imagined,鈥� he says. 鈥淚鈥檇 love to be able to recommend a treatment that actually works to users struggling to quit 鈥� we need all the help we can get.鈥�

This article appeared in print under the headline 鈥淎 helping hand鈥�