Drugs & Clinical Trials – Brain Blogger http://brainblogger.com Health and Science Blog Covering Brain Topics Sat, 30 Dec 2017 16:30:10 +0000 en-US hourly 1 https://wordpress.org/?v=4.9.1 Psychedelics and Drug Addiction http://brainblogger.com/2017/11/01/psychedelics-and-drug-addiction/ http://brainblogger.com/2017/11/01/psychedelics-and-drug-addiction/#respond Wed, 01 Nov 2017 15:00:37 +0000 http://brainblogger.com/?p=23047 Overindulgence in anything can be intoxicating, even if it is something as essential as water. Though we all try to rationalize these things, sometimes we simply fail. Gone are the days when the word “addiction” was associated with some poorer and less educated parts of society. It is a fact that today substance abuse is equally prevalent among successful and intelligent people.

The American Psychiatric Association defines addiction as something that a person keeps indulging in despite the harmful consequences of overindulgence. The person has a compulsion or focus on taking that particular substance or practicing that particular habit. Addiction results in distorted thinking, it changes behavior and body functions. This addiction leads to changes in wiring of the brain. Addiction is also characterized by building up tolerance, meaning that a person needs higher doses with time.

There are two broad reasons for addiction, psychological and physiological. The psychological component is present in every addiction, as a person seeks and gets pleasure from his or her addiction. Some seek enjoyment, others look for stress relief. Some people even believe that addiction improves their performance, mental or physical. Physiological addiction develops when the body becomes dependent on the substance for normal functioning. For example, long time smokers have a problem with bowel movement after quitting the habit.

Fortunately, addiction can be treated, but only if a person is willing to get rid of it. After all, it has lots to do with the habit forming, pleasure-seeking nature of humans, a part of the physiological dependence.

Still, the effectiveness of addiction therapy is very low because few people sincerely wish to give up their addiction. Consciously or not, many addicts look for an excuse to continue.  Statistics show that as few as 10% of people who attempts to quit their addiction actually succeed.

The use of psychedelic drugs is banned almost universally, even scientific studies on their effects are prohibited in most countries. Nonetheless, it appears that some specific properties of psychedelics can be used to successfully treat a variety of addictions.

The logic here is to use one mind-altering agent to overcome dependence on another. The dose makes the poison: a poisonous compound can be an efficient medicine when used at the right dosage. Psychedelic drugs may help to cure addiction when they are used under controlled conditions and at the right dose. This is precisely what many researchers are trying to do.

Psychedelic drugs differ from other addictive drugs in their mind alternating properties: they alter thinking processes and perception through their action on serotonin receptors. They are known to change the level of consciousness experienced. People taking these drugs feel as if they are in a kind of trance. Some of the conventional psychedelic drugs include “magic mushroom” hallucinogens (psilocybin), LSD, and mescaline. There has been several trials and observational studies showing that these drugs are capable of altering the brain by resetting thinking patterns.

Ibogaine is one such psychedelic drug that is being studied. It is a potent hallucinogen that brings various memories and experiences to the person taking it that has been traditionally used in shamanic rituals in western Africa. Many underground clinics for treatment of severe drug addiction have reported the wonderful effects of even a single dose of this plant-derived drug. But this drug is highly toxic, and many pharmaceutical companies are trying to come up with an analogue that is safe for humans, free from hallucinogenic effect, and still has potency to treat addiction. Very little is known about the mode of action of this drug. Moreover, some people in the scientific community think that only natural ibogaine will have the desired properties. Medical professionals caution against the use of this drug in underground clinics, as ibogaine is known to cause seizures and heart failure.

Another natural compound that shows promising results in the treatment of drug addiction and some psychiatric illnesses is psilocybin, a compound found in magic mushrooms. A recent small scale proof-of-concept trial done by Johns Hopkins University in Baltimore, Maryland, demonstrated that the drug can help lifelong smokers to quit the habit. The therapy with psilocybin worked much better than any other currently known forms of anti-smoking treatment.

In another study, psilocybin was used to treat alcohol addiction. This study was rather specific, as only people with the most extreme cases of alcohol addiction were accepted for the trial. Though this was a small scale study, it had terrific results in overcoming the years of alcohol addiction and completely changing the outlook for the participants.

LSD is perhaps one of the best-known psychedelics. It is used as a recreational and addictive drug, although it was banned in the 1960s and 1970s in most countries around the globe. But very few people know that LSD is the most intensively tested in clinical trials for the treatment of addictions.

In one of the large-scale studies performed in six hospitals across Saskatchewan, Canada, more than 1000 alcoholics were treated for their addiction with LSD. The study enrolled people known to be resistant to other forms of treatment for addiction, people with broken lives, former prisoners, and people with severely damaged health. The majority of those treated with LSD were able to stay away from alcohol for quite a long time. In fact, the researchers reported a success rate of 70%. Considering the statistics and the scale of the study, this is not something to be neglected. However, due to the criminalization of LSD, it could neither be used for treatment of alcohol addiction, nor could further clinical trials could be carried out.

Bearing in mind that psychedelic drugs have consistently provided excellent results in the treatment of various addictions, we should probably reconsider the total ban on their use for research and medical purposes. One future direction could be the development of synthetic analogues of psychedelics with lesser side effects but similar mind-altering properties. Taking into account the growing epidemics of opioid addiction in the US, psychedelics should be seriously considered for their potential to contribute positively to the solution for this problem.

References:

Jacobson, R. (2017, January 1). Treating Addiction with Psychedelics. doi:10.1038/scientificamericanmind0117-10

Johnson M, Garcia-Romeu A & Cosimano MP. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology. 2014;28(11):983–992. doi: 10.1177/0269881114548296

Krebs TS & Johansen P-Ø. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. Journal of Psychopharmacology. 2012;26(7):994–1002. doi:10.1177/0269881112439253

Schenberg EE et al. Treating drug dependence with the aid of ibogaine: A retrospective study. Journal of Psychpharmacology 2014;28:993–1000. doi:10.1177/0269881114552713

Studerus E, Kometer M & Hasler F. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology 2011;25:1434–1452. doi:10.1177/0269881110382466

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Diabetes Drug for Addiction Treatment http://brainblogger.com/2016/10/05/diabetes-drug-for-addiction-treatment/ http://brainblogger.com/2016/10/05/diabetes-drug-for-addiction-treatment/#respond Wed, 05 Oct 2016 15:00:33 +0000 http://brainblogger.com/?p=22059 A relatively new class of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, have had much success in the treatment of type 2 diabetes. Now, these drugs may offer support in the treatment of addiction and drug abuse.

A new study, published in Translational Psychiatry, reports that GLP-1 receptors may be a target for treating drug abuse. The study was conducted in mice, but it calls attention to previous reports with similar findings.

Dopamine is essential to reward pathways that influence drug abuse and addiction. Endocannabinoids and arachidonic acid, which are also naturally present in the brain, affect the function of dopamine transporters. Activation of GLP-1 receptors reduces arachidonic acid in areas of the brain that are associated with reward; dopamine levels, in turn, reduce. In the current study, the long-lasting GLP-1 receptor agonist, exenatide, abolished cocaine-induced increases in dopamine levels.

GLP-1 is normally found in the gut and influences satiety signaling. In part, GLP-1 agonists, which mimic the activity of naturally-occurring GLP-1, regulate glucose homeostasis in type 2 diabetes by promoting a feeling of fullness. These drugs have been shown to aid in weight loss in patients with type 2 diabetes. These effects might also be due to the reduction in the rewarding effects of food, owing to GLP-1 action in regulating dopamine transporter activity and reducing reward related to food intake.

Both illicit drugs and palatable foods activate reward pathways in the brain. Therefore, pharmacologic modulation of these central nervous system circuits holds promise for reducing unwanted or abusive behaviors. The role of naturally occurring GLP-1 in affecting reward is unknown. The beneficial effects of GLP-1 agonist activity are now believed to extend not just to food, but alcohol and to psychostimulants, such as cocaine and amphetamine.

Several recent studies have highlighted the mechanism by which GLP-1 agonists influence reward-inducing behaviors in the central nervous system. While the place in therapy is not clearly defined, these findings could expand the therapeutic potential of this entire class of drugs.

References

Harasta AE, Power JM, von Jonquieres G, et al. Septal glucagon-like peptide 1 receptor expression determines suppression of cocaine-induced behavior (2015) Neuropsychopharmacology, 40(8):1969-78. PMID: 25669605

Reddy IA, Pino JA, Weikop P, et al. Glucagon-like peptide-1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels (2016) Transl Psychiatry, 6:e809. PMID: 27187231

Richards JE, Anderberg RH, Goteson, et al. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system (2015) PLoS One, 110(3):e0119034. PMID: 25793511

Sirohi S, Schurdak JD, Seeley RJ, et al. Contral peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors (2016) Physiol Behav, 161:140-4. PMID: 27072507

Skibicka KP. The central GLP-1: implications for food and drug reward (2013) Front Neurosci 7:181. PMID: 24133407

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Genetics Behind Response to Parkinson’s Drugs http://brainblogger.com/2016/08/30/genetics-behind-response-to-parkinsons-drugs/ http://brainblogger.com/2016/08/30/genetics-behind-response-to-parkinsons-drugs/#respond Tue, 30 Aug 2016 15:00:47 +0000 http://brainblogger.com/?p=22083 Since achieving the goals of the “mission impossible” Human Genome Project in 2003, biomedical sciences entered the new era of genetically informed use of pharmaceuticals. The Project helped in our understanding of how genes affect an individual’s response to drugs.

Although it was known for decades that the response to drugs depends on genetic background of each individual, the knowledge of key mechanisms involved in these processes was mostly missing. Genetics finally provided a definite understanding of pharmacokinetics, the branch of science studying what the body does to the drugs. This article will look at how drug response may vary between individuals, and how genetics play an important role in the drug response in patients with Parkinson’s disease.

Why drug responses vary

In general, there are three main reasons why response to a particular drug may vary from one individual to another. These factors are:

  1. The responsiveness of the site of drug action
  2. The drug concentration (reflected by its plasma level)
  3. The type or sub-type of the disease itself.

Nonetheless, in most cases, the drug plasma concentration plays the central role. Most of the drugs taken orally undergo metabolism once they enter the body. In this process, the drug will be changed into its active or metabolite form. The rate of metabolism differs between individuals, resulting in different drug plasma concentrations. The drug metabolism process is carried out by various enzymes depending on the nature of the drug. The levels and activity of these enzymes are also different between individuals. This is a critical factor in determining or predicting the response to a drug.

The activity and expression level of enzymes involved in drug metabolism is determined by genes. Even single mutations, or single nucleotide polymorphisms (SNPs) in genes’ DNA sequence can cause a huge difference to the individual metabolism of a particular drug. Mutations in genes’ regulatory sequences can also seriously influence the levels of key enzymes.

Parkinson’s disease & drug responses

Parkinson’s disease is an age-related, debilitating neurodegenerative disorder that mainly affects the motor system. People with this disease experience shaking, rigidity, slowness of movement, and difficulties with walking. Parkinson’s disease is marked by a loss of dopamine-producing neurons in the brain.

Today, one of the treatments to improve the condition of patients involves the use of drugs that mimic or increase levels of dopamine. However, using drugs to regain the normal level of dopamine can be complex, as the level of this neuromediator should not go too high (when it produces undesirable side effects), nor remain too low (when no effect is observed).

It is well established that drugs against Parkinson’s disease have different efficiency between patients. Recent research has revealed genetic determinant of this difference. The findings might inform better drug prescription and allow physicians to tailor targeted therapy for individuals suffering from this neurodegenerative condition.

The pharmacogenetics of the drug levodopa

Levodopa is a common medication for Parkinson’s disease and has been considered a gold standard since the 1960s. The drug is a direct metabolic precursor of dopamine in the body and thus can increase dopamine levels. However, 35-40% of patients develop side effects such as dyskinesia and motor fluctuation after 4-6 years of using it.

A number of studies have revealed various mutations and SNPs in genes related to levodopa metabolism, responsible for these side effects. A recent research study published earlier this year demonstrated that SV2C gene variants may modulate the amount of levodopa and suggests that the dose of levodopa should be reduced in people with this gene variant to prevent possible side effects.

Another study published three years ago showed that the effect of levodopa treatment on motor skills varies between individuals. The treatment in patient with low dopamine transmission gives better motor learning outcomes compared to the same treatment in patients with high dopamine transmission. The authors of the study stated that DRD2 gene polymorphism contributes to these varying outcomes.

Fortunately, the mutations or SNPs in the genes are not always a bad news. Recent research published this year demonstrates that two SNPs in the DRD2 gene brings good outcomes in patients treated with rasagiline monotherapy. Rasagiline is a selective, irreversible inhibitor of monoamine oxidase B and has been approved by the FDA as a symptomatic treatment for Parkinson’s disease. This research is the first study to be conducted in patients with early-onset Parkinson’s disease.

Methods for identification of patients who might experience side effects from using the dopamine agonists are also being explored. Recent findings from a group of Australian researchers provide preliminary evidence that dopamine gene profiling may be useful for identifying people at risk of developing side effects from dopamine agonists, the drug called ropinirole in particular. This study also explored the usefulness of an individualized treatment approach.

Unfortunately, the therapeutic options for patients suffering from Parkinson’s disease are very limited at the present time. Personalised genetic profiling may advise the optimal strategy for using this limited arsenal of therapeutic tools in each individual case. This approach will minimize the potential side effects and optimize drug efficiency.

New drugs for Parkinson’s are being developed, and there are several very interesting candidates in the pipeline. But it may still take many years to find something more efficient than we have now. In the meantime, it will be useful to dedicate more  research to the issue of genetically determined drug response in relation to Parkinson’s disease. This will likely enable physicians to adjust treatments for individual patients and thus provide them with significant health benefits in the short term.

References

Altmann, V., Schumacher-Schuh, A., Rieck, M., Callegari-Jacques, S., Rieder, C., & Hutz, M. (2016). Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson’s disease Pharmacogenomics, 17 (5), 481-488 DOI: 10.2217/pgs.15.183

Connolly, B., & Lang, A. (2014). Pharmacological Treatment of Parkinson Disease JAMA, 311 (16) DOI: 10.1001/jama.2014.3654

MacDonald, H., Stinear, C., Ren, A., Coxon, J., Kao, J., Macdonald, L., Snow, B., Cramer, S., & Byblow, W. (2016). Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole Journal of Cognitive Neuroscience, 28 (7), 909-919 DOI: 10.1162/jocn_a_00946

Masellis, M., Collinson, S., Freeman, N., Tampakeras, M., Levy, J., Tchelet, A., Eyal, E., Berkovich, E., Eliaz, R., Abler, V., Grossman, I., Fitzer-Attas, C., Tiwari, A., Hayden, M., Kennedy, J., Lang, A., Knight, J., & , . (2016). Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study Brain, 139 (7), 2050-2062 DOI: 10.1093/brain/aww109

Pearson-Fuhrhop, K., Minton, B., Acevedo, D., Shahbaba, B., & Cramer, S. (2013). Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa PLoS ONE, 8 (4) DOI: 10.1371/journal.pone.0061197

Image via PublicDomainPictures / Pixabay.

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Huntington’s Disease – A High-Tech Solution? http://brainblogger.com/2016/08/21/huntingtons-disease-a-high-tech-solution/ http://brainblogger.com/2016/08/21/huntingtons-disease-a-high-tech-solution/#respond Sun, 21 Aug 2016 15:00:55 +0000 http://brainblogger.com/?p=22034 Huntington’s disease is a genetic disorder that causes the progressive death of brain’s nerve cells. This gradually results in to the loss of functional abilities and ultimately causes severe movement and cognitive impairments. The disease often strikes during a person’s prime working years and to date, there is no known cure. However, new developments in gene therapy may provide a long-awaited treatment for Huntington’s disease.

Case study: an experimental drug trial for Huntington’s disease: a future cure in sight?

To this end, an experimental drug based on the principle of gene used to treat Huntington’s disease has recently been tested on patients in London. Since the discovery of the gene responsible for Huntington’s disease in 1993, this could potentially represent a key milestone in the long-standing battle against this devastating neurodegenerative disease.

The exciting discovery here is that this drug, named ISIS-HTTRx, goes straight for the primary cause of the disease – a protein called mutant huntingtin that is caused by a genetic defect in brain cells, whereby there is an expansion of CAG (cytosine-adenine-guanine) triple repeats in the gene coding for the Huntingtin protein.

The administration of this drug is carried out at the base of the patients’ spine, directly into the cerebrospinal fluid (the fluid surrounding the brain and spinal cord). From there, the drug then migrates to the brain. In patients with Huntington’s disease, the faulty gene produces messenger RNA molecules which causes mutant huntingtin protein to be generated in the brain.

The drug has been engineered to be able to bind to these messenger molecules, and this forces the cells to dispose of the RNA molecules rather than produce the toxic mutant huntingtin protein. More importantly, it is pertinent to note that this treatment (known as an “antisense” drug) could theoretically prevent and/or reverse the effects of the toxic protein.

The human trial described herein aims to test the safety of the drug in patients who are in the early stages of Huntington’s disease by investigating if increasing the dosage of ISIS-HTTRx leads to any adverse effect. Moreover, the level of mutant huntingtin protein in the cerebrospinal fluid would also be measured to determine if the drug was achieving the effect of reducing its level. At the same time, though, it is also important to realize in the later phases of testing in humans, further assessments would still be carried out to ascertain the effectiveness of the drug.

Currently, research using mouse models of Huntington’s disease has shown much promise. These mice exhibit Huntington’s disease-like symptoms similar to those in patients, and help to facilitate investigations into the pathogenesis of the disease. Notably, when the ISI-HTTRx was administered to these “Huntington’s” mice, there were significant improvements in their Huntington’s-like symptoms with minimal severe side-effects. The next step would then be to carry the drug through to testing its efficacy and licensing it.

Concurrently, finding a solution to Huntington’s can also be complicated in the social aspect. In this regard, efforts to treat patients with Huntington’s disease by and large involve the development of drugs which would most likely be expensive.

Importantly, this would prohibit the poor communities who participate in the research studies, such as for those in South America, from being able to reap the downstream benefits of the research conducted. Even if cost was not a problem, the lack of local access of medical care and infrastructure to deliver the drugs would be major factors which prevent the treatment from getting to these people. This remains a pressing issue and is an increasingly important area of concern to healthcare professionals and policymakers alike.

New technologies to treat Huntington’s: gene silencing versus gene editing

Consider this: if we edited the DNA of patients with Huntington’s disease and removed the mutation causing all these problems, wouldn’t that cure this disease? Of course, this is all easier said than done – but advances in genome editing technologies in recent years have made what once seemed like an impossible task much closer to reality.

The nifty method to carry out genome editing is known as the CRISPR-Cas9 system. The inspiration for this technology came from the system used by bacteria naturally to protect themselves against viral infections. To put it simply, the technology consists of a synthetic guide RNA and Cas9 protein. Cas9 is an endonuclease enzyme that can cut DNA. The guide RNA is designed to match the target, and this RNA then guides the enzyme to the target DNA (or more recently RNA as well). Cas9 then uses two “molecular scissors” to carry out editing of the specific DNA of interest, which can serve a multitude of purposes.

Some potential gene editing applications to treat Huntington’s disease could include cutting out some of the extra copies of the CAG repeats which cause the disease. If the editing tool could be used to snip out part of the mutant Huntingtin gene, this would lead to it not being translated into the toxic mutant Huntingtin protein. Furthermore, the combination of stem cell and gene therapy could open up a plethora of possibilities in both the treatment of Huntington’s disease as well as many other neurodegenerative disorders. Researchers hope that this can be the first step in bringing hope to patients with such diseases that one day their conditions could potentially be cured with the development of novel treatment methods.

References

Abudayyeh, O., Gootenberg, J., Konermann, S., Joung, J., Slaymaker, I., Cox, D., Shmakov, S., Makarova, K., Semenova, E., Minakhin, L., Severinov, K., Regev, A., Lander, E., Koonin, E., & Zhang, F. (2016). C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector Science DOI: 10.1126/science.aaf5573

Leavitt, B., Tabrizi, S., Kordasiewicz, H., Landwehrmeyer, B., Henry, S., et al. (2016). Discovery and Early Clinical Development of ISIS-HTTRx, the First HTT-Lowering Drug to Be Tested in Patients with Huntington’s Disease. Neurology. 86:16 Supplement PL01.002.

Pouladi MA, Morton AJ, & Hayden MR (2013). Choosing an animal model for the study of Huntington’s disease. Nature reviews. Neuroscience, 14 (10), 708-21 PMID: 24052178

Sun YM, Zhang YB, & Wu ZY (2016). Huntington’s Disease: Relationship Between Phenotype and Genotype. Molecular neurobiology PMID: 26742514

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Cannabinoids Hold Promise for Alzheimer’s Disease Treatment http://brainblogger.com/2016/07/26/cannabinoids-hold-promise-for-alzheimers-disease-treatment/ http://brainblogger.com/2016/07/26/cannabinoids-hold-promise-for-alzheimers-disease-treatment/#respond Tue, 26 Jul 2016 15:00:09 +0000 http://brainblogger.com/?p=21984 Alzheimer’s disease (AD) is a neurodegenerative condition and the most common form of dementia worldwide, accounting for around 70% of dementia cases. Deposition of the amyloid-beta (A-beta) peptide in the form of amyloid plaques is one of the hallmarks of the disease, occurring early in the development of this condition. As disease progresses, degenerative changes accumulate, leading to neuronal death, oxidative damage, and neuroinflammation.

The exact pathological mechanisms that drive Alzheimer’s disease remain to be clarified and are the subject of extensive research (and debate). With the goal of further elucidating some of the processes that drive Alzheimer’s progression, new research published in the Nature Partner Journal Aging and Mechanisms of Disease studied the association between A-beta accumulation and the development of neuroinflammation, as well as possible therapeutic interventions. Their results were promising.

Does A-beta accumulation cause inflammation?

Neuroinflammation is a characteristic of the aging process and is one of the main causes of cognitive impairment. In the context of neurodegenerative diseases, inflammatory responses are further increased and contribute to the accelerated rate of cognitive decline that is observed. The increased inflammatory response found in the brain of Alzheimer’s patients has been mostly regarded as a consequence of the activation of glial cells in the brain.

This study, carried out in vitro, indicates that this may not be so: it establishes a direct link between A-beta and inflammation, demonstrating that A-beta production in cultured human central nervous system neurons leads to the synthesis of a number of proinflammatory molecules and to the activation of inflammatory pathways. Most of the proinflammatory molecules known to be excessively produced in the brain of Alzheimer’s patients were shown to also be overproduced in neurons after the induction of A-beta production.

Furthermore, these results suggest that A-beta production in neurons may induce inflammation even before it starts accumulating and forming amyloid plaques in the brain.

Are NSAIDs a bad choice for Alzheimer’s patients?

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to delay clinical features of Alzheimer’s disease, but clinical trials have never supported that idea. NSAIDs act by inhibiting a family of enzymes called cyclooxygenases (COX), which are responsible for the production of prostaglandins. Since prostaglandins can induce inflammatory responses, the inhibition of COX by NSAIDs results in decreased inflammation. Since COX-2 is known to be increased in the brain of Alzheimer’s patients, in theory, blocking the action of COX-2 using NSAIDs should be beneficial.

But the regulation of inflammation is not the only function of prostaglandins, which actually depends on the receptors they activate. As it turns out, according to this study, the prostaglandins PGE2 and PGD2 are actually neuroprotective, similarly to what has been found in ischemic stroke and in other neurodegeneration models. The increase in COX-2 production may therefore be a defense mechanism that neurons set in motion. By inhibiting this defense system, NSAIDs may actually promote further cellular damage.

This work showed that the detrimental action of A-beta can be mediated by the action of molecules produced by another enzyme called 5-lipoxygenase (5-LOX). These molecules, called leukotrienes, seem to be the ones that potentiate A-beta’s toxicity. It was shown that the inhibition of 5-LOX was able to prevent cell death, therefore holding better therapeutic potential than NSAIDs.

Cannabinoids effectively block A-beta toxicity

Interestingly, both prostaglandins and leukotrienes derive from the same molecule: arachidonic acid. And arachidonic acid is also a component of a family of endogenous cannabinoids produced in the brain.

Cannabinoids had already been studied in the context of Alzheimer’s disease, having been shown that they can reduce A-beta accumulation and improve memory. Not only endogenous cannabinoids, but also tetrahydrocannabinol (THC), the main psychoactive component of cannabis, are also known to be able to reduce inflammation.

Therefore, this study also investigated whether cannabinoids could have therapeutic potential for Alzheimer’s disease. It was shown that an endocannabinoid called arachidonoyl ethanol amide (AEA), as well as synthetic analogs to this molecule, could promote neuronal survival and block A-beta accumulation. The inhibition of the enzyme that degrades AEA was also shown to be protective.

THC was also tested in this study and the results were very promising: THC had a marked protective effect, being able to remove intraneuronal A-beta, to dramatically reduce the elevated production of damaging leukotrienes, and to block neuronal cell death.

The results of this study show that cannabinoids may indeed hold promise for the treatment of Alzheimer’s disease. It remains to be determined if similar effects will also be obtained in vivo.

References

Bayer, . (2010). Intracellular accumulation of amyloid-beta – a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease Frontiers in Aging Neuroscience DOI: 10.3389/fnagi.2010.00008

Burstein, S., & Zurier, R. (2009). Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation The AAPS Journal, 11 (1), 109-119 DOI: 10.1208/s12248-009-9084-5

Campbell, V., & Gowran, A. (2009). Alzheimer’s disease; taking the edge off with cannabinoids? British Journal of Pharmacology, 152 (5), 655-662 DOI: 10.1038/sj.bjp.0707446

Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., & Schubert, D. (2016). Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids npj Aging and Mechanisms of Disease, 2 DOI: 10.1038/npjamd.2016.12

Kim, E., Kwon, K., Park, J., Lee, S., Moon, C., & Baik, E. (2002). Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation Journal of Neuroscience Research, 70 (1), 97-107 DOI: 10.1002/jnr.10373

Martín-Moreno, A., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M., Innamorato, N., Cuadrado, A., & de Ceballos, M. (2012). Prolonged oral cannabinoid administration prevents neuroinflammation, lowers ?-amyloid levels and improves cognitive performance in Tg APP 2576 mice Journal of Neuroinflammation, 9 (1) DOI: 10.1186/1742-2094-9-8

Valera, E., Dargusch, R., Maher, P., & Schubert, D. (2013). Modulation of 5-Lipoxygenase in Proteotoxicity and Alzheimer’s Disease Journal of Neuroscience, 33 (25), 10512-10525 DOI: 10.1523/JNEUROSCI.5183-12.2013

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Why Are Benzodiazepines and Z-Drugs Still Prescribed Indefinitely For Insomnia? http://brainblogger.com/2016/02/11/why-are-benzodiazepines-and-z-drugs-still-prescribed-indefinitely-for-insomnia/ http://brainblogger.com/2016/02/11/why-are-benzodiazepines-and-z-drugs-still-prescribed-indefinitely-for-insomnia/#respond Thu, 11 Feb 2016 16:00:28 +0000 http://brainblogger.com/?p=20941 The official guidelines indicate that benzodiazepines and z-drugs (e.g. Ambien) should be used for the short-term management of insomnia. Yet many patients are prescribed these drugs indefinitely. What accounts for this discrepancy between guidelines and clinical practice?

Admittedly, many patients suffer from intractable insomnia that only responds to z-drugs or benzodiazepines. But physicians tend to prescribe these medications as first-line agents for patients presenting with insomnia. This leaves alternative drugs that may be safer for long-term use unexplored.

Protracted benzodiazepine use is a significant risk factor for the later development of dementia. This raises the question how to better observe the short-term use of these drugs in clinical practice. One possibility is that alternative drugs could be prioritized in treatment algorithms, like suvorexant, remelteon and hydroxyzine.

Orphan drugs could also be repurposed as sleep aids safer for long-term use. The antihistamine latrepirdine, which has a short half-life limiting the next-day hangover effect, is a prime candidate.

Sleep Disorders and Mental Health

It has long been appreciated that sleep disorders are highly comorbid with psychiatric illness. Ford and Kamerow’s epidemiological study suggests that 40% of respondents with insomnia and 46.5% of respondents with hypersomnia suffer with concurrent mental illness.

Depression is associated with altered sleep architecture, shortened rapid eye movement (REM) sleep latency, increased REM density, and impaired slow wave sleep (SWS). Moreover, the vast majority of antidepressants suppress and in some cases abolish REM sleep. Chronically suppressed REM sleep results in a robust REM rebound upon antidepressant discontinuation.

The link between sleep disorders and major depressive disorder (MDD) is so significant that some neuropsychiatrists have speculated that depression may be primarily a sleep disorder. At minimum, depression involves dysregulated circadian rhythm and sleep homeostasis.

The causality of this link remains nebulous because acute sleep-deprivation results in a rapid antidepressant effect, whereas chronic, uncontrolled insomnia likely contributes to the pathogenesis of depression. The former observation has served as the basis for the argument that insomnia and especially early morning awakening may be a compensatory response to restore neurotransmitter homeostasis and combat depressive symptomatology.

Treatment Algorithms For Insomnia

The observation that sleep disturbances are core features of depression highlights the importance of identifying a pharmacological strategy for patients with a concurrent sleep disorder and psychiatric illness. The most widely-adopted approach is to exploit the side effect profiles of sedating antidepressants like mirtazepine or doxepin. These medications are commonly used off-label for insomnia. The alpha-adrenergic antagonist Trazodone has also been employed for this purpose. However, recent evidence has emerged suggesting that Trazodone loses efficacy after two weeks of use, putatively due to adrenergic receptor upregulation.

Therefore, polypharmacy may be indicated if patients are uncomfortable with the side effect burden of sedating antidepressants. Side effects may range from the insidious onset of weight gain to anticholingeric-related cognitive impairment in the elderly.

The tricyclic antidepressant trimipramine has been used successfully for the treatment of insomnia for decades, but this drug is an acetylcholine receptor antagonist and therefore may contribute to cognitive impairment in vulnerable populations.

Are Recently Approved Sleep Drugs Any Better?

What, then, are the best sleep medications when a sedating antidepressant has unacceptable side effects?

The recently-approved drugs suvorexant and ramelteon might represent the best first-line agents to treat comorbid sleep disorders and psychiatric illness in this context. However, we should be cautious until postmarketing surveillance confirms the safety of these newer drugs.

Suvorexant and ramelteon are sleep-promoting medications with novel pharmacodynamic profiles. Remelteon is a melatonin agonist which binds to the melatonin receptors MT1 and MT2 with high affinity and specificity, whereas suvorexant highjacks endogenous orexinergic circuits by antagonizing orexin receptors to promote sleep. (Melatonin is an endogenous sleep-promoting, chronobiotic neurohormone produced by the pineal gland and orexin is a wake-promoting neuropeptide implicated in the pathogenesis of narcolepsy.)

Some psychiatrists have expressed skepticism about the superiority of remelteon over simple supplementation with exogenous melatonin. Others have argued that remelteon may be more effective because it has a six-fold higher binding potency for the MT1 receptor and a three-fold higher affinity for the MT2 receptor.

The efficacy of these newer agents is hit-or-miss compared with benzodiazepines and z-drugs. But if they don’t carry the same risk of cognitive impairment and early mortality, it’s worth asking whether they might be more suitable for the long-term management of insomnia (if they work in the first place).

Cognitive Dissonance in Psychiatry

Cognitive dissonance exists vis-à-vis the use of benzodiazepines and z-drugs. The official recommendation is that these medications should be used for the short-term management of insomnia only (i.e., 2-4 weeks). In practice, a large segment of the patient population is dependent on these drugs indefinitely.

Benzodiazepines and z-drugs are effective because they enhance inward chloride currents by modulating the GABA-A receptor. But they’re associated with protracted cognitive impairment that in some cases does not remit upon discontinuation of the offending drug. Globally “turning down the gain” on neurotransmission by manipulating the ratio of excitatory to inhibitory inputs represents a kind of shotgun approach to the problem of insomnia. By comparison, suvorexant and remelteon are agents which more selectively affect sleep/wake circuitry by targeting melatonin and orexin receptors.

Additional clinical experience and research is needed to clarify the actual efficacy of these newer drugs. But it is worth asking whether non-GABAergic drugs should be prioritized in treatment algorithms. It is also interesting that no short-acting antihistamines have been repurposed for the treatment of insomnia, given that currently available antihistamine sleep aids (e.g. hydroxyzine) have long half-lives that can impair next-day functioning.

Sleep quality and parameters like delta power are important correlates of both IQ and resilience to dementia. Enhancing sleep quality with more selective drugs in patients presenting with low sleep efficiency may be a promising strategy to enhance cognitive function. Sleep enhancement may also mitigate the risk of later developing neurodegenerative disease, and improve mood and general well being in the long run.

References

Bunney, B., & Bunney, W. (2013). Mechanisms of Rapid Antidepressant Effects of Sleep Deprivation Therapy: Clock Genes and Circadian Rhythms Biological Psychiatry, 73 (12), 1164-1171 DOI: 10.1016/j.biopsych.2012.07.020

Ford, D. (1989). Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA: The Journal of the American Medical Association, 262 (11), 1479-1484 DOI: 10.1001/jama.262.11.1479

Mendelson, W. (2005). A Review of the Evidence for the Efficacy and Safety of Trazodone in Insomnia The Journal of Clinical Psychiatry, 66 (04), 469-476 DOI: 10.4088/JCP.v66n0409

Mets MA, van Deventer KR, Olivier B, & Verster JC (2010). Critical appraisal of ramelteon in the treatment of insomnia. Nature and science of sleep, 2, 257-66 PMID: 23616713

Nutt D, Wilson S, & Paterson L (2008). Sleep disorders as core symptoms of depression. Dialogues in clinical neuroscience, 10 (3), 329-36 PMID: 18979946

Image via Palau / Shutterstock.

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Psychotic Toddlers? http://brainblogger.com/2016/01/24/psychotic-toddlers/ http://brainblogger.com/2016/01/24/psychotic-toddlers/#respond Sun, 24 Jan 2016 16:00:51 +0000 http://brainblogger.com/?p=21105 A recent New York Times article by Alan Schwartz reveals a very disturbing trend in regards to the growing use of neuroleptics in youngsters under the age of five, even two years or younger. In his article he discusses Andrew, who at five months of age was diagnosed with seizures.

Andrew was prescribed anti-convulsants. In a year or so, the toddler became increasingly aggressive and “violent”. The neurologist treating him prescribed the antipsychotic Risperdal, for what some refer to as behavioral dyscontrol.

As a class of psychotropics, they reveal very disturbing side-effects and adverse events. They are not approved at all for children under the age of eight. They have never been researched in this age group because of clinical and ethical concerns. They are usually approved for mania and psychosis in persons with schizophrenia.

According to the article, the use of neuroleptics in toddlers reveals a 50% increase in their use, along with a 23% jump in antidepressants and ADHD prescriptions. All psychotropic agents for ADHD are Schedule 2 controlled agents, are highly addictive, and can trigger psychosis. The U.S. consumes 85% of the world’s market!

Major side-effects include rapid weight gain, diabetes, rapid lowering of white blood cells to name just a few. As far as adverse events, these include tardive dyskinesia (TD), which are painful and irreversible movements and tremors of major muscle groups. Worst yet, they can trigger neuromalignant syndrome, that is amplified TD with death.

The reporter discusses this situation with child experts in the field. One of them is Dr. Ed Tronick, who is professor of developmental brain science at the University of Massachusetts. Dr. Tronick is very clear that these agents will impact the developing brain in ways that we cannot predict. We know that protracted and high dose use in adults, destroys brain tissue and neurons. And in fact, Dr. Tronic voices that the use of the above agents are “nuts”.

I agree with him based on my 43 years of clinical experience.

Both he and I know that physicians often prescribe “off label”, which means that they are not approved by the FDA for certain disorders. And all prescribing done in this manner also seriously deviates from all best, consensual clinical practices. This includes the American Association of Pediatrics.

By the way, antipsychotics are over prescribed in youngsters with autism who show “autistic irritability”. We are also overprescribing them to the aged who develop Alzheimer’s disease. It is my professional opinion that should always be prescribed with written informed consent, as I consider all psychotropics to be pervasive in regard to psychokinetic actions.

Ethically, all clinicians take an oath to “do no harm”. I’ve added a second obligation, that “when clinically necessary, do the least harm possible”. Finally, both Dr. Tronick and I know that a number of psychosocial interventions are known to be efficacious in the intervention of the above disoders, and show very few side-effects and no adverse events.

I strongly encourage parents and others who are concerned about toddlers to become much more aware and informed of these psychotropic agents. When used for the right disorders, and used within clinical guidelines, they reduce suffering, and even save lives.

Reference

Schwartz, Alan. (Dec 10, 2015). Still in a Crib, Yet Being Given Antipsychotics. New York Times.

Image via Sergey Novikov / Shutterstock.

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The Most Popular Psychiatric Drugs Alter Decisions to Cause Harm http://brainblogger.com/2015/07/15/the-most-popular-psychiatric-drugs-alter-decisions-to-cause-harm/ http://brainblogger.com/2015/07/15/the-most-popular-psychiatric-drugs-alter-decisions-to-cause-harm/#respond Wed, 15 Jul 2015 15:00:10 +0000 http://brainblogger.com/?p=20112 Citalopram (Celexa®) and levodopa (Larodopa®), considered to be the most commonly prescribed antidepressant and Parkinson’s drug respectively, have been shown in a new study to alter how healthy individuals make moral decisions to harm both oneself and other people. Conducted by researchers from UCL and Oxford University the research investigated how taking citalopram or levodopa altered participants’ decisions to inflict pain on themselves or strangers in exchange for money…the results are both concerning and promising.

The experiment involved 175 healthy adults, 89 of which were randomized to receive serotonin-boosting citalopram or placebo and the remaining 86 randomized to receive dopamine-boosting levodopa or placebo. The participants had to make choices in a harm aversion experiment regarding giving both themselves and other participants electric shocks for financial gain.

Entering separate testing rooms without seeing each other, the participants were given the drugs and waited until the peak drug absorption time was reached, 3 hours or 60 minutes for citalopram and levodopa respectively. With the drugs influence at its peak the harm aversion experiment began.

86 times the participants were asked to decide between receiving a lower amount of money for less shocks to themselves or more money for more shocks. Likewise, they also had to make choices 86 times for shocking anonymous strangers, where the participant had to decide on which tradeoff was better, receive more money for themselves by inflicting a greater number of shocks to a stranger, or receive less money for themselves in order to electrocute the stranger a fewer number of times.

The researchers had previously published a study of the harm aversion experiment that revealed that most people show a greater aversion to inflicting pain on others than towards themselves, which they coined being a hyperaltruistic disposition.

However, in the present experiment the participants in the test condition were given commonly prescribed drugs that influence the levels of common, multifunctional neurotransmitters in the brain that are involved in a myriad of cognitive functions, namely serotonin (citalopram) and dopamine (levodopa).

For those who had a pharmacological enhancement of serotonin by taking citalopram, they were more likely to avoid harming both themselves and others, choosing to receive less money rather than inflict pain compared with drug-free controls. This is promising news considering reduced harm aversion is a risk factor for both preplanned and in the moment reactive aggression that are both common features of the mental illnesses and disorders that citalopram and similar serotonin reuptake inhibitors are prescribed to treat.

Whereas those who had a pharmacological enhancement of dopamine by taking levodopa had their hyperaltruism reduced, and were more likely to inflict pain on others than themselves compared with control. Ultimately, this means that taking levodopa increases selfishness for monetary reward, which is backed by other studies.

Interestingly, these decision altering affects of both drugs were dose dependent, meaning that the higher quantity of the drug that was taken, the stronger the effect on moral decision making.

Looking at how quickly decisions were made on both drugs was also enlightening when considering other research on uncertainty. With citalopram it took longer for the participants to make their decision which the researchers interpreted as erring on the side of caution to avoid imposing unwanted levels of shocking pain on others.

However, it is also important to note that citalopram enhanced the participants’ negative affect, which includes negative emotions like anger, contempt, disgust, guilt, fear and nervousness. It may be that enhanced worry and nervousness caused by healthy people taking citalopram and abnormally enhancing serotonin levels promotes harm aversion and cautious behavior, which may not be useful for overly harm avoidant, fearful and withdrawn psychiatric patients.

With levodopa on the other hand the authors suggest a mechanism by which levodopa reduces hyperaltruism through boosted dopamine levels reducing the variability of neural representations of other people, making the decision to cause pain a quicker and easier than without levodopa, in line with the current neuroscientific perspective on empathy.

Dr Molly Crockett, lead author of the study reminds us that psychiatric drugs influencing moral decisions in healthy people has serious ethical implications of pharmacological interventions however,

“It is important to stress…that these drugs may have different effects in psychiatric patients compared to healthy people. More research is needed to determine whether [and how] these drugs affect moral decisions in [different groups of people] that take them for medical reasons.”

References

Main DOI: http://dx.doi.org/10.1016/j.cub.2015.05.021

Previous research: 10.1073/pnas.1408988111

Aggression and psycopath: 10.1016/0010-0277(95)00676-P

dopamine and selfishness: 10.1007/s00213-013-3210-x

empathy neuroscience: 10.1038/nn.3085

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Cartoon – Antibiotic Overuse in America http://brainblogger.com/2015/06/17/cartoon-antibiotic-overuse-in-america/ http://brainblogger.com/2015/06/17/cartoon-antibiotic-overuse-in-america/#respond Thu, 18 Jun 2015 01:30:39 +0000 http://brainblogger.com/?p=19899 Reference

Hicks LA, Bartoces MG, Roberts RM, Suda KJ, Hunkler RJ, Taylor TH Jr, & Schrag SJ (2015). US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 60 (9), 1308-16 PMID: 25747410

Image created by Jerry King for Brain Blogger.

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Prescription Drug Monitoring Programs – Much Promise But Limited Progress http://brainblogger.com/2015/03/22/prescription-drug-monitoring-programs-much-promise-but-limited-progress/ http://brainblogger.com/2015/03/22/prescription-drug-monitoring-programs-much-promise-but-limited-progress/#respond Sun, 22 Mar 2015 12:54:34 +0000 http://brainblogger.com/?p=19208 The Problems of Opioids

During roughly the past two decades there have been significant increases in the prescription of opioid analgesics for helping millions of patients with pain disorders. At the same time, the United States is in the midst of an epidemic of misuse of these drugs and related abuse, addiction, overdose, and deaths.

For example, the prescribing of opioid analgesics has more than doubled since the 1990s. At the same time, sales of opioids quadrupled and there was a 6-fold increase in admissions to substance abuse treatment programs. Most importantly, opioid-related deaths have more than tripled, with unintentional deaths due opioid overdose exceeding those of heroin and cocaine combined.

As one tool for addressing the problems associated with opioid analgesics, prescription drug monitoring programs (PDMPs) have been developed over the years. These programs are intended to medically benefit patient care, and also as a tool for law enforcement and other agencies concerned with stemming the tide of opioid-related threats to the public health.

PDMPs: Simple in Concept, Complex in Execution

Fundamentally, a PDMP is a central repository of prescribing and dispensing records pertaining to medications classified as scheduled, controlled substances by the U.S. Drug Enforcement Administration, but a PDMP may include any drug/substance of interest or determined to have abuse potential. These days, the information is stored in online electronic databases allowing easy access to authorized individuals or agencies, such as law enforcement and drug control agencies, practitioner licensure boards, medical examiners, drug courts and criminal diversion programs, addiction treatment programs, public and private third-party payers, medication dispensers (e.g., pharmacies) and prescribers, and other healthcare providers. States vary widely in which categories of users are permitted to request and receive prescription history reports and under what conditions.

Individual state PDMPs also differ as to required prescribing information — such as, drugs of interest, dose/quantity, date dispensed, and dispenser, prescriber, and patient information, etc. — and time of entry into the database. Only one state, Oklahoma, collects data in real time — that is, at the same time that a prescription is filled — whereas, most states allow up to a week or longer for submission of data to the PDMP.

In using the data, PDMPs may be categorized as being a) reactive, b) proactive, or c) a combination of the two. A reactive approach passively relies on inquiries (solicitations) from authorized agencies or individuals before generating reports; for example, a physician might query the PDMP database prior to prescribing an opioid for a patient. Or, PDMPs may be more proactively designed to watch for patterns of prescribing or dispensing that raise red flags and then provide unsolicited reports to authorized agencies or individuals for further action. In some cases, state PDMPs use a combination of both approaches.

A Long Evolution of PDMPs

According to research conducted for the Pew Charitable Trusts, PDMPs are not a new concept. In fact, as of 1990 there had been 9 PDMPs developed, dating from the earliest in California in 1939. Most of the programs were initiated by law enforcement and/or regulatory agencies and all of them only collected data on Schedule II prescriptions (i.e., opioids) using multi-page, serialized prescription forms requiring manual data entry at the PDMP. There was an emphasis on controlling illicit channels of opioid purchase or distribution and these early PDMPs provided reports on request (solicited) as well as unsolicited reports to law enforcement personnel, regulatory agencies, or professional licensing agencies; no reports were provided to prescribers or pharmacists.

Beyond 1990, and with support from the U.S. Drug Enforcement Administration (DEA), PDMP administrators formed an alliance for mutual support and information exchange, and to help promote expansion of PDMPs to other states. At this time, PDMPs also started to extend data collection beyond Schedule II drugs; although, each state was free to select the drugs included. This also marked a new generation of PDMPs using electronic technology for prescription information collection, largely abandoning the need for serialized prescription forms. Initially, reports were transmitted by fax, but online systems soon allowed more expedient inquiries.

Continued interest at the federal level, and focusing on reducing opioid-related problems, resulted in various economic support programs; e.g., Harold Rogers Prescription Drug Monitoring Program Grants and the National All Schedules Prescription Electronic Reporting (NASPER) Act. The U.S. Bureau of Justice Assistance helped to form PDMP assistance and training programs with a special emphasis on evidence-based practices. Through the years, other government agencies (e.g., ONDCP, CDC, etc.) and private industry (Purdue Pharma) provided additional assistance and support for program development.

According to the most current information, by the end of 2014 all 50 states and the District of Columbia (Washington DC) had or were nearing realization of a PDMP; Washington DC enacted legislation but did not have an operational program and Missouri was nearing legislative authorization of a PDMP. Still, there are many inconsistencies across state programs, for example:

  • Many, but not all, programs allow sharing of their information with other state PDMPs; however, in many cases there are problems with data formatting and transmission that are barriers to such sharing.
  • In 5 states, PDMPs are still housed in law enforcement agencies.
  • When it comes to proactively sending unsolicited reports, there are many differences in who is contacted, whether it be prescribers, pharmacists, law enforcement, or licensing entities.
  • Less than a quarter of states (12) require that patients are notified when or if their prescription information might be accessed.

As a newly added concern, the recent hacking of online, electronic databases threatens the integrity of PDMP programs and the security of confidential patient information. According to news reports, hacker attacks in Oregon and South Carolina exposed social security numbers and other personal information housed in state databases. Last August, a collective of activist hackers known as “Anonymous” brought the Missouri state database servers to a halt temporarily, which may threaten passage of PDMP legislation in the state.

Serving Multiple Roles

The early and ongoing development of PDMPs has been principally driven by concerns about opioid-related problems — e.g., diversion, abuse, deaths — so the programs were designed foremost to serve regulatory and law enforcement agencies. For example, the database can be used at the individual-patient level to identify those obtaining prescriptions for drugs of concern from multiple prescribers and/or pharmacies during a brief timeframe (known as “Doctor Shoppers”); in response, the prescribers can be proactively alerted. On a larger scale, PDMP records can help to identify medical practices or clinics that appear to over-prescribe controlled substances of concern (“Pill Mills”), which may trigger investigations leading to regulatory or law enforcement actions. In other cases, PDMP records may be used to identify insurance fraud in billing for certain drugs and possible drug diversion within a particular locale.

Of greatest interest currently is having medical professionals use PDMPs as a tool for reducing the abuse, addiction, and diversion of opioid analgesics and other prescription drugs. For example, prescribers are urged to proactively use the database to detect alleged “Dr. Shoppers” so such behavior can be deterred at the point-of-care. Another potential benefit of PDMPs is the improved patient care and safety afforded by prescribers knowing of all controlled substances patients are being prescribed by all healthcare providers, since patients may not report complete information in their health history. Ideally, PDMP reports would include data on all prescription medications, beyond just CII opioids, but most PDMPs are not designed to capture such extensive information.

Although PDMPs have significant potential to improve public health and patient care outcomes, they remain a substantially underutilized resource. Reasons for this include differences in the data individual state PDMPs collect, whether and how data quality is ensured, the kinds of data analyses and reports that are produced, and to which users and under what conditions data are made available. Furthermore, while it is claimed that PDMPs do not infringe on the legitimate prescribing of controlled substances and simply make it possible to spot potential problems in patients deserving a closer look, an end result often has been a “chilling effect” on the prescribing of opioids overall.

Evidence Lacking to Support PDMPs

Early PDMPs in the pre-electronic era had limited effects due to the lag time inherent in reporting information via paper documentation, the minimal data collected, the need for manual data entry, the absence of off-hours access to data, and the voluntary nature of reporting. Since 2001, with the advent of newer and improved PDMPs, there still have been no federally-mandated rules to enforce consistency and compatibility among those programs, which makes doing research across programs more challenging.

Several dozen published and unpublished empirical studies on PDMP effectiveness have been summarized in the Pew report, which more than anything points to the difficulties of such investigations. At best, studies have been observational in nature, but most have been case reports of select aspects of PDMPs (e.g., increases in user satisfaction); the vast majority of studies reported favorable outcomes related to PDMP applications and practices. It is important to note, however, that none of the studies were of high quality and none examined improvements in patient care or health outcomes as a result of PDMP implementation and use.

The few broader-scope comparisons of all states with versus states without PDMP programs did not show outcomes favoring PDMPs. For example, an observational study by Paulozzi, Jones, et al. (2011) of early program effectiveness, spanning 1999 through 2005, found that states with PDMPs demonstrated unfavorably increased trends in drug overdoses and mortality, along with significantly greater consumption of hydrocodone. Interestingly, the only states showing improvements in overdose deaths and opioid consumption at the time included 3 states with PDMPs still using special prescription forms rather than newer electronic approaches. This suggested there were many challenges still to be overcome in developing electronic PDMPs and, while it cannot be stated that PDMPs themselves caused negative outcomes, the researchers concluded that, “…it can be said unequivocally that PDMP states did not do any better than the non-PDMP states in controlling the rise in drug overdose mortality.”

Further studies are needed to assess individual state programs as well as PDMPs grouped on a regional and nationwide basis. Along with that, however, many potentially confounding factors must be considered. For example, several government agencies have been developing and promoting educational and regulatory programs that impact some of the same outcome variables measured for PDMP programs. For example, reductions in opioid-related overdoses and deaths during recent years might be attributed to successes of the FDA’s REMS (Risk Evaluation and Mitigation Strategies) programs for opioid analgesics.

Prescriber Dilemmas

Prescribers have not widely embraced the use of PDMPs, even though there could be some advantages of PDMPs for patient care. For example, a comprehensive and accurate history of pharmacotherapy-management is essential for clinical evaluation of a new patient with chronic pain. While reliance on the patient’s self-reported history is generally considered acceptable, it may lead to dangerous misprescribing. A PDMP might help to identify patients who are receiving multiple legitimate prescriptions for opioids or benzodiazepines, from different healthcare providers, and are at risk for complications from polypharmacy — but only if the PDMP tracks more than class CII opioids.

Online electronic PDMPs help to solve many of the problems that restrained earlier, paper-based systems, but they also raise new concerns. In one survey of prescribers, the respondents cited time restraints and access difficulty issues as barriers to using PDMPs. A newly-reported nationwide survey, by researchers at the Johns Hopkins Bloomberg School of Public Health, found that among the 420 randomly-selected eligible physicians questioned more than one-fifth (22%) were not aware of their state’s PDMP and only 53% had actually used the program.

The researchers suggest that usage might be improved if more states allow physicians to appoint a proxy such as a staff member who can do the work of accessing the database. Another problem noted is that, in some state databases, the information is not clearly presented, making it difficult to interpret. Furthermore, only 21 states presently require prescribers to register with their PDMP and only 16 states require that prescribers use PDMP information.

In that regard, a cross-sectional study of 33 PDMP programs found that only slightly more than half of clinicians on average within the states were registered to use the PDMP, with many who did register using it infrequently. In states with PDMPs administered by law enforcement agencies, usage by healthcare providers was lower than in states with PDMPs managed by health or pharmacy boards.

In a recent survey of PDMP users in Oregon, almost all (95%) reported accessing the database when they suspected drug abuse or diversion in a patient, but fewer than half checked it routinely for every new patient or every time they prescribed a controlled drug. Clinicians also reported a variety of problems that arose when a PDMP report included “worrisome” information: patients often reacted with anger or denial (at least 88% reacted this way sometimes); nearly three-quarters of clinicians (73%) said that those patients sometimes did not return; less than a quarter (22%) reported that the confronted patients asked for help with drug addiction or dependence problems.

Overall, the data at hand suggest that prescribers generally do not perceive PDMPs as an essential tool for improving patient care in their practices, and the detriments may overshadow advantages. While most practitioners believe that they can detect “problem patients” on their own, research has shown this to be untrue. Additionally, accessing PDMPs incurs extra time in busy healthcare practices, whether by the clinician or a proxy staff member, without added compensation. Plus, the uncovering of “worrisome” data opens a proverbial “can of worms,” requiring further uncompensated time with patients to discuss information that may not be accurate, that may be upsetting to patients and damaging to practitioner-patient relationships, and that the clinician may be uneducated to manage.

Many Challenges Ahead

There still seem to be questions about whether PDMPs successfully serve the interests of public health (e.g. to stem opioid abuse, drug trafficking, deaths) or better patient care (e.g., to avoid harmful drug interactions and help guide opioid prescribing) or both objectives. Clinicians are facing the challenge of caring for an increasing number of patients with chronic pain who may benefit from opioid therapy. At the same time, increased opioid prescribing has correlated with soaring rates of abuse, diversion, addiction, overdose and deaths. PDMPs are no panacea for addressing the problems.

There are realistic concerns that PDMPs can be burdensome for prescribers and dispensers, and a “chilling effect” of these programs may inappropriately reduce the amount of opioid analgesics prescribed as an unintended consequence. Many clinicians are still unaware of the PDMPs in their states and those who are aware also realize that their prescribing practices are being monitored by law enforcement, regulatory, and licensing agencies. Concerns about punitive action for falsely-perceived misprescribing or overprescribing practices may foster apprehensions among prescribers and medical boards to adopt and use PDMPs. This, in itself, may alter prescribing habits in ways that adversely affect patient care.

Online database security and patient confidentiality also are of concern, particularly when PDMP databases expand to include multiple state programs or are consolidated nationally and inadvertently become appealing targets for hackers. The costs of implementing secure PDMPs are significant and, beyond infrastructure and administrative costs, the time and effort required to use PDMPs effectively must be considered.

Research examining outcome effects of PDMPs has been hampered by the variations in individual state’s program designs. As states develop, expand, or retool their PDMPs, the most successful characteristics of existing programs must be identified and applied to enhance the future impact and effectiveness of all PDMPs. Along with that, there must be a common goal of facilitating the legitimate prescription of controlled substances for patient well-being while mitigating the prescription drug abuse epidemic and associated public health problems via appropriate uses of PDMPs and their data.

References

Clark T, Eadie J, Kreiner P, Strickler G. Prescription Drug Monitoring Programs: An Assessment of the Evidence. The Prescription Drug Monitoring Program Center of Excellence; Heller School for Social Policy and Management, Brandeis University; September 20, 2012. A report for the Pew Charitable Trusts.

CMS (Centers for Medicare and Medicaid Services). The Role of a Prescription Drug Monitoring Program in Reducing Prescription Drug Diversion, Misuse, and Abuse. U.S. Department of Health and Human Services; June 2014.

DEA (U.S. Drug Enforcement Administration). Drug Schedules. Undated.

Fleming ML, Chandwani H, Barner JC, et al. Prescribers and pharmacists requests for prescription monitoring program (PMP) data: Does PMP structure matter? J Pain Palliat Care Pharmacother. 2013;27:136-142.

Frenk SM, Porter KS, Paulozzi LJ. Prescription Opioid Analgesic Use Among Adults: United states, 1999–2012. National Center for Health Statistics; NCHS Data Brief. 2015(Feb):189.

Goldberg S. Missouri House Bill Seeks Prescription Drug Monitoring. Business Insurance; February 27, 2015.

Irvine JM, Hallvik SE, Hildebran C, et al. Who uses a prescription drug monitoring program and how? Insights from a statewide survey of Oregon clinicians. J Pain. 2014;15(7):747-755.

NAMDSL (National Alliance for Model State Drug Laws). Compilation of Prescription Monitoring Program Maps. NAMDSL, Charlottesville, VA; 2015.

ONDCP (Office of National Drug Control Policy). Epidemic: responding to America’s prescription drug abuse crisis. Washington, DC: Office of National Drug Control Policy, 2011.

Paulozzi LJ, Jones CM, Mack KA, Rudd RA. Vital Signs: Overdoses of Prescription Opioid Pain Relievers — United states, 1999-2008. MMWR. 2011(Nov 1);60. Available at:

Paulozzi LJ, Kilbourne EM, Desai HA. Prescription Drug Monitoring Programs and Death Rates from Drug Overdose. Pain Med. 2011:12(5):747-754.

Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med. 2012;13:87-95.

Perrone J, Nelson LS. Medication Reconciliation for Controlled Substances — An “Ideal” Prescription-Drug Monitoring Program. N Engl J Med. 2012;366:2341-2343.

Rutkow L, Turner L, Lucas E, et al. Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access. Health Aff. 2015(Mar);34(3):484-492.

Stukey A. House Budget Committee Cuts State’s IT Budget, Despite Cyber Threats. St. Louis Post Dispatch; March 9, 2015.

Image via David Smart / Shutterstock.

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Opioids for Chronic Pain – An Interview with Dr. Webster, Pain Guru http://brainblogger.com/2015/01/30/opioids-for-chronic-pain-an-interview-with-dr-webster-pain-guru/ http://brainblogger.com/2015/01/30/opioids-for-chronic-pain-an-interview-with-dr-webster-pain-guru/#respond Fri, 30 Jan 2015 12:00:54 +0000 http://brainblogger.com/?p=18330 With chronic pain has come a debate on how to treat it, and some controversy on whether opioid use is effective or not. Lynn R. Webster, M.D., is one the nation’s leading researchers and experts in the field of chronic pain management.

Dr. Webster is the Vice President of Scientific Affairs of PRA Health Sciences and immediate past president of the American Academy of Pain Medicine. Practicing medicine for over three decades, Dr. Webster has authored Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. As developer of the Opioid Risk Tool (ORT), he is considered a world authority on how to assess patients for abuse risk with opioid medications, and in trying to help physicians safely treat pain patients while actively working within the industry to develop safer and more effective therapies for chronic pain and addiction. Here, I interview Dr. Webster on prescription opioids for pain.

Lakhan: What are the indications for long-term opioid prescriptions?

Lynn WebsterWebster: Chronic opioid therapy should be reserved for patients who have pain severe enough to warrant a strong analgesic and no other options to effectively relieve the pain. The precise number of people in this category is unclear and is often determined by what a payer is willing to cover, because most alternative treatments are unaffordable to most patients. Chronic opioid therapy can produce side effects, including sexual dysfunction, constipation, hyperalgesia and sleep apnea. Of course exposure to an opioid may also lead to abuse or addiction in a subset of the population with genetic and environmental vulnerabilities.

Lakhan: Are there certain individuals who should NOT be prescribed opioids?

Webster: As with all medications, a risk-benefit analysis is necessary to determine the potential benefit versus harm. People at high risk of harm would be people with an active opioid addiction, significant genetic risks for opioid addiction, abuse of or addiction to other psychoactive drugs, morbid obesity, serious mental health disorders and individuals who are unreliable or who have a history of poor adherence to medical direction. Opioids may be necessary for these people during an acute injury or surgery with appropriate monitoring, but chronic opioid use should be avoided in these populations.

Lakhan: What are the dangers on long-term opioid use?

Webster: “Dangers” implies serious adverse outcomes like addiction or overdose death rather than a common side effect like constipation or sexual dysfunction. The most serious outcome is respiratory depression leading to death. This risk is heightened when combining an opioid with a benzodiazepine or other central nervous system depressant. Respiratory depression can occur if more opioid is circulating when a concomitant medication is added that slows the metabolism of the opioid. Respiratory infections can reduce the pulmonary reserve, increasing the risk of hypoxia and respiratory failure leading to death. That said, even the more common side effects like constipation or sexual dysfunction can cause serious difficulty if not managed.

Conflicting reports have assessed the risk of long-term opioid use in the development of addiction. In general, long-term use of opioids has not been associated with an increased risk of addiction per se. That is because the dose of an opioid and duration of exposure are not necessarily risk factors for opioid addiction. People can be harmed at a low dose or a high dose and with short-term exposure as well as long-term exposure to opioids.

Lakhan: How do patients become addicted to opioids?

Webster: Addiction is a brain disease. Opioid addiction, in contrast to some other types of addiction, has approximately two equal contributions to its expression: 50% genetic and 50% environmental. This means that most people who develop an addiction to an opioid have some genetic vulnerability and an environment that allows or induces the vulnerability to be expressed. There are many single nucleotide polymorphisms (SNPs) that appear to contribute to the genetic vulnerability.

Most people have some of the SNPs, but even those who have a strong genetic vulnerability could be spared an opioid addiction if they live in a protective environment. The environmental factors that contribute to the expression of an addiction are multiple, but stress appears to be one of the more significant contributing factors. Unfortunately, severe pain is one of the most stressful conditions that exists and can trigger the expression of addiction in a genetically vulnerable person. A quick survey of a person’s family can provide some insight into the possible genetic risks to an opioid addiction.

The number of people who are prescribed an opioid and develop addiction is hotly debated. Studies suggest anywhere from 3% to 40% of people prescribed opioids develop an abuse or addiction problem. The reason for such a large range is that the definitions used to define abuse and addiction vary tremendously depending upon who is speaking. There are many biases and prejudices toward people who use opioids for pain. Often, any deviation in expected behavior with using opioids is documented on the spectrum of behaviors associated with addiction.

Lakhan: Where are people sourcing opoids from?

People with opioid addictions can get their supply from a number of different sources. Most opioids obtained for non-medical use are obtained from family or friends who have been prescribed opioids for a legitimate medical purpose. These drugs are either stolen by, sold to, or given to the abuser. Only about 10-15% of opioids used for non-medical purposes are prescribed directly to the abuser.

Lakhan: What measures can be taken to prevent opioid abuse and addiction?

Webster: I think the first step is to understand that as long as any rewarding substance is prescribed, a subset of the population will abuse or become addicted to that substance. This is part of our biology and applies to opioids and many other rewarding drugs used in medicine. However, there are many things we can do to mitigate the harm and reduce the risk of opioid-related aberrant behaviors. In general, prescribers and patients need to understand the risk and be cognizant of the signs of addiction. This requires rudimentary education.

To develop an addiction, a person must be exposed to the drug. Avoiding the use of opioids whenever possible decreases exposure. Decreasing exposure reduces the chance for the disease of addiction to be expressed. Since we cannot know for sure a prioi who is genetically vulnerable, we should only use opioids long term when other alternatives are ineffective or unavailable.

If an opioid is to be prescribed, an assessment for risk factors should be performed followed by close monitoring for aberrant behavior. Addiction can be triggered with the first dose or develop after prolonged exposure. People with a “loaded” genome may express an addiction earlier than those who are spared many of the genetic risks. People who develop an addiction later may have less of a genetic vulnerability, but the stress associated with chronic pain can tip toward destructive use behaviors. Using urine drug testing and prescription drug monitoring is essential to detecting non-adherence, which could be a sign of addiction.

For more on how to prevent opioid addiction see my book, Avoiding Opioid Abuse While Managing Pain

Lakhan: What are the “eight principles” for safer opioid prescribing?

Webster: The most serious adverse outcome from prescribing an opioid is an unintended death from overdose. The eight principles are an evidence-based guide on how to reduce the risk of unintended overdoses if an opioid is prescribed. There are many causes for overdoses, but the eight principles identify the factors that appear to contribute often. If all prescribers understood the eight principles, the number of opioid-related deaths should be reduced.

Lakhan: How do opioid abusers circumvent the deterrent properties of the abuse-deterrent opioid formulations? What is promising in this arena?

Webster: Abuse-deterrent formulations are meant to prevent a manipulation of the formulation that would increase the speed of delivery or amount of the drug to an individual for use in an unintended way. The intention is to decrease the user’s ability to crush and thereby extract the opioid molecule from the formulation, making it more difficult to snort or inject. In an extended-release formulation, the abuse-deterrent properties prevent the conversion to an immediate-release formulation. In other words, they prevent a dose dumping or a bolus of drug to be delivered.

There is debate about whether all extended-release formulations should have abuse-deterrent properties. I personally believe that the FDA should set a deadline for when all ER formulations must meet a minimum standard of abuse-deterrent properties to remain on the market. If this were to occur, the cost of ER formulations would likely increase, but this may be a reasonable trade-off for potentially safer products. Of course, this move will not eliminate all dangers; people can still overdose if they take multiple pills of an abuse-deterrent formulation.

Promising research indicates that some new formulations could be inert if injected, snorted or crushed, meaning the opioid would only be active when taken as directed. If someone takes a higher dose than prescribed, the technology is designed to deactivate the molecule, thereby preventing an overdose. There is even more promising research in development investigating an opioid without rewarding properties or respiratory-depressant effects within the therapeutic range. This would be a major advance in analgesic drug development.

Lakhan: Should prescription drug monitoring, which is currently done on a state level, be nationalized?

Webster: All states but Missouri have prescription drug monitoring programs or plans to develop one. The programs are operated differently from state to state, so criteria for using them will vary. Access to timely information is variable as well. It is important that prescribers have access to interstate data sharing because patients can easily move from one area to another if they intend to deceive the prescriber. In some cases, physicians can access data from prescription monitoring programs in surrounding states by contacting those states, but this takes more time and work than is desirable.

For years there has been a push for a nationally centralized database of prescriptions. However, funding has been lacking to make that happen. States have seen the value in sharing their information with physicians in surrounding areas, so some “exchanges” for states to share their databases have been set up. Ultimately, utilization of the databases is what is important. In most states less than a third of physicians use the databases when prescribing an opioid. This needs to change if we are going to identify most of the “doctor shoppers” and curb the epidemic of drug abuse.

Lakhan: What is the future of opioid research?

Webster: The future of opioid research is exciting. In the not-too-distant future we should be able to replace the current mu agonists with opioids that are not nearly as addictive or associated with the same magnitude of adverse effects. This is a field that is only beginning to produce candidates for further development, but there is real optimism and hope that we will one day have a class of opioid drugs that is closer to the Holy Grail of powerful analgesics without addictive properties than anyone could have dreamed possible.

Lakhan: Any final remarks for our readers?

Webster: The reason we have a problem with opioids is because of the prevalence of severe pain and lack of alternative therapies. Nearly one-third of all Americans have chronic pain. Chronic pain is the most prevalent medical problem today, but we spend less than 1% of the National Institutes of Health research budget on finding safer, more effective therapies. To ultimately solve the opioid problem we will need to find better ways to treat pain. This will require an unprecedented commitment of resources.

We need something like a Manhattan Project. We cannot ignore the millions of Americans whose lives are torn apart by pain or accept the large number of people who are harmed from opioids. After all, each reader of this article is likely to experience chronic pain or be close to someone who does. As of now, chronic pain has the power to alter lives forever. We need a societal commitment to find safer and more effective therapies for mankind’s primal enemy – pain.

Image via Michal Kowalski / Shutterstock.

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Memory Enhancement – Nootropics and Electromagnetic Stimulation http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/ http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/#respond Tue, 18 Nov 2014 12:00:21 +0000 http://brainblogger.com/?p=17379 Memories naturally degrade with the passing of time. Although the information is initially registered and stored, after a couple of days, weeks, or even years, it is simply erased from storage. The decline of memory function, be it due to normal aging or due to specific medical conditions, greatly affects one’s day-to-day life. Consequently, it is no surprise that the search for ways of improving memory has thousands of years of history.

The vast majority of the retrieval processes (i.e. most of remembering) happens without us even realizing. It is automatic and requires little to no effort or planning. Interestingly, the information that our subconscious identifies as being important or truly relevant tends to be kept in storage for as long as we need it. This can range from a transient need, like the information that you studied for a school exam, to a permanent, primary need, like recognizing your family’s faces and names.

Memory improvement strategies that have been employed throughout the centuries range from simple cognitive exercises and diet modifications to actual pharmaceutical products which influence the molecular pathways at play in memory processes. While many of these strategies have failed to produce any desirable effects, some substances have actually provided with interesting results in different settings.

Nootropics

Nootropics are a group of such substances which show evidence of positively affecting one or more aspects of memory functions. These substances includes not only drugs, but also supplements, “nutraceuticals”, and functional foods.

Notwithstanding the diversity of nootropic compounds, it is possible to summarize their mechanisms of action as follows:

  • increasing circulation to the brain
  • providing precursors to neurotransmitters
  • improving neuronal function
  • preventing oxidative neuronal damage
  • providing energy sources to the brain.

Perhaps the most famous type of nootropics are racetams, which include various structurally similar compounds, such as piracetam and oxiracetam. Little is known about their precise actions at the molecular level, but there are a few clinical studies indicating their potential when prescribed to individuals with specific memory problems.

For instances, in a study of oxiracetam therapy in patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID) of mild to moderate degree, significant improvements were observed. Nootropics are also very popular for being available over-the-counter and for having virtually no undesirable side effects.

Dietary supplements, such as vitamins and omega-3, are considered nootropics as well, thanks to their influence on memory, learning, concentration and decision-making.

Other popular classes of nootropics include:

  • stimulants, such as amphetamines and xanthines (e.g. caffeine)
  • dopaminergics, affecting the neurotransmitter dopamine or the components of the nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention, alertness, and antioxidant activity
  • cholinergics, including acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors
  • nutraceuticals, including Bacopa monnieri, isoflavones and Gingko biloba.

One of the nootropic substances that has sparked a lot of scientific curiosity is nicotine. Famously known for its carcinogenic potential and a myriad of other adverse effects on smokers’ health, researchers have long been aware of the ability of nicotine to influence cognitive performance.

For example, difficulty in concentrating is one of the symptoms of nicotine withdrawal, but for a long time this was regarded as a mere relapse factor. Still, as smokers repeatedly reported that one of the reasons they smoke is for the perceived cognitive improvement that smoking gives them, experiments have been attempting, for more than 40 years, to validate these claims and to delineate the conditions under which nicotine might enhance the various domains of human performance.

Biologically, there is a basis for the influence of nicotine in cognitive processes. Nicotine binds to presynaptic nicotinic acetylcholine receptors in the brain, facilitating the release of acetylcholine, dopamine, serotonin, glutamate, and other neurotransmitters known to be involved in these processes.

A meta-analysis of the acute and long-term effects of nicotine on human performance, which looked at the results of a number of studies on the topic, revealed impressive results. Nicotine appears to actually have a significant, positive impact on six domains: fine motor, alerting attention-accuracy, response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT.

Despite these positive effects, it is important to stress that nicotine should not be the nootropic of choice for anyone seeking to improve their memory functions, due to the numerous medical issues it potentiates and the dependence it causes.

As one would expect, like all pharmaceutical products, nootropics have risks as well as benefits. Most of these enhancers are being used with little scientific data to support them, and while some compounds are known to have a good safety profile, others have a risk of unintended side effects that is both high and consequential. It is also important to stress that having an acceptable safety profile is actually dependent on the circumstances under which the product is administered. For example, a drug that restored good cognitive functioning to people with severe dementia but caused serious adverse medical events might be deemed reasonable to prescribe to these patients under the light of its great benefits, but not to healthy individuals who are only seeking enhancement.

Even in terms of practical efficacy, there is much to be said about nootropics. Despite the fact that some studies have shown impressive results, the truth is that there is a lot of heterogeneity (not to mention transiency) in response.

But science is an ever moving field, and recent studies have provided some insight into what might be a revolution in the area of cognitive enhancement. A groundbreaking investigation, published just this year in the renowned journal Science, suggests that there might be a more effective, alternative strategy to stimulate and improve the processes underlying memory formation.

Electromagnetic stimulation

We have known for quite some time now, mainly in the aftermath of very select cases of severe brain injuries which are illuminating by virtue of the impairments they produce, that the hippocampus plays a decisive role in the works of memory. Naturally, the hippocampus does not work on its own, and a team of American researchers took advantage of these complex interactions to test its function.

Using the technique of noninvasive electromagnetic stimulation – never tested in humans before – researchers altered the interactions between the networks of hippocampal and cortical neurons and registered the effects of such modulation on memory. After multiple sessions of electromagnetic stimulation, there was a clear functional increase in the transmission of neural impulses between those neurons. Concomitantly, associate memory performance of the subjects involved improved significantly, persisting about 24 hours after stimulation.

While these results are promising and may constitute a new window into the mechanics of memory formation and memory enhancement, they are also preliminary findings that still leave many questions unanswered. Further investigations, both in healthy individuals and in people with medical issues associated with memory formation, will be necessary for the scientific community to really understand the benefits and risks of electromagnetic stimulation.

References

Greely, H. (2013). Some First Steps Toward Responsible Use of Cognitive-Enhancing Drugs by the Healthy The American Journal of Bioethics, 13 (7), 39-41 DOI: 10.1080/15265161.2013.795823

Gruneberg, M. and Morris, P.E. (1994). Theoretical Aspects of Memory, Volume 2, Routledge.

Heishman SJ, Kleykamp BA, & Singleton EG (2010). Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology, 210 (4), 453-69 PMID: 20414766

Rosenbaum RS, Gilboa A, & Moscovitch M (2014). Case studies continue to illuminate the cognitive neuroscience of memory. Annals of the New York Academy of Sciences, 1316, 105-33 PMID: 24871381

Villardita C, Grioli S, Lomeo C, Cattaneo C, & Parini J (1992). Clinical studies with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia of mild to moderate degree. Neuropsychobiology, 25 (1), 24-8 PMID: 1603291

Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, & Voss JL (2014). Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science (New York, N.Y.), 345 (6200), 1054-7 PMID: 25170153

Image via Africa Studio / Shutterstock.

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Why Are We Still Developing Brain Drugs? http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/ http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/#comments Tue, 11 Feb 2014 12:00:59 +0000 http://brainblogger.com/?p=15909 The social stigma surrounding the pharmaceutical industry has gotten pretty bad lately. The business of saving lives is now rated positively by only 32% of the public, tucked neatly between oil and banking in consumer confidence polls – down eight places since 1996. Without dwelling too much into the reasons for pharma’s tumbling social status, one can sense an undeniable skepticism surrounding the intentions of the industry, and, most frighteningly, the effectiveness of its drugs.

It would be bitterly unfair to agree with the hardline pharma critics in that drugs simply do not work. After all, antibiotics, HIV retrovirals, chemotherapy and heart disease drugs continue to attest to just the opposite. Survival prognosis for infection, atherosclerosis or even cancer is so great today, that 95% more people reach the age of 80 than they did a century ago.

But with longer-living populations come older-age diseases, and the therapeutic landscape begins to dramatically shift towards diseases like dementia, Alzheimer’s and Parkinson’s, and diseases which have remained poorly treated, such as schizophrenia, bipolar disorder and depression.

Brain Drugs: 50 years later, we still can’t tell you how they work

Note that the common denominator of all “modern” disorders is that they are all diseases of the brain. These ailments bear an economic burden of more than $2 trillion in the US and EU and rake in upwards of $80 billion a year for the pharmaceutical industry.

But nearly all brain medications have come about serendipitously — through observation that certain chemicals improved certain symptoms, rather than through research tailored to the disease. An overwhelming majority of today’s Thorazines, Valiums, Prozacs and Xanaxes are still characterized by widely unknown mechanisms of action 60 years after their market debuts. Even more frighteningly, in recent clinical trial re-runs involving Prozac and Xanax the drugs fared hardly better than placebo.

Is Big Pharma shying away from CNS drugs?

Because the brain remains so poorly understood, Big Pharma are having a bad time developing pharmaceuticals which act upon the central nervous system (CNS). After a number of very loud and painful CNS clinical trial failures in recent years, GSK, AstraZeneca and Novartis have announced total closures of neuroscience divisions globally. Meanwhile Pfizer, Sanofi, Janssen and Merck have begun to significantly downsize CNS operations.

Few remain in the race. And who can blame them, when CNS drug development can cost billions more than any other therapeutic area, yet has a 45% higher chance of failure than drugs targeting other disorders?

Electricity and chemistry rule the brain in equal measure

The complexity of the brain is unrivaled. The intricate network of neuronal connections (the “connectome”), the densely populated molecular environment, and the electric behavior of brain cells, all in addition to the vast individual genomics and metabolomics of any given brain are difficult to ponder even in a single sentence. Unlike the peripheral nervous system, where molecules govern tissues, the central nervous system is just as much ruled by the binary patterns of electrical stimulation as by the neurotransmitter molecules which carry brain messages throughout the body.

And this is the crucial point: chemicals and electricity share a 50:50 responsibility in the brain. A chemical release between two neurons will cause the downstream neuron to “electrically detonate”, sending the message forward, yet electric stimulation of the upstream neuron will succeed to do just the same, albeit without collateral damage to much of the neuronal neighborhood (chemicals spread multridirectionally, whilst electricity does not).

The future is electric

Scientists have known of the effectiveness of neuro-electric brain therapy for decades, and many such systems are already in use today. Deep Transcranial Magnetic Stimulation (Deep TMS), for instance, is a novel, non-invasive, FDA-approved therapy to-date found effective for the treatment of Parkinson’s disease, depression, chronic pain and schizophrenia.

Deep TMS involves magneto-electric activation of regions deep (up to 7cm) within the brain. The stimulation can be applied at virtually any 3D brain coordinates. Thus the more we map the brain, the more useful the treatment becomes.

Pill lovers needn’t get disheartened by the prospect of an electric future, either. Meticulous brain mapping and advances in drug delivery systems could potentially culminate in the birth of a highly lucrative pharmaceutical — the electroceutical — or, rather more bluntly, electricity in a pill.

Electroceuticals may eventually take the form of electro-charged nano-robots we ingest in a pill, which would, with military precision, deliver electric current to any desired brain coordinates. In the era of electroceuticals, chemical “cross-contamination” of tissues and brain areas, along with unwanted side effects and liver toxicity would become a figment of the past.

How close are we to the electric future?

An often surprising fact is that electric therapy is already very widely used in the hospital, even in what would be considered traditional surgical settings. According to Itzhak Fried — Israel’s leading brain surgeon famed for his 22-hour separation surgery on Siamese twins literally sharing a brain — many procedures performed at his department already require an electric element.

In a breakthrough surgery two years ago, Fried’s team implanted tiny electrodes into the brain of an epilepsy patient. The electrodes, much like a tape recorder, listened to and recorded the activity of neurons in an area suspected of generating seizures. The “playback” of the recorded cell activity then gave clues as to the exact location of where the seizures originated. This turned out to be a tiny brain area next to the speech center of the brain which then was safely and successfully excised. Just a millimeter in the wrong direction could have rendered the patient forever unable to speak. All hail electricity.

Obama thinks the future is electric, too

And here is why all the electricity talk is not just cuckoo clairvoyance. Firstly, there is an unmissable brain project frenzy scurrying across the world. Projects like the “Brain Research through Advancing Innovative Neurotechnologies” (BRAIN), initiated by President Obama in the U.S., The Human Brain Project in Europe and Israel Brain Technologies are all aimed at electrically mapping the brain. Some lab projects have gone so far as to make mouse skulls completely transparent or to implant fiber optics into rat brains.

An equally telling development is the injection (or diversion from previous CNS research and development) of funds into electroceutical research done by Big Pharma themselves. In August 2013, GSK unveiled a $50 million bioelectrics venture fund aimed at sponsoring projects “that begin detailing how nerves in the body are related to particular diseases, understand the firing patterns of those nerves, and explore new technologies that will enable us to interface with multiple individual nerve fibres”. As CNS departments are ubiquitously shutting down, other players are left with no choice but to shortly follow suit.

It certainly seems that there is one thing neurosurgeons, neuroscientists and Big Pharma all finally agree on: neuro-chemistry is just so 2004.

Image via Palau / Shutterstock.

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Ambien Zombies, Murder, and Other Disturbing Behavior http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/ http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/#respond Sat, 25 Jan 2014 21:12:23 +0000 http://brainblogger.com/?p=15821 Ambien is one of a number of Controlled Schedule 4 agents designed as sedative hypnotics. Like other sedative hypnotics they are usually effective for about two weeks, largely to relieve persisting insomnia. These agents, especially Ambien, are linked to sleep-driving, eating, and even sex.

Sedative hypnotics impact mostly the neurotransmitter, GABA, which is inhibitory in its psychokinetic impact. As with other psychotropics, there is a darker side of the experience, though rare.

On March 29, 2009, Robert Stewart, 45, stormed into the Pinelake Health and Rehab nursing home in Carthage, North Carolina and opened fire, killing eight people and wounding two. Stewart’s apparent target was his estranged wife, who worked as a nurse in the home. She hid in a bathroom and was unharmed.

Stewart was charged with eight counts of first-degree murder; if convicted, he could face the death penalty. Even though there was evidence that Stewart’s actions were premeditated (he allegedly had a target), Stewart’s defense team successfully argued that since he was under the influence of Ambien, a sleep aid, at the time of the shooting, he was not in control of his actions. Instead of the charges sought by the prosecutors, Stewart was convicted on eight counts of second-degree murder. He received 142 – 179 years in prison.

After its approval, Ambien quickly rose to dominance in the sleep aid market. Travelers swore by it to combat jet lag. And women, who suffer more insomnia than men, purchased it in droves. Sanofi, Ambien’s French manufacturer, made $2 billion in sales at its peak. In 2007 the generic version of Ambien was released, Zolpidem, and at less than $2 per pill, it still remains one of the most prescribed drugs in America, outselling popular painkillers like Percocet and prescription strength ibuprofen.

Not all prosecutors will consider the Ambien defense, and its position within established criminal rules is tenuous. It does not really fall under “voluntary intoxication,” in which someone is responsible for his own intoxication and any events that occur as a result of that intoxication.

Image via Corepics VOF / Shutterstock.

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Medical Marijuana – A Magic Bullet for Treating PTSD? http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/ http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/#comments Sat, 07 Dec 2013 12:00:52 +0000 http://brainblogger.com/?p=15638 A new battle has been waged on Capitol Hill surrounding the much-debated legalization of medical marijuana. As research continues solidifying the positive effects of using cannabis to treat certain clinical symptoms, some research is focusing on the possible effects it may have on treating Post Traumatic Stress Disorder (PTSD).

Since the 1990s, organizations including the Multidisciplinary Association for Psychedelic Studies (MAPS) have attempted to further the development of research protocols surrounding the use of medical marijuana.

It was not until March 2011 that the National Cancer Institute acknowledged the viability of using marijuana in various treatment protocols. MAPS has continued its work to initiate further research and legislation requiring the National Institute on Drug Abuse and the Drug Enforcement Administration to loosen its reins and allow scientific organizations to grow their own cannabis for research purposes.

Viable research continues to evidence the positive impact medical marijuana has had on the lives of those suffering from cancer, glaucoma, multiple sclerosis, and other symptomatic disorders and diseases. It is also widely recognized that some individuals suffering from PTSD already use recreational drugs, including the illegal use of marijuana, to offset symptoms of the disorder. A 2012 case study focusing on a male patient with a variety of PTSD symptoms, severe in nature, revealed some symptoms were significantly reduced “by smoking cannabis resin.”

Further studies have focused on the molecular etiology of PTSD in reference to elevated brain cannabinoid CB1 receptors, along with endocannabinoid signaling systems. Research implies that the increased CB1 receptor-mediated anandamide signaling may play a role in some PTSD symptoms. As such, this research may provide evidence-based opportunities for drug therapies by utilizing a neurobiological model as presented in positron emission tomography studies.

The field of psychiatric medicine recognizes the distinct commonality of specific symptoms associated with PTSD, including severe flashbacks as well as uncontrollable panic attacks. How and why do memories of traumatic events affect the biological nature of the brain with such intensity? Evidence continues to support the theory that the endocannabinoid system holds primary influence over the regulation of memory and emotional behavior. Therefore it is reasoned that the evidence-based research focusing on the affects that THC and medical marijuana have had in other case studies may provide the same results with some symptoms exhibited in patients suffering from the PTSD.

Many social and political barriers continue to plague the future of not only the research of possible treatment options for medical marijuana, but also the legalization and use of its byproducts. It is difficult for society to erase the visual memories of soldiers smoking marijuana depicted through media sources throughout the Vietnam War. Vivid memories of young “hippie-garbed” individuals dancing in the rain while listening to rock-and-roll music and smoking “reefer” often wash over the eyes of many Americans who struggle with the concept of legalizing medical marijuana. Many politicians recognize the possible fall-out that may occur in supporting the legalization of medical marijuana, along with the difficulties involved in management of the sale and use of a perceived controlled substance.

There is no cut and dried solution to overcoming the possible negative implications of complete legalization of a product, such as marijuana, for medical purposes. Many government agencies are cautious of approving less restrictive regulations surrounding prescribed treatments using cannabis.

Yet, the number of individuals suffering from PTSD continues to grow. Many of these people maintain an active search for treatments that provide even the slightest bit of relief from often debilitating symptoms. The addition of military personnel suffering from PTSD is likely to lend greater support for continued research and legalization of medical marijuana as a viable treatment option.

References

Akirav I. (2013). Targeting the endocannaabinoid system to treat haunting traumatic memories. Frontiers in Behavioral Neuroscience 7: 124. PMCID: PMC3776936

Neumeister A, Normandin MD, Pietrzak RH, Piomelli D, Zheng MQ, Gujarro-Anton A, Potenza MN, Bailey CR, Lin SF, Najafzadeh S, Ropchan J, Henry S, Corsi-Travali S, Carson RE, & Huang Y (2013). Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Molecular psychiatry, 18 (9), 1034-40. PMID: 23670490

Passie T, Emrich HM, Karst M, Brandt SD, & Halpern JH (2012). Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug testing and analysis, 4 (7-8), 649-59 PMID: 22736575

Image via Yarygin / Shutterstock.

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