OTC painkiller may blunt memory loss from puffing pot

Pot’s not the best thing for your memory. Yes, I know there are functional potheads who enjoy their greens and get also their work done. Still, it’s hard to ignore the legions of studies that show Δ9-THC consumption impairs spatial learning and working memory – that is, the ability to hold several pieces of information in mind and manipulate them to reach a mental goal.


Welcome to downtown BC and BC Bud! Source: cannabisculture.com

Yet paradoxically, THC may benefit those with Alzheimer’s disease. Previous research in rats show that the compound breaks down clumps of disease-causing proteins (called β-amyloid plagues) by upregulating a “scissor” enzyme that chops them up. Sweeping out these junk protein plagues decreased the number of dying neurons in the hippocampus, a brain area crucial for learning and memory. THC also has powerful anti-oxidant effects and may protect the integrity of mitochondria – the “power plants” of our cells.

So here’s the dilemma: THC may potentially battle dementia, yet it also naturally impairs memory. In an unexpected turn of events, scientists from Louisiana State University discovered a key protein that mediates THC-caused memory loss, and show in mice that you can have your edibles and eat it too.

The protein in question is COX-2, a crucial player in inflammatory pain – think headaches, muscle pains and fever. Sound familiar? That’s because COX-2 is one of the targets of OTC painkillers such as Asprin and Tylenol (the other one is COX-1). Scientists have previously linked 2-AG, a THC-like substance produced endogenously in the brain, to inhibiting COX-2 signaling. Blocking COX-2 led to problems with memory retention. So naturally, they wondered whether THC impaired memory in the same way.

Screen Shot 2013-11-27 at 1.12.56 PMScreen Shot 2013-11-27 at 1.13.13 PM

They found the opposite. As you can see on the left (blue bars), a single injection of THC boosted the level of COX-2 in both neurons and astroglias (“structural” non-neurons that play a role in memory and inflammation) in the hippocampus; the more THC, the more COX-2. This effect went away by 48hrs after the injection, but when the mice went on a weeklong THC binge (1 dose/day), their COX-2 levels remained chronically high cough unregulated (right graph, red bar compared to control black bar). When researchers blocked the THC/endocannabinoid receptor CB1R by either genetically deleting it or using a selective pharmaceutical blocker, the effect went away, showing that THC administration is indeed the cause of COX-2 increase.

Why would endogenous cannabinoids (2-AG) and THC have polar effects? Further molecular sleuthing revealed that it’s all in the messenger: although both 2-AG and THC activated the same receptor, 2-AG recruited Gα as courier, while THC opted for Gβγ. It’s like slapping a different address sticker on two boxes shipped to the same sorting facility; they’re now going different places. Indeed, Gβγ triggered a molecular cascade that activated several proteins previously shown to impair memory.

Naturally, researchers went on to block COX-2. After a week of THC, neurons begin to loose their spines – that is, little protrusions along the dendrite that house proteins necessary for forming and maintaining synapses (compare red bar/THC to black bar/control below). The breakdown of spines caused a decrease in the many proteins and receptors needed for normal excitatory signal transmission. Unsurprisingly, eliminating these channels of communication blunted the response of a cohort of neurons in the hippocampus after electrical stimulation. However, giving a COX-2 selective blocker concurrently with THC rescued all these deficits – structural, molecular and electrical (green bar – the spines are back!).

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Spines come in all shapes and sizes. Grey bar: COX-2 inhibitor alone; Green bar: THC+COX-2 inhibitor

As for mutant mice that lack COX-2 at birth? They didn’t suffer any of these problems associated with THC. In the case of spines, as you can see above, THC (burgundy bar) had no effects compared to control (blue).

Do any of these “under-the-hood” changes lead to observable behaviour? In a fear-conditioning experiment, researchers trained mice to associate a box with electrical shocks. They then gave some of the mice 7 days of THC with or without a COX-2 inhibitor. When tested 24hrs later – presumably to weed out THC’s effect on anxiety* – stoner mice showed little fear when put back into the box. Those on the multi-drug regime, however, froze in fear. Like their sober peers, they retained and retrieved the fear memory. (The half-life of THC is ~20.1 hrs in mice, so they might have still been high at the time of testing.)

In a spatial memory task, researchers trained mice to find a hidden platform in a big tub of water. After 5 days of training, they then gave a subgroup a single injection of THC 30min before the test, which resulted in these mice taking roughly twice as long to find the platform as the controls. Once again, concurrent COX-2 administration “saved” the memory of the platform location. 24hrs later, after the mice had sobered up, they were tested again – same results.

Amazingly, inhibiting COX-2 did not destroy THC’s ability to wipeout Alzheimer’s-related protein plagues in a mice model of the disease. Treatment with THC once daily for a month, with or without the OTC COX-2 inhibitor Celebrex, significantly decreased the number of protein clumps (green below) and protected hippocampal neurons (blue).

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Top row: control, middle: THC, bottom: THC+COX-2. Last lane is a magnified look.

Before you reach for the bottle of aspirin, joint in hand, maybe hold back on the self-medication just yet. For one, it’s hard to extrapolate these findings to humans, there are some interspecies differences in THC metabolism. Second, chronic COX-2 inhibition is linked to serious side effects such as ulcers and heart problems (think Tylenol is safe? Think again). Third, mice with inhibited COX-2 showed didn’t seem as couch-locked as they normally would; so if you’re after that body high, an aspirin would be rather counter-productive.

As a molecular neuroscientist, I love the detailed characterization of THC-CB1R signalling pathway, but the behaviour data could use some strengthening. Although researchers claimed that the water maze task assessed working memory, the protocol they used looks at normal spatial memory. To specifically probe working memory, they would’ve needed to move the platform to different locations and see how well the mice updated their memory. The results also directly counter those of a previous study, which showed that once the mice learn the location of the platform, THC did not impair the memory. They also didn’t report whether THC mice were simply too stoned to swim (or motivated enough) – tracking total swimming distance and speed at the time of testing would’ve helped .

This study focuses mostly on neurons*; a previous study published in March 2012 showed that THC impairs memory through a type of glia called astrocytes (the non-neuron brain cells); in fact, marijuana impaired working memory only when it was able to bind to the CB1Rs on astrocytes. That study pointed to deregulation of excitatory neurotransmitters as the cause of memory impairment; could COX-2, which is expressed in glia, also have a role?

*Edit: HT to reddit/u/superkuh. The text suggests that the authors of this paper did not consider the role of astroglia; in fact they explicitly did, when they showed that COX-2 upregulation occurred greater in astrocytes than neurons. The authors also showed that the reduction of glutamate (excitatory) receptors was due to COX-2-induced increase in glutamate release from both neurons and glia.

Rongqing Chen et al (2013). Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling Cell, 155 (5), 1154-1165


#SfN13 Tackling depression from both ends

503.Mood Disorders: Preclinical Studies and Animal Models.

503.08. Characterization of CX614, an AMPAkine, as a fast onset antidepressant
Biomed. Sci., Florida State Univ., Tallahassee, FL

503.09. Vortioxetine improves a reversal learning deficit in rats induced by serotonin depletion or chronic stress. DA MORILAK, A WALLACE, A PEHRSON, C SANCHEZ-MORILLO; Pharmacol. and Ctr. for Biomed. Neurosci., Univ. of Texas Hlth. Sci. Ctr., SAN ANTONIO, TX; Lundbeck Res. USA, Paramus, NJ


            Source: http://www.rochetfamilychiro.com

People generally consider depression as something purely emotional – an inescapable distaste towards oneself, an unshakable apathy towards the world, a persistent slow, sticky feeling of exhaustion, as if walking the path of life with glue on both feet.

Yet depression has a strong cognitive component, one so powerful that some scientists believe it to be the root of emotional imbalance. Many sufferers describe their thought patterns as “stuck in a rut”, where they’re only capable of framing things in a negative light, thus seeing the world as pale and hopeless. This observation has prompted two groups of researchers to ask: can we treat depression by targeting cognitive inflexibility?

AMP-A(p) the synapse

Luckily for researchers from Florida State University, we already have a class of cognitive enhancers on the market. AMPAkines are known to enhance attention span and improve learning and memory in the elderly and those suffering from neurodegenerative diseases. These drugs get their name from strongly enhancing the function of the AMPA receptor as a positive modulator. Interestingly, ketamine, the club-drug-turned-fast-acting-anti-depressant requires AMPAR activation to work, suggesting that AMPAkines may not only alleviate depressive symptoms but also act more rapidly than traditional anti-depressants.

Researchers gave a group of young adult rats a single injection of either ketamine or CX614, one of the best-characterized AMPAkines. 24hrs later, they exposed the rats to water and measured how long they swam before giving up in despair. Compared to saline-injected control animals, both ketamine and CX614 reduced the amount of time they spent immobile, though ketamine was slightly more effective at the doses used.

In another cohort of rats, researchers used a stressor (they didn’t say what, but it could be anything from bullies to cats to robots) to acutely trigger depression-like symptoms. Rats have quite the sweet tooth; normally given the choice between sugar and plain water, they lap up the sweet stuff in earnest. However, once depressed, they seem to loose the ability to enjoy life’s pleasures and no longer prefer the treat. Once again, a single injection of either ketamine or CX614 restored their love for sugar within a day. Remarkably, the antidepressant-like effects of CX614 lasted up to 8 days, even longer than that of ketamine.

On the molecular level, many previous studies show that depression reduces the number of synapses, thus negatively affecting the way neurons communicate. In fact, ketamine is known to rapidly reverse this defect, which may be one of the reasons behind its anti-depressant effect. Does CX614 work in the same way?

Using brain tissue isolated from CX614-injected animals, researchers found that within 30min neurons in the hippocampus were actively making more proteins, as evidenced by increased activity of the protein translation machinery. At the same time, CX614 also triggered a cascade of molecular signalling to reconstruct and stabilize actin, a “skeletal” protein that helps a cell maintain or alter its structure.


Anatomy of a spine. Wikipedia

These two processes – protein translation and actin remodelling – allow neurons to form new spines, the little protrusions along dendrites that host synapses formed with (typically) another neuron. In other words, spines provide an anatomical structure for synaptic transmission. Although researchers did not directly prove their case with imaging techniques, these molecular changes certainly suggest that CX614 increases synapse formation.

Thus, like ketamine, AMPAKines may rapidly reduce depressive symptoms; unlike ketamine, they have very low potential for abuse. Whether their cognitive enhancing effects directly contribute to anti-depression though will have to be answered another day.

Flexible thoughts, sunny mind?

Researchers from the University of Texas and Lundbeck Research took the opposite approach – they picked an anti-depressant and investigated its cognitive enhancing effects. Vortioxetine is a selective serotonin reuptake inhibitor (SSRI) like Zoloft and Celexa. However, it also directly binds to and activates numerous types of serotonin receptors, giving it a unique pharmacological profile.

As mentioned above, patients with depression are often unable to flexibly reframe their thoughts. Neuroscientists can identify and measure a similar deficit in rats with a rather sneaky task. They first trained rats to dig for cheerios (yum!) from several pots, some of which smelled like cloves, others nutmeg; some filled with dry grainy sand, others with moist soft dirt. Unbeknownst to the rat, the digging material was just a distraction. Scent was the only clue they had to follow to find the treat.

After rats finally figured out the rules of the game, researchers suddenly switched the cheerios from the clove-sand pot to the nutmeg-sand pot, sat back, and watched how fast the rats updated their strategy as a measure of cognitive flexibility. In the first set of rats, researchers depleted ~90% of their serotonin levels with a chemical, thus coarsely mimicking the dearth of serotonin transmission seen in depressive patients. Unsurprisingly, they performed horribly, steadily going back to the original pot. However, when researchers gave them an injection of Vortioxetine 30min before testing, they rapidly ditched the old pot for the new.

Researchers then stressed a new group of rats with bouts of intense and unpredictable cold for 14 days straight. This treatment is often used to trigger deficits in reversal learning as well as depression-like behaviours (imagine being randomly thrown into a fridge for two weeks – you’d be constantly on edge and most likely depressed by the end too!). In the meantime, some rats received Vortioxetine in their food while others got placebo. In the end, those on placebo failed miserably on the cheerio-finding task, while those treated with Vortioxetine performed just as well as non-stressed controls.

These results suggest that Vortioxetine, an SSRI-type antidepressant, improves cognitive flexibility in stressed-out (and perhaps depressed) rats. However, the researchers did not show whether it also relived depressive-like symptoms at the doses used, how long the effect lasted, or whether the drug would perform in other (arguably more common) models of depression such as social defeat.

Taken together, these two studies complement each other beautifully, even though the results are still preliminary. Depression is a tough nut to crack, but the search for novel and fast-acting anti-depressants is in full swing. Among those presented at #SfN13 are the anesthetic gas isofluorane and the anti-cough medication dextromethorphan. Unfortunately as of now neither are ready for clinical use for depression.

The discovery of ketamine revolutionized the field of anti-depressant research in the last decade or so. Perhaps tackling depression on both cognitive and emotional ends – with cognitive enhancers or others – will prove to be even more effective at taming the beast.

Sappy little end-note: Back when I was studying pharmacy the best we could offer depressive patients were the atypical SSRIs, which takes weeks to months to start working. Many don’t respond to them at all and those who do built tolerance quickly. I’m so happy to have watched the story of ketamine unfold. If you’d like to know more, Gary Stix has a great 3-part series on Scientific American that’s well worth a read.

Check out my previous post on another potentially fast-acting anti-depressant L- acetyl-carnitine, a common fitness supplement.

The straight dope on rational drug addicts

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


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.

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?

Screen Shot 2013-07-01 at 7.10.42 PM

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.)

Screen Shot 2013-07-01 at 7.10.49 PM

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.

Screen Shot 2013-07-01 at 7.25.00 PM

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?

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

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

Ladies: why Ritalin may not always be helpful. (Hint: sex, genes and dem hormones)

Little note: Since this post, I’ve been mulling over why Ritalin/Adderall doesn’t affect cognitive performance of healthy volunteers. Several reasons come to mind. I wasn’t reading the “right” literature (ie studies with positive results – any suggestions?). Stimulants may only influence brain activation patterns, but not performance. In this case, we can only detect differences by fMRI or other direct imagining techniques. Or individual differences confounded the results – especially differences in basal dopamine levels and how dopamine is processed after its release. I’m going to focus on the last bit here.  

As a fellow XX member of society, I know very well how much ladies are controlled by their monthly cycle. Thinking appetite and mood? That’s just the beginning. The rise and fall of estrogen and progesterone also influence sound processing, neurogenesis and vulnerability to drug addiction. And that’s not all.

Estrogen directly impacts how well you think.


Estrogen targets your brain. Source: cbc

Jabobs E and D’Esposito MD. 2011. Estrogen Shapes Dopamine-Dependent Cognitive Processes: Implications for Women’s Health. The Journal of Neuroscience. 31(14): 5286-5293.

Ok, I was being overdramatic. But based on results from this study, estrogen seems to impact one important aspect of cognition: working memory. Working memory is a fundamental cognitive ability to hold information in mind while manipulating it towards a goal. It supports a massive array of complex thinking, such as problem analyzing and updating your ideas/strategies when new information comes in. To some, working memory is a good surrogate marker (albeit not the only one) for intelligence.

The part of the brain supporting working memory is called the prefrontal cortex (PFC). For the PFC to function optimally, it needs to be in the Goldilocks’ zone of dopamine concentration: too low or too high, and PFC function deteriorates. Think of an inverted “U” (see the graph below).

Screen Shot 2013-05-15 at 6.43.08 PM

This is where estrogen and genes come into play. Estrogen (or estradiol, to be more precise) enhances dopamine. Simple. Genes are slightly less straightforward. The concentration of PFC dopamine in the synaptic cleft (where it is released) is mostly determined by an enzyme called COMT. COMT comes in two flavors: the met/met variant, which has low activity and consequently higher dopamine, and it’s opposite, the val/val variant, which results in less dopamine. As of now, we think met/met individuals have near-optimal dopamine concentrations at baseline, while val/val carriers are a little short from optimum PFC function. Since estrogen enhances dopamine, the authors in this study asked: how will estrogen fluctuations influence a women’s working memory based on her genotype?

The authors recruited 24 healthy young women, rigorously tracked their cycles, and genotyped them for val/val or met/met alleles. The women were then invited back on two occasions – with estrogen levels at its highest and lowest – and performed a grueling task called the N-back while in an fMRI scanner.

Screen Shot 2013-05-15 at 6.43.18 PM

Here’s how N-back works: for example, in the 2-back, subjects see a string of letters one-by-one, and need to pick out a letter that matched the one they saw 2 letters ago (“B”). To make things harder, researchers set up “lures”, where a letter matched a previously seen one, just not 2 letters ago (“R”). Although both 2 and 3-back trials depend on working memory, lure trails are exquisitely sensitive in differences in PFC function.

Not surprisingly, all women, regardless of cycle and genotype, performed worse as the load increased (needing to remember more letters), especially for lure trials. However, as seen below, in the 2-back, val/val women (less basal dopamine) performed much better when their estrogen was high (B) compared to low (A). Met/met women showed the opposite trend, with performance declining as estrogen went up. Dopamine levels seem to account for these observations: under high estrogen conditions (which boosts dopamine), increasing COMT enzyme activity (which degrades more dopamine) correlated with better accuracy. However, low estrogen (less dopamine) requires low COMT activity (slow degradation) for good performance.

Screen Shot 2013-05-15 at 6.43.53 PM

A to C is significant. No info on anything else. Sad face.

These results suggest that estrogen is controlling working memory performance through dopamine. For met/met women, who already function well at baseline(C), increasing estrogen pushes them past the optimal dopamine peak, resulting in poorer function (D). For val/val women, who are slightly deficient in dopamine, estrogen is essentially a “smart drug”, boosting their performance by raising their dopamine levels to near optimum (A to B). Unfortunately, the authors only showed a significant difference between low dopamine (val/val, low estrogen, A) and high dopamine (met/met, low estrogen, C) conditions. I would love to know whether estrogen can boost val/val women’s performance to that comparable or above that of met/met women’s (C), and vice-versa, if the decreased met/met women’s performance is like that of val/val women’s at low estrogren (A) (confusing, I know).

Looking at the fRMI, the authors showed that the more the PFC (specifically, a part of the PFC called the middle frontal gyrus) activates, the better the women performs on lure trials, regardless of estrogen levels or gentotype. The activity level of PFC tightly correlated with COMT activity, with lower COMT activity (more dopamine) leading to higher PFC activation during the lure trials. Finally, the researchers found that women who had near-optimal dopamine levels (val/val high estrogen and met/met low estrogen) had the largest increase in PFC activity, and hence performed more accurately.

These results suggest that working memory, a key component of cognition, is dependent on the interplay between genes, neurotransmitters and hormones. If you’re a val/val, it may be beneficial to perform cognitively challenging tasks during the late follicular phase, when estrogen levels are high. If you’re a met/met, maybe save those tasks for the beginning of your cycle, when estrogen levels are low. Of course, this is heavy extrapolation, as the study only focused on dopamine and estrogen, without looking at the myriad of other neurotransmitter (especially norepinephrine, which also greatly influences PFC function) and sex hormones.

The study also hints that not every woman at every time will benefit from taking stimulants, such as Adderall or Ritalin. Stimulants enhance PFC function in ADHD individuals by increasing levels of dopamine. Hence, if you’re a val/val, stimulants may help improve working memory when estrogen levels are low (and possibly when high – we don’t have data to analyze this). On the other hand, if you’re a met/met already functioning at optimal dopamine concentrations, taking stimulants may instead decrease working memory performance, especially when your estrogen levels are high.

Linking back to the “smart drugs” post, since most studies didn’t screen for genotype and estrus cycle, could it be that different individual responses masked a net positive gain from stimulants? I’d love to know your thoughts.

Jacobs E, & D’Esposito M (2011). Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (14), 5286-93 PMID: 21471363

Shot for shot: a vaccine against heroin relapse?

A particularly sinister aspect of drug addiction is relapse. To the ex-addict, environmental cues, life stressors and even the drug itself serve as the sirens’ call, beckoning them back into the deadly realm of abuse. Currently, doctors battle heroin temptations with psychotherapy and replacement opioid drugs, such as methadone. While effective, these treatments rely heavily on the user’s cooperation and require continuous, uninterrupted access to medical personnel.

What if, instead of using drugs to counteract relapse, we train the body to recognize and attack heroin before it reaches the brain?


This is the dream. Source: io9

 Scholsburg JE et al (2013). Dynamic vaccine blocks relapse to compulsive intake of heroin. PNAS Early Edition. doi: 10.1073/pnas.1219159110

One way to do this is to design a vaccine against heroin. Like vaccines against measles or influenza, a heroin vaccine trains the body’s immune system to produce antibodies that recognize and neutralize heroin molecules in the bloodstream. Although seemingly straightforward conceptually, in practice it’s far more difficult, partly because heroin is broken down rapidly into psychoactive metabolites (6-AM and morphine) within seconds of entering the body.

Researchers now think they might have overcome this problem by designing a dynamic vaccine that targets both heroin and its metabolites. And it does seem to work. Vaccinated rats, when given heroin, had more of the molecule and its breakdown products sequestered in the bloodstream. This means less is getting into the brain to do its evil deeds. Vaccination dampened heroin’s painkilling effect, to the point that ~6times more heroin was required to produce a similar pain response in vaccinated rats as compared to unvaccinated ones.

But did it curb addiction?

In the first test, researchers first vaccinated the rats, and then injected them with heroin in a chamber (let’s call it A, see below) for 4 days. Like humans, rats associate pleasurable drug high with the place they were given the drug. When given the choice of two chambers (A and B), heroin-addicted rats will spend more time in A. This was indeed the case for unvaccinated rats. However, vaccinated ones didn’t care for the drug chamber, spending a similar amount of time in A and B. So it looks like vaccination before heroin addiction can block drug-seeking behaviors.


When given heroin in A, rats like A over B.

So what about relapse? Rats were trained to press a lever for heroin. Every time they got a hit a light would come on, causing them to associated light with high. Some rats were then vaccinated, and all were sent to rat rehab (extinction training), where pressing a lever didn’t give them any drug. By the end of extinction training rats refused to work hard for heroin. Researchers then challenged the rat with several drug-seeking cues (including a dose of heroin, a chemical stressor, and the light cue) to see if this would cause them to crave heroin again. Indeed, unvaccinated rats started furiously pressing for heroin after any of the cues. Vaccinated rats, however, weren’t motivated to press for more when heroin was the cue. Unfortunately, vaccination didn’t protect rats from either the stressor or the light cue – they relapsed just like their unvaccinated peers.

Unfazed, the researchers then tested the rats on a powerful model of compulsive heroin self-administration (see below). Rats were given free access to as much heroin as they wanted for 12hour periods over several weeks. Their dose soon skyrocketed to levels that would’ve killed naïve rats, and started developing symptoms of physical addiction (compare “baseline” and “escalated” in the graph below). They were then forced to go cold turkey for 30 days, during which a subgroup was given the vaccine. Once the abstinent period was over, non-vaccinated rats quickly went back to their old ways, “catching up on missed time” by escalating their heroin dose even further than before (both KLH cues and no cues group). Although vaccinated rats also went back to pressing for heroin, their dose remained steady (Her-KLH cues group). This continued lever-pressing behavior might be due to the light cue – when rats were trained without the light cue, vaccination abolished lever pressing after abstinence (Her-KLH no cues group). When researchers went on to see how much these rats were willing to work for their heroin (requiring more lever presses to get a hit), vaccinated rats were far less willing to work for their drugs compared to unvaccinated ones. This shows that vaccination drastically decreased the addict’s drive for heroin.

Screen Shot 2013-05-07 at 3.11.15 PM

The control (non-vaccinated) groups are KLH (cues) and KLH (no cues). The experimental groups are Her-KLH (cues) and Her-KLH (no cues) . “Cue” here refers to the light cue presented with heroin.

So is this the end of heroin addiction? Unfortunately, no. The vaccine can only eliminate heroin from the user’s bloodstream, which blocks the “high”. That’s all it does (but it’s no small feat!). If the addict increases his or her dosage, the vaccine’s effects might be overcome. It also doesn’t block cue-associated relapse, when on the streets, cues are a major trigger for drug craving and seeking. It also doesn’t stop a heroin addict from switching to another drug-of-choice, sidestepping the vaccine’s effects.

However, the data presented here shows that by itself, this heroin vaccine can break the cycle of addicts taking more and more of the drug, especially after relapse. It also lasts longer than Naltrexone (anti-heroin antibodies stay around for at least 52 days after one injection), which also blocks heroin’s actions. The vaccine can also be used in tandem with already available treatments, such as therapy, methadone and naltrexone.

In the end, a heroin vaccine is not a “magic bullet” to block all aspects of addiction. It’s like the rope that tied Odysseus to the ship mast – only one of the many aspects that kept him at bay from the siren’s calls. However, if the vaccine (or its upgrades) passes through human trials, it could be a promising and innovative tool against heroin relapse.

Schlosburg, J., Vendruscolo, L., Bremer, P., Lockner, J., Wade, C., Nunes, A., Stowe, G., Edwards, S., Janda, K., & Koob, G. (2013). Dynamic vaccine blocks relapse to compulsive intake of heroin Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1219159110

Pills for Bites: The Alarming Link between Drug Abuse and Eating Disorders

This is a guest post for ScienceofEDs blog. If you’re interested in research relating to eating disorders, ScienceofED is the place to go.

I recently stumbled across a disturbing post on a forum. In it, the author gushed about taking prescription stimulants to ensure weight loss and keep it off. A chorus of approval followed, with no regards to side effects and no qualms about lying to get the pills.

The association between drug abuse and eating disorders (EDs) isn’t new. Or even surprising. Since the 1970s, doctors have reported higher incidents of self-medication and drug abuse in a subset of eating disorder patients. Drugs, in this context, cover everything from laxatives, diet pills, alcohol to street drugs. What’s shocking is the extent of the problem. In a report detailing the most comprehensive review on the topic, the National Center on Addiction and Substance Abuse concluded: “Individuals with eating disorders are up to five times likelier to abuse alcohol or illicit drugs and those who abuses alcohol or illicit drugs are up to 11 times likelier to have eating disorders”.

The report is available online for free, and I highly recommend reading the entire document. However, if you’re pressed on time, here are some of their main findings.

  • The link is strong: Between 30-50% of bulimia nervosa (BN) patients and between 12-18% anorexia nervosa (AN) patients abuse or are dependent on alcohol or drugs, compared to roughly 9% of the general population. This may be an underestimation, as the rates do not include many individual with eating disorders who smoke or abuse prescription medication. Eating disorders not otherwise specified (EDNOS) and Binge eating disorder (BED) does not seem to be included in these rates, and no further explanation was given. However, the report did note that individual with BED are more likely than obese individuals to abuse illicit drugs.
  • The link is reciprocal: Up to 35% of individuals who abuse or are dependent on alcohol or drugs also have an eating disorder, compared to up to 3% in the general population.
  • The link starts young and occurs even in sub-clinical cases: Preadolescent and adolescent girls and boys with strong weight concerns are roughly twice as likely to start smoking or smoke daily than those less concerned about their weight. A similar correlation in seen with drinking, where girls who engage in unhealthy dieting behaviors (fasting, diet pills, or binging and purging) as twice as likely to begin drinking and drink considerably more than non-dieting peers.
  • The link between alcohol/illicit drug use is stronger for BN than AN. Alcohol abuse is more common in people with bulimia, who report higher rates of suicide attempts, anxiety/personality/conduct disorders and other substance dependence than non-alcoholic BN patients.  BN patients, compared to AN patients, are more likely to have abused amphetamines, barbiturates, marijuana, tranquilizers and cocaine. The highest rate of illicit drug use is associated with BN binge-purge type, some of whom use heroin to facilitate vomiting. Stimulants (cocaine, Ritalin and Adderall) are used to suppress appetite and to induce a sense of self-control. Similar results are found in a sample of women including both college students and community members, who exhibit disordered eating behaviors but do not have an ED diagnosis.
  • The report points to a rise in ED occurrence in males, athletes and racial/ethnic minorities, but did not have any data on concurrent drug abuse in this population.
  • The casual relationship between ED and drug abuse is not well understood.

EDs and substance abuse have many shared risk factors, which may explain the high rate of co-occurrence. These include:

  • Biological factors: Both disorders operate on the same reward and motivational systems in the brain, precipitating an obsessive preoccupation with a substance, intense cravings and compulsive behavior.
  • Personality risks: Both disorders may represent ways for certain people to cope with stress and transition. High-risk personality traits include low self-esteem, depression and anxiety. The strong link between BN and drug abuse may be partially explained by high impulsivity in individuals with both disorders.
  • Parental and environmental risks: Both disorders may be influenced by unhealthy parental behavior, social pressure and the advertising, marketing and entertainment industries.

It is difficult to pinpoint which risk factors are the main contributors to the development of each or both disorders. However, these shared traits may explain why in some cases ED predisposes the individual to substance abuse (and vise-versa).

The prevention and treatment of co-occurring EDs and substance abuse will have to depend on many parties, including parents, schools, health professionals, policy makers and researchers. Parents and schools are especially important in educating young individuals, by modeling and promoting messages about healthy eating and dangers of drug use. Health professionals need to recognize and screen for the co-occurrence of both disorders. Unfortunately, at the time of the report (late 2003), few effective treatment programs exist for addressing both disorders simultaneously. At the moment, the body of literature concerning this topic tends to be more descriptive (“a link exists”) than mechanistic (“this is why is exists”).

Researchers will need to work with clinicians to develop better approaches to preventing, assessing, diagnosing and treating substance abuse and eating disorders. Specific guidelines are outlined in Chapters 3 and 4 of the report.

Finally, the dangers of co-occurring drug abuse and ED cannot be overstated. ED patients often suffer hair loss, tooth decay, osteoporosis, and weakening of the heart. Stimulants, such as Adderall, Ritalin, cocaine and nicotine (found in tobacco) further stress the cardiovascular system, which can lead to high blood pressure, stroke and even heart failure. With the rise of “study drug” abuse in both students and professionals, these dangerous consequences are becoming increasingly relevant to those with EDs.

Once again, I recommend reading the full report “Food for Thought: Substance Abuse and Eating Disorders” (link here, pdf warning). I’d love to hear your thoughts: why do you think some individuals with EDs are more likely to abuse drugs? Or is substance abuse inherent in some types of EDs, as a symptom?