The straight dope on rational drug addicts

Crack, dope, ice…One hit, and you’re hooked for life.

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Meth: one strike you’re out? Source: http://heisenbergchronicles.tumblr.com/

That’s what the war on drugs has been telling us for years. And for a while neuroscience seemed to back it up. Drugs of abuse stimulate our dopaminergic reward centers, causing a surge of dopamine efflux that changes synaptic transmission, “rewiring” the brain to create intense feelings of craving and drug-seeking behaviours. Lab rats hooked on cocaine will keep pressing a lever for another hit, eschewing food and rest until they die. Addicts beg and steal, enslaved to their drug of choice with a relapse rate as high as 97%.

But 80-90% of people who use methamphetamine and heroin don’t get addicted; not all ex-addicts relapse. In an unpopular series of studies, collectively called “Rat Park”, rats turned their noses at free-for-all morphine, preferring instead to socialize with their rat buddies in an enriched environment.

“Drugs have the power to rob us of our free will” – is this scientific fact, or social-politically construed caricature?

Hart, CL (2000) Alternative reinforcers differentially modify cocaine self-administration by humans. Behavioural Pharmacology. 2000; 11:87-91

The authors recruited 6 experienced crack cocaine smokers, and watched how they responded when offered a choice of between pharmaceutical grade cocaine versus a $5 monetary voucher, or a $5 merchandise voucher which can be used at local stores. In other words, they were offered drugs or an alternative award.

The volunteers were invited to stay at a Clinical Research Facility with TVs, radio and movies for entertainment. They had free access to cigarettes when not in session, but weren’t allowed “extra-curricular” doses of cocaine. At the start of each experimental session, researchers presented the addicts with a voucher indicating what the alternative award is. Addicts then pressed the spacebar a keyboard to “work” for a hit of cocaine, while blindfolded so that they couldn’t tell the dose.

In the subsequent trials, addicts had the freedom to choose to get the same dose of cocaine as the sample trial. But they were also offered an alternative reward: in the first four sessions, it was 5 bucks hard cash; in the last four, a voucher worth 5 bucks which they could trade for merchandise.

As you can see below, at lower cocaine doses (0 and 12mg), addicts choose to receive the voucher (black) or the money (white) more than half of the time. At higher doses though, addicts lusted after the cocaine hit 4-5 times out of the 5 trials.

Screen Shot 2013-09-18 at 9.13.48 PMWhen researchers pool all the data at various cocaine doses together, they found that out of the available 20 doses of cocaine, the addicts requested to smoke 2 doses LESS when cash was available compared to when merchandise vouchers were available. In other words, cash is a more competitive alternative reward. However, because the study did not include a condition where the participants smoked cocaine without the availability of either voucher, it’s impossible to say in absolute terms how much either the $5 or voucher decreased cocaine self-administration.

All the users in the study were kept abstinent except during the trial, except for that one tease at the start of each session. According to popular beliefs, that should have triggered insane cocaine cravings and driven them to choose the drug in subsequent trials regardless of dosage. When given an alternate to cocaine, the addicts were capable of deciding that a low dose wasn’t “worth it”. They made a rational choice. Presumably the effect size would’ve been larger if the monetary reward was higher  – this was indeed the case in a follow-up study with meth addicts, when the monetary reward was upped to $20.

The study is not without its faults. First, it suffers all the problems of small sample size, especially generalizability. Second, the addicts had to work for cocaine, while the alternative reward was readily available (albeit one can argue whether pressing a space bar several times can be counted as “work”). I would’ve loved to know what would’ve happened if they were offered the money first, then given the choice to keep it or spend it on a hit in the lab? And what did the addicts DO with the money after the study – did they use it to buy more drugs?

Nonetheless, the author of this study stresses that neuroscience has a lot to loose by caricaturizing addiction as the “one-hit you’re done” boogeyman – it essentially takes out all social-economic factors, and solely focuses on the drug’s pharmacology. This is understandable in one sense – studying drugs in a sterile lab out of context is simple – but perhaps a more useful approach is to understand why some, but not others, get hooked for life. The personal traits and environmental influences that bias someone towards drug addiction are mainly still unknown, though individual differences in cognitive control and early-life stressors definitely play a role.

As Mind Hacks eloquently puts it:

“Nonetheless the research does demonstrate that the standard ‘exposure model’ of addiction is woefully incomplete. It takes far more than the simple experience of a drug – even drugs as powerful as cocaine and heroin – to make you an addict. The alternatives you have to drug use, which will be influenced by your social and physical environment, play important roles as well as the brute pleasure delivered via the chemical assault on your reward circuits.”

Head over there if you’d like to read more about Rat Park and the complexity of addiction.

Hat tip to @Scicurious for news on the lead author of this study, Dr. Carl Hart, who has a book out on the topic – looks like an interesting read.

ResearchBlogging.org
Hart CL, Haney M, Foltin RW, & Fischman MW (2000). Alternative reinforcers differentially modify cocaine self-administration by humans. Behavioural pharmacology, 11 (1), 87-91 PMID: 10821213

“Cocaine addiction may be cured by Ritalin!” …Hmm, really?

I saw this headline from an r/science thread the other day, and had to look into it. As you’ve probably guessed, the answer is no, but the idea behind it is still a fascinating story.

Lots of people experiment with drugs; only some become addicted. Many addicts try to quit; only some succeed without relapse. Why?

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Anatomy time!! Source: Baler R & Volkow ND. (2006) Drug addiction: the neurobiology of disrupted self-control. Trends in Molecular Medicine 12(12) 559

One idea is that people have a different baseline of self-control. The decision to take (“go”) or not take (“no go”) a drug comes from the orbitofrontal cortex (OFC – green in the graph above), a part of the frontal lobe in charge of thinking through a decision making process. The OFC gets its info from two regions: the nucleus accumbens (NAcc – red), which learns about rewards, and the prefrontal cortex (PFC) and Anterior Cingulate Cortex (ACC -blue), which inhibits impulse and restrains craving. (The hippocampus and amygdala, in purple, are important for drug-reward learning and memory.)

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In a non-addict, the ACC-PFC (blue) usually wins out, telling the “judge” OFC to deny the motion. You don’t take the drug. However, in some vulnerable individuals the NAcc (red) wins out, and every time they take a drug – say, cocaine – it changes this pleasure-sensing, reward-predicting part of your brain, increasing its sensitivity to both the drug and its associated cues. At the same time, it also weakens inhibitory control, which skews the OFC towards a “go” decision. This breakdown of self-control clearly sets up the stage for unrestrained cycles that eventually results in compulsive drug taking.

So what if we can use a drug to bring back cognitive control and reset the circuitry? Would that treat addiction?

Here’s where Ritalin comes in. Like cocaine, Ritalin (methylphenidate) is a stimulant that increases dopamine level, just at a much slower pace with longer duration. Since there’s no spike in dopamine, there’s no rush. So, just like using the longer-lasting methadone to wean opiate addicts off heroin, it seems reasonable that Ritalin could be a used as a cocaine substitute on the route of recovery. However, Ritalin packs a one-two punch (otherwise it would be a “oh-duh!” story). As a medication for ADHD, one of its major effects is to strengthen cognitive control. It works especially well in this regard in people who have lower baselines of cognitive inhibition to begin with, like drug addicts. Put the two together, and Ritalin seems like the perfect candidate for battling cocaine addiction.

Problem is, on the behavioural level, it doesn’t work. Double-blind studies show that users didn’t report lower cravings in response to cocaine-associated cues, nor did they lower their drug use or relapse rates. However, these results are plagued by the curses of small sample size and high dropout rates, so researchers aren’t ready to throw Ritalin out the window just yet. Unfazed, they decided to directly peek into the brain with fMRI, to see if Ritalin has a more profound effect at the neural level.

In a 2010 study, researchers recruited 13 cocaine addicts (~18 years use) and 14 controls, stuck them in an fMRI while they completed a task. Here’s how it went: the volunteers were shown two types of words, either neutral or drug-related. All the words were in colour, and they had to press a button corresponding to the colour as fast as they could.

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Under placebo (blue circle, left graph), the coke-abuser’s ACC (which controls inhibition) showed very low response to drug-related words; when given Ritalin (red circle), the ACC’s response shot up to that higher than controls’ (purple arrow). In a sense, Ritalin re-sensitized the coke addicts’ control center to drug-related cues. In terms of task performance, Ritalin also decreased impulsivity, evidenced by the lower number of errors they made (yellow arrow, right graph) – but the same also happed to healthy controls when given Ritalin. In fact, the addicts didn’t significantly perform worse than the controls, even with ACC hypo-activation. So under the hood, Ritalin seems to be strengthening cognitive control – it’s just not reflected in behaviour.

Now in a new study, the researchers wanted to know if Ritalin can change brain connectivity under a resting state. “Resting state” is quite the oxymoron, as the brain never shuts down completely. Instead, it exhibits spontaneous fluctuations in neural activity between brain regions, which also goes awry in cocaine addiction. Researchers recruited 18 volunteers who fit the criteria for cocaine addiction, but were otherwise healthy and not taking any medications. The volunteers when then given either placebo or Ritalin (20mg) and had their brain imaged. Here’re the findings: compared to placebo, Ritalin normalized the strength of 6 connectivity pathways related to emotional regulation, memory formation, craving suppression and inhibitory control. Ritalin had a similar degree of effect on all volunteers, regardless of how severe their cocaine addiction is. In this study, the researchers didn’t check for subjective feelings of craving after Ritalin administration.

So what’s the verdict? Can Ritalin help cocaine addiction? The evidence really isn’t strong. Nevertheless, it’s interesting that one dose of the “cognitive enhancer” can rectify some of the neural connectivity problems seen in addiction. In all honesty, I would be surprised if one dose of Ritalin can “treat” cocaine addiction, in terms of decreasing craving and drug-seeking. After all, the addiction to drugs of abuse doesn’t happen in a day with one dose either. In future studies, it would be interesting to see if multiple treatments with Ritalin, over a long period of time, can exert a behavioural effect in addition to the neural one. It would also be interesting to test the effects of Ritalin and cognitive-behavioural therapy (CBT), and see if this combo is stronger than CBT alone.

The idea of using cognitive enhancers for addiction therapy is gaining steam. Clinical trials with AdderallRitalin and Modafinil are all ongoing, and hopefully, larger studies with longer timeframes will give us a more conclusive result.

What do you guys think? Are scientists beating a dead horse, or is there actually something worth pursuing?

ResearchBlogging.org
Konova AB, Moeller SJ, Tomasi D, Volkow ND, & Goldstein RZ (2013). Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction. JAMA psychiatry (Chicago, Ill.), 1-11 PMID: 23803700

ResearchBlogging.org
Goldstein RZ, & Volkow ND (2011). Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36 (1), 366-7 PMID: 21116260