Eternal sunshine of the drugless mind…

What if you could wipe the memories of drugs from your mind? What if the sweet taste of relapse was no longer a fear for recovering drug users?

Wiping drug memories

Relapse back into drug use is complex. Taking into account the environmental cues that come along with using drugs. The effect of the drug is only one part. The other part being the trigger. After a while it becomes a conditioned response, making relapse an all-too-easy mechanism to fall into.

As a treatment target, relapse remains an infant, almost non-existent field. However, recently published research suggests that the memories elicited by drug cues and contexts (those environmental factors that lead to relapse) can be diminished, and hence possibly reducing or negating their impact on relapse in both animals and people addicted to drugs.

Diminishing of those drug-associated cues is brought about by pharmacologically interference. The only problem is only one of the pharmacological compounds used is suitable for human use. This means studies done in rats have yet to be mimicked in human clinical models.

However, a non-pharmacological alternative may be possible — the “memory retrieval-extinction” behavioral procedure is used to interfere with how the cues and stimuli in addicts are formed and retrieved.

What do rats and drug users have in common?

What researchers did was to manipulate the memory processes — essentially overwriting the original memory. The so called “extinction procedure” is commonly employed clinically to suppress conditioned responses to drug cues. What they describe is a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts.

What is common in all of this is a reemergence of extinguished responses — that is to say it is not a long-lived effect. Either re-exposure to drugs, re-exposure to the drug-associated environment, or simply the passage of time can reinstate that memory.

Rats that were taught to self-administer cocaine and heroin were used in studies where drug-cues were formed. Then this bond was tested as the animals underwent “extinction training”. Essentially, the experiment induces the drug-associated condition, extinguished, then tested (and reinstated) by injecting the drug into the rats. The test is to see if the rats revert to old behaviour and recommence self-administering their drugs.

After being assessed one month later, only the group that had received the reminder and extinction training showed a reduced tendency to resume drug-seeking behaviour following  exposure to either drug-associated cues or a reminder injection of cocaine or heroin.

In the study, authors were able to translate their work in rats to a human clinical setting, with detoxified heroin addicts. Three groups of patients were briefly exposed to a drug-relevant video or a control; then exposed to relevant drug-associated cues and stimuli (imagery and drug paraphernalia) to see if relapse would occur. Much like in the rats, the group that had the brief 10 minute delay between the heroin video and extinction showed a significant reduction in craving and blood pressure after presentation of drug-associated cues.

This study is one that successfully mimics a pharmacological effect in a behavioural setting, despite the ambiguousness of the mechanisms at play. And hopes to formulate a new route towards different kinds of treatment targets.

Originally appearing in The All Results Journals

Milton AL, & Everitt BJ (2012). Neuroscience. Wiping drug memories. Science (New York, N.Y.), 336 (6078), 167-8 PMID: 22499932

Xue YX, Luo YX, Wu P, Shi HS, Xue LF, Chen C, Zhu WL, Ding ZB, Bao YP, Shi J, Epstein DH, Shaham Y, & Lu L (2012). A memory retrieval-extinction procedure to prevent drug craving and relapse. Science (New York, N.Y.), 336 (6078), 241-5 PMID: 22499948

Ceci n’est pas la marijuana…

“You have been assigned to the condition to smoke an active marijuana cigarette that contains THC. THC is the primary psychoactive cannabinoid that gets people high.”

Does the fact that you are told you are taking a drug effect your reaction to that drug… or the drug’s effect itself? This was the simple question posed by a group of researchers publishing in Psychopharmacology. The effect of taking a drug is one thing. The effect you expect it to have is something altogether different.

“…users believing they are smoking marijuana may compensate for expected intoxication effects when engaged in deliberate decision-making by making less impulsive and risky decisions.”

34 subjects at a time were given the task to smoke a cigarette that contained marijuana or a cigarette that contained a placebo. Participants were selected based on an interesting set of criteria; native English speakers, 18 to 30 years of age, frequent marijuana use over the past month (at least once a week and at least ten times in the past 6 months), and self-reported ability to abstain from marijuana for 24 h without withdrawal.

This was a balanced placebo design experiment, examining the relative effects of expecting to receive active marijuana. These regular marijuana smokers, randomly assigned into one of four groups:

• Told they were getting THC but got a placebo

• Told they were getting THC and got THC

• Told they were getting a placebo but got THC

• Told they were getting a placebo and got a placebo

All rather deceitful and standard practice for a placebo trial.

What came next was probably the most regimented smoking session the participants had ever undertaken. Smoking sessions occurred in a 75-square-feet ventilated smoking room, with standard-issue humidified cigarettes that are rolled at both ends. And smoked according to the “standardized paced puffing procedure” — until the ash reached a mark 10 mm from the end.

Subjects and participants were then evaluated for subjective intoxication, behavioral impulsivity, and decision-making related to risky behaviours.

The laboratory test known as the Stop Signal Task is one commonly employed as a laboratory measure of inhibitory control. In essence, it uses an external stimulus to signal participants to interrupt or inhibit an already-initiated motor response. Simply put, subjects are asked to respond as fast as they can to symbols on a screen. Then an auditory tone tells the participant that they are to try and withhold their response to the current symbol on the screen. The tone occurs occasionally, in an unpredictable way, and at various latencies after the appearance of the letter on the screen. The stop signal reaction time, is an estimation of the time an individual needs to stop their usual behavior in response to the stop signal. Active THC, regardless of whether subjects were told or expected it, impaired inhibition on the Stop Signal Task.

Out of all the participants only a small proportion suspected that they were being deceived. Suspicions about the THC content were only reported by two participants (in the Told THC/Received Placebo condition) and by seven participants (in the Told Placebo/Received THC condition). In all cases, Both THC dose and marijuana expectancy independently increased subjective intoxication.

It is commonly known that real or perceived expectancies can play a part in influencing responses to other drugs, such as alcohol. Here, expectancy of smoking THC in combination with active THC increased perceptions of risk from risky alcohol use.

The effect of THC somewhat contributed to impaired inhibition — that is the pharmacological effect and not the perceived effect. Whereas expectancy of having smoked THC affected impulsive decision-making, with a compensatory direction of effect on some measures of risky decision-making. For example, independently from the THC administration, expectancy also increased perceived risk from coercive sex among women.

Researchers showed that THC can affect some mechanisms underlying impulsive behaviors while not affecting others. The study represents the first evaluation of independent and combined effects of smoking and expecting to smoke active marijuana on multiple measures of risk taking and impulsivity, using a balanced placebo design. It proved a way to independently tease out the expectancy that marijuana was smoked from the pharmacologic effect of delta-9-tetrahydrocannabinol (THC).

Originally appearing at All Results Journals

Image — source

Metrik J, Kahler CW, Reynolds B, McGeary JE, Monti PM, Haney M, de Wit H, & Rohsenow DJ (2012). Balanced placebo design with marijuana: Pharmacological and expectancy effects on impulsivity and risk taking. Psychopharmacology PMID: 22588253

Addicted to Love…

The ultimate reductio ad absurdum argument is that any behaviour can become potentially addictive.

Which leads to the next logical question: are there any good addictions? Researchers today talk of addiction as a disease. And in that trope, the “disease concept” of addiction is really just a metaphor. A metaphor with connotations.

Researchers posit that for a behaviour to become harmfully addictive, it would involve some type of “rush” effect, time-intensive repetition, intense behavioural or cognitive preoccupation, loss of control, and negative consequences.

At this point in time, we have a long list of things that can be counted as addictive, including prayer, meditation, and even religion. But for now we focus on perhaps the oldest of all behaviours — love.

The relationship between passionate love and addiction has been debated exhaustively amongst social science circles for many years. It began with Sigmund Freud, who had intimated the existence of a similarity between amorous passion and drug addiction. Currently this is ill-defined. That is to say, there are no recognized or standard definitions or diagnostic criteria for “love addiction”, “love passion”, or “sex addiction”.

Is there a difference between love and addiction? Is being addicted to love a disease? Is social attachment an addictive behaviour?

All loaded questions with no easy answers. Some sort of parlance on the subject comes from the world experts in all things pertaining to love and sex — the French. A group of French researchers, publishing in The American Journal of Drug and Alcohol Abuse, describe the clinical distinctions between “love passion,” “love addiction,” and “sex addiction”. Using advances in neurobiology to compare clinical, neuropsychological, neurobiological, and neuroimaging data on love and passion.

They begin with the most pertinent question: “Is there any legitimate reason to associate a pathological condition (addiction) and a natural, pleasurable one [love]?”

With there being no recognized definition or diagnostic criteria for “love addiction” it is hard to posit an idea. But the bare bones of it all has some similarities to substance dependence:

“euphoria and unrestrained desire in the presence of the love object or associated stimuli (drug intoxication); negative mood, anhedonia, and sleep disturbance when separated from the love object (drug withdrawal); focussed attention on and intrusive thoughts about the love object; and maladaptive or problematic patterns of behavior (love relation) leading to clinically significant impairment or distress, with pursuit despite knowledge of adverse consequences.”

The notion of love as an addiction is described pertaining to all the usual disease addiction tropes — from a clinical description, comparing the absence of love to substance withdrawal, and — most importantly — the shift that occurs from normal to addictive state. A shift that is barely perceivable due to the simple fact that such a dependence is present in both states.

“Addiction would be defined as the stage where desire becomes a compulsive need, when suffering replaces pleasure, when one persists in the relationship despite knowledge of adverse consequences (including humiliation and shame).”

The fact that there is currently no data on the epidemiology, genetics, co-morbidity, or treatment of love addiction lead the researchers to conclude that to place some cases of “love passion” within a clinical disorder spectrum or to firmly classify it as a behavioural addiction (or to a lesser extent a disorder of impulse control) would be premature.

Addictions, particularly those to substance, short-circuit and often circumvent the natural and complex mechanisms for managing a whole range of humanistic behaviours — sensations, emotions, cognition and relationships. Add to this the fact that certain mechanisms are not well understood. Making it hard to apply it to love.

A further complication is the simple and often overlooked fact that “love” is the source of the strongest sensations, emotions, and passions known to human beings.

Originally appearing at The All Results Journal

Reynaud, M., Karila, L., Blecha, L., & Benyamina, A. (2010). Is Love Passion an Addictive Disorder? The American Journal of Drug and Alcohol Abuse, 36 (5), 261-267 DOI: 10.3109/00952990.2010.495183

The Death of TC-5214…

All too often, experimental drugs post stellar results from studies conducted in Russia, India and other less developed regions, leading to inflated stocks for the company and misplaced hopes. Only to blow up after the data cannot be replicated in the United States or Europe.

TC-5214 is one such example.

Targacept Incorporated is a biopharmaceutical company that is in the business of creating a new class of drugs that treat multiple diseases and disorders of the nervous system. The drugs they design and engineer selectively target the neuronal nicotinic receptors (NNRs) that are widely distributed throughout nerve cells of the central nervous system. TC-5214 is one such class of compound.

In fact, over the last ten years more than 1000 articles have been published describing the use of these types of compounds (mecamylamines) as a pharmacological tool to confirm the involvement of nicotinic receptors in various physiological and pharmacological effects.

In the winter of 2008, a paper was published that spoke to the potential therapeutic benefit of modulating activities of these NNRs in the central nervous system.

Functional NNRs are widely distributed in the brain, and numerous studies have shown that mecamylamine blocks nicotinic-induced mnemonic effects in normal and aged animals and in humans.

TC-5214 (or mecamylamine) acts as a noncompetitive NNR antagonist, and showed some positive effects in a number of animal models of depression and anxiety.

The forced swim test (the behavioural despair test or the Porsolt test) is a test frequently employed as a measure of the effect of antidepressant drugs on the behaviour of lab mice or rats. The procedure is simple. The mice are subjected to two trials during which they are forced to swim in an acrylic glass cylinder filled with water. One from which they cannot get out. The first trial, lasting 15 minutes, is followed by a second after 24 hours, lasting just 5 minutes. The measure is the time that the animal spends without moving in the second trial. And this immobility time is decreased by antidepressants. With immobility taken as a behavioural correlate for a negative mood.

TC-5214 was active in the forced swim test in rats and it was also active in the behavioral despair test in mice. The researchers concluded that their results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic (anti-anxiety) effects and highlighted the potential of NNR antagonists as therapeutics for the treatment of anxiety and depression.

Today, TC-5214, representing the most promising drug in the Targacept Inc. pipeline, has come to a screeching halt after it failed the final two clinical trials for major depressive disorder. TC-5214 was positioned to be an add-on treatment to existing anti-depressants.

Targacept’s TC-5214 compound previously failed two short-term Phase 3 clinical trials in 2011, showing no significant difference in patients when compared to a placebo. The company needs two successful results to pursue Food and Drug Administration’s approval of the compound. As such, with this recent failure, the pursuit of TC-5214 as a possible treatment has been abandoned.

This fail of a drug happens all the time. But this one arouses a certain facet of the discussion. Namely, the difficulty in reproducing clinical trial results across different countries. TC-5214 showed outstanding results in Phase 2b clinical trials in India, but that level of excitement failed to be reproduced in the USA (the only country that counts for FDA approval).

Image — source.

Originally appearing at the All Results Journals

Fedorov, N., Benson, L., Graef, J., Lippiello, P., & Bencherif, M. (2008). Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition Journal of Pharmacology and Experimental Therapeutics, 328 (2), 525-532 DOI: 10.1124/jpet.108.146910

Lippiello, P., Beaver, J., Gatto, G., James, J., Jordan, K., Traina, V., Xie, J., & Bencherif, M. (2008). TC-5214 (S-(+)-Mecamylamine): A Neuronal Nicotinic Receptor Modulator with Antidepressant Activity CNS Neuroscience & Therapeutics, 14 (4), 266-277 DOI: 10.1111/j.1755-5949.2008.00054.x

How many genes does it take to vote…?

“2 genes predict voter turnout”

If it was as simple as that we can forego all the campaigning. That was the headline that came with a 2008 study — a watershed moment — in which in which two authors claimed that they sufficiently demonstrated that when it comes to political ideology, genes count for more than environment. The whole spectrum of political ideology and affiliation, they could distill into liberal or conservative. And, better yet, they could distill down to just two genes.

That watershed moment was probably the first in a long line of research within a growing subfield of political science known as genopolitics. Simply put, the study of genetics can be used to help us understand political behaviour and how people vote.

This follows a trend — domains and schools of thought, once the purview and authority of the human and social sciences, are now being encroached upon, infiltrated and assimilated by the harder sciences. The neurosciences has contributed more recently to the understanding of human thought than philosophers would like to admit. Throwing up conceptual issues and dilemmas that threaten to leave the philosophers behind.

The suggestion that humans exhibit inherent variability in their willingness to participate in politics is one that unlocks a whole manner of Orwellian thinking. In 2008 James Fowler and Christopher Dawes put forth that people in their study showed a gene interaction that increased the likelihood of voting. The two genes they pinpointed were monoamine oxidase (MAOA) and the serotonin transport protein 5HTT. The finding that those that had the “high” variant of the gene voted at a higher rate than those with the “low” variant.

But is it as simple as that?

The genome is a large place. The simple fact is that hundreds of genes, both in combination and permutations, have their influence on any number of social cues. This is why most studies bypass looking at the whole picture. Choosing, instead, to focus on “candidate” genes, in what is called a candidate gene association study, where gene variant is proposed to predict a given behaviour. The inherent simplicity of conducting a study in this way has, undoubtedly, shown some remarkable results. With researchers linking genes to all manner of social behaviours — from predicting voting behavior, partisanship and party identification, liberal political ideology, credit card debt, to antisocial personality, and even leadership.

The genes coded for MAOA and 5-HTT are two genes among an estimated 25,000–30,000 genes (an estimation of only protein coding genes). The two simple “high” and “low” variant polymorphisms of the two genes that the researchers looked at are simply a handful in anywhere from 3–15 million possible polymorphisms throughout the human genome. Add to this, hundreds of single nucleotide polymorphisms and structural variations, the likelihood of a specific predictive behavioural outcome becomes less and less.

In a world where every vote counts the genetics of political behaviour are becoming an increasingly interesting area of science to look at. One that straddles both sides of the fence, incorporating both social and genetic sciences. But without a more robust way of measuring genotype against phenotype (the vast array of complex behavioral traits that rely on an outdated genetic paradigm), it seems a little like robbing Peter to pay Paul.

Image — source

CHARNEY, E., & ENGLISH, W. (2012). Candidate Genes and Political Behavior American Political Science Review, 106 (01), 1-34 DOI: 10.1017/S0003055411000554

ALFORD, J., FUNK, C., & HIBBING, J. (2005). Are Political Orientations Genetically Transmitted? American Political Science Review, 99 (02) DOI: 10.1017/S0003055405051579

Fowler, J., & Dawes, C. (2008). Two Genes Predict Voter Turnout The Journal of Politics, 70 (03) DOI: 10.1017/S0022381608080638