Faking it

There is a significant and growing international business in the manufacture and sale of counterfeit medicines. The World Health Organization (WHO) estimates that up to 20% of all medicines in some areas of the world are fake. Customs data from the European Union shows that 34 million counterfeit pills, valued at €89m, were seized between October and December 2008. The European Medicines Agency (EMEA) is warning that criminal gangs are currently busy trying to cash in on the H1N1 flu pandemic by selling fake or low-quality antiviral medicines and vaccines.

Counterfeit medicines, which can be either branded or generic, appear in a variety of guises. Some contain no active ingredients while others, according to industry sources, are laced with sugar, unrelated medicines or even rat poison. While the dangers of taking a medication containing traces of poison are obvious, counterfeit drugs that contain no active ingredients can be equally damaging if they deprive a patient of an essential treatment.

Many of the counterfeit drugs in circulation are purchased online, and patients should always be wary of obtaining medications in this way. However, fake drugs can also reach patients through apparently reputable pharmacies in cases when the supply chain is not 100% secure.

Pharmaceutical companies, regulators, law enforcement authorities, and healthcare professionals have joined forces to try to combat the threat of counterfeit medicines. The Partnership for Safe Medicines is a US-based group of organizations and individuals dedicated to protecting consumers from counterfeit or contraband medicines. The European Alliance for Access to Safe Medicines (EAASM) was founded in 2007 with the objective of fighting against counterfeit medicines and promoting patient safety around Europe.

Technology also has an important part to play in tackling the problem of counterfeit drugs. The US Food and Drug Administration (FDA) is developing an electronic pedigree (ePedigree) system, scheduled for launch in 2011, to track the movement of prescription drugs throughout the entire supply chain. This technology is intended to prevent the diversion or counterfeiting of drugs by allowing wholesalers and pharmacists to determine the identity of individual products. Other technological solutions include the use of radio frequency identification to track and identify pharmaceutical products by through individual serial numbers, while techniques such as Raman spectroscopy and Energy Dispersive X-Ray Diffraction (EDXRD) can be used to uncover counterfeit drugs while still inside their packaging.

It seems that the scale of the problem is starting to be appreciated by patients. In recent research carried out by ICM, on behalf of patient safety communications company, Aegate, 61 per cent of those surveyed in Europe were aware that prescription medicines could be faked and 79 per cent of consumers reported that they feared counterfeit medicine more than any other fake product. However, even with the combined efforts of industry, patients and regulatory authorities, we may have to learn to exercise a little more caution over the medications that we routinely receive.

References

WHO Counterfeit Medicines Factsheet, July 2009. http://www.who.int/medicines/services/counterfeit/CfeitsFactSheetJuly09.pdf

Rankin J. Fake medicines…genuine solutions? Europeanvoice.com, November 2009. http://www.who.int/medicines/services/counterfeit/CfeitsFactSheetJuly09.pdf

Medicines top counterfeit concern list in Europe – consumers call for tougher safety measures. Press release, November 2009. http://www.aegate.com/aegate-news/medicines-top-counterfeit-concern-list-in-europe-consumers-call-for-tougher-safety-measures.html

The authors of a recent study published in the journal Pediatrics evaluated 140 white male children with ADHD over a 10-year period. They assessed the relationship between treatment with stimulants in childhood and adolescence and the later development of psychiatric disorders, as well as grade level retention. The subjects with ADHD were compared to a group of 120 age- and gender-matched children without ADHD. At the beginning of the study, the children were between the ages of 6 and 18 years old; at the 10-year follow-up, the mean age was 22 years. Nearly three-fourths of the children with ADHD had been treated with stimulants sometime during the 10-year study period. The authors reported that these children were significantly less likely to develop anxiety and depressive disorders or exhibit disruptive behavior in young adulthood compared to ADHD children not treated with stimulants. These children were also less likely to repeat a grade level compared with untreated children. Overall, the authors conclude that stimulant treatment decreases the risk for the development of psychiatric disorders and academic failure in children with ADHD.

<Untreated ADHD is associated with the development of significant and potentially dangerous disorders: major depression, anxiety disorders, conduct disorders, oppositional-defiant disorders, and bipolar disorders. In the Pediatrics study, the only disorder for which the risk was not lowered with the use of stimulant medication was bipolar disorder. This is likely due to the fact that bipolar disorder has very different causes than the other ADHD-related conditions.

The same authors of the Pediatrics study published related findings in the American Journal of Psychiatry in 2008. Evaluating the same group of children, the authors reported that there was no statistically significant association between stimulant use in childhood or adolescence and later alcohol, drug, or nicotine abuse. Another study that examined the link between age at initiation of stimulant treatment and later substance abuse also concluded that early treatment with stimulant medication does not increase the risk of substance use disorders. Specifically, the study found that the later the stimulant was initiated, the greater the chance of developing a substance disorder. The hypothesis is that early use of stimulants may actually increase the white matter in the brain of ADHD children, which is often smaller than in children without ADHD, during a period of immense brain growth.

All of these studies, while positive for advocates of the use of stimulants, do not account for the effects of early ADHD diagnosis, referral, and treatment, independent of medication administration. Possibly, any treatment, whether with stimulant medication, non-stimulant medication, or behavioral therapy, contributes to the decreased risk of psychological disorders and academic failures later in life. Perhaps the conditions associated with ADHD are the result of untreated ADHD, and not the ADHD itself. For example, if untreated ADHD leads to failure at school and a loss of self-esteem and self-confidence, children and adolescents may develop depression and turn to drugs and alcohol in order to self-medicate.

Medicating young children, particularly with stimulants, will remain controversial. But, leaving ADHD untreated is also a contentious issue. The latest guidelines issued by the National Institute for Health and Clinical Excellence advises that psychotherapy should be first-line therapy for children with ADHD, causing concern among many health care providers. New information will at least arm parents with the knowledge that stimulants may not cause as much harm in children as once believed, and may actually do a lot of good. Parents, clinicians, and patients must evaluate the risks and benefits of any treatment for their own use.

References

Biederman, J., Monuteaux, M., Spencer, T., Wilens, T., MacPherson, H., & Faraone, S. (2008). Stimulant Therapy and Risk for Subsequent Substance Use Disorders in Male Adults With ADHD: A Naturalistic Controlled 10-Year Follow-Up Study American Journal of Psychiatry, 165 (5), 597-603 DOI: 10.1176/appi.ajp.2007.07091486

Mannuzza, S., Klein, R., Truong, N., Moulton, J., Roizen, E., Howell, K., & Castellanos, F. (2008). Age of Methylphenidate Treatment Initiation in Children With ADHD and Later Substance Abuse: Prospective Follow-Up Into Adulthood American Journal of Psychiatry, 165 (5), 604-609 DOI: 10.1176/appi.ajp.2008.07091465

Brimble MJ. Diagnosis and management of ADHD: a new way forward? Community Pract 2009;82(10):34-7.
Nair R, Moss SB. Management of attention-deficit hyperactivity disorder in adults: focus on methylphenidate hydrochloride. Neuropsychiatric disease and treatment 2009;5:421-32.

Biederman J, Monuteaux MC, Spencer T, Wilens TE, Faraone SV. Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study. Pediatrics 2009;124(1):71-8.

Researching and developing new drugs based on genetics is costly and time consuming. Reinvesting time and money in older drugs to improve the effectiveness and safety may produce more “bang for the buck” in the move towards personalized medicine. Research is increasingly focused on learning why existing drugs work better in some people than others. Genetic markers are offering clues to why patients respond well, or not, to cancer protocols, cardiovascular drugs, psychiatric medications, and kidney disease treatments, to name a few. Someday, perhaps drug companies will move away from continuously developing newer, costlier agents and focus on using the old drugs for new tricks.

Many new drugs come to market with accompanying diagnostic and genetic tests to establish safety and efficacy goals, but these are costly analyses. Simple tests, though, such as blood tests or cheek swabs, may be useful in determining if a patient will respond well to a commonly prescribed medication. These fast, relatively inexpensive tests could improve the overall cost-effectiveness of drug therapy.

The complex diseases that plague society are not the result of one gene or event, but, rather, a dynamic combination of factors. By evaluating individual genomes and studying the relationship to environmental factors, clinicians will learn how to identify susceptible groups of people and tailor disease prevention strategies and optimize treatment protocols. Physicians and pharmacists will be able to determine which patients will respond well to chemotherapy regimens, who will experience adverse drug reactions from a cholesterol drug, and who will have worsening asthma from an inhaled medication.

The advent of personalized medicine and the departure from the current one-size-fits-all health care model requires a paradigm shift for patients and providers. New standards will emerge for the management of genetic information and education will be paramount for clinicians and patients. There are still more questions than answers regarding personalized medicine and tailoring therapy to each individual, but, hopefully, personalized medicine will be a large piece of the future health care puzzle, allowing more preventive medicine and evidence-based treatment selection.

References

Abrahams, E., Ginsburg, G., & Silver, M. (2005). The Personalized Medicine Coalition American Journal of PharmacoGenomics, 5 (6), 345-355 DOI: 10.2165/00129785-200505060-00002

Dean, C. (2009). Personalized Medicine: Boon or Budget-Buster? Annals of Pharmacotherapy, 43 (5), 958-962 DOI: 10.1345/aph.1L563

Leeder, J., & Spielberg, S. (2009). Personalized Medicine: Reality and Reality Checks Annals of Pharmacotherapy, 43 (5), 963-966 DOI: 10.1345/aph.1M065

Tan DS, Thomas GV, Garrett MD, et al. Biomarker-Driven Early Clinical Trials in Oncology: A Paradigm Shift in Drug Development. Cancer J. September/October 2009;15(5):406-420.

Rovin, B., McKinley, A., & Birmingham, D. (2009). Can We Personalize Treatment for Kidney Diseases? Clinical Journal of the American Society of Nephrology, 4 (10), 1670-1676 DOI: 10.2215/CJN.04140609

Wiechec, E., & Hansen, L. (2009). The effect of genetic variability on drug response in conventional breast cancer treatment European Journal of Pharmacology, 625 (1-3), 122-130 DOI: 10.1016/j.ejphar.2009.08.045

Campbell, D., & Levitt, P. (2008). Future of individualized psychiatric treatment Pharmacogenomics, 9 (5), 493-495 DOI: 10.2217/14622416.9.5.493

However, even without the verification of the FDA, cognitive enhancers have supporters in the scientific and medical community. Psychiatrist Daniel G. Amen in Magnificent Mind at Any Age, states that after taking images of thousands of patient’s brains, the most “beautiful” brains are those on ginkgo biloba. He also routinely suggests to his patients that they take piracetam or vinpocetine to increase mental acuity. Particularly, vinpocetine, derived from periwinkle leaves, has been proven by researchers to stimulate brain plasticity.  Plasticity is the ability of our brains to allow our nerve cells to grow and change in response to memory retrieval, learning, and development.

Since vinpocetine has been proven in studies to enhance the plastic functions of the normal brain, researchers at Virginia Commonwealth University hypothesized that it may also aide in correcting developmental impairments such as those brought on by Fetal Alcohol Syndrome (FAS). Researchers Alexander Medina and colleagues created a study that examined brain plasticity in ferrets emulating FAS. The scientists tested to see how each ferret’s brain would respond to having only one working eye. In past studies on cats, suturing one eye shut demonstrated that the cells of the working eye take over the inactive brain cells of the sutured eye. The process is much like a person who gains better hearing as a result of being blind. Accordingly, researchers prepared two groups of FAS ferrets, one that underwent no treatment and one that received a dosage of vinpocetine.

Medina’s study found that the group of FAS ferrets receiving no treatment did not show the plasticity typical of normal brains; that is, they were unable to take over their deprived brain cells. However, ferrets emulating FAS and undergoing vinpocetine treatment remarkably functioned like normal brains; the working eye was able to assimilate the cells of the closed eye. Since enhanced nerve cell growth was shown in such a dramatic example as the ability of one eye to become stronger when another eye is blinded, the researchers concluded that vinpocetine could potentially aid more subtle brain defects like the impairments brought on by FAS.

These findings suggest the first clinical application of cognitive enhancers. However, being the first study on the topic, this research must be taken speculatively. Vinpocetine supporters have claimed in the past that the drug could potentially treat the brain degenerative effects of Alzheimer’s disease. However, a recent Cochran review deemed results from such studies to be negligible. Still, FAS is very different from Alzheimer’s disease.

Due to vinpocetine, the unfortunate child of someone who abused alcohol would not have to needlessly suffer because of his or her parent’s carelessness. This infliction that has been without possibility of medical treatment now has a potentially viable solution in drugs used in the past as mere study aids.

References

Amen, Daniel G. Magnificent Mind at Any Age: Natural Ways to Unleash Your Brain’s Maximum Potential. Harmony. 2008 Dec 2.

Hubel DH, Wiesel TN, & LeVay S (1977). Plasticity of ocular dominance columns in monkey striate cortex. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 278 (961), 377-409 PMID: 19791

Medina AE, Krahe TE, & Ramoa AS (2006). Restoration of neuronal plasticity by a phosphodiesterase type 1 inhibitor in a model of fetal alcohol exposure. The Journal of neuroscience : the official journal of the Society for Neuroscience, 26 (3), 1057-60 PMID: 16421325

Molnár P, & Gaál L (1992). Effect of different subtypes of cognition enhancers on long-term potentiation in the rat dentate gyrus in vivo. European journal of pharmacology, 215 (1), 17-22 PMID: 1516646

Szatmari SZ, & Whitehouse PJ (2003). Vinpocetine for cognitive impairment and dementia. Cochrane database of systematic reviews (Online) (1) PMID: 12535455

The new study, recently published in Psychiatric Services, reports that among the nearly 300,000 veterans who received a prescription for an antipsychotic medication in 2007, more than 60% had no record of a diagnosis for which the drug was approved. Most of the drugs carried an indication for schizophrenia or bipolar disorder. Most (more than 40%) of the patients had a diagnosis of PTSD. Other patients receiving off-label antipsychotics had diagnoses of major or minor depression, anxiety disorder, or alcohol or drug use or dependence. Quetiapine and risperidone were the two most frequently prescribed off-label drugs.

The authors estimate that this off-label use of psychiatric medications translates to $4 to $5 billion in health care expenditures. From a public health perspective, especially in the climate of controlling health care costs and reforming the health care system, these are significant resources that could be used in other ways. But even if the costs were not an issue, psychiatric medications pose significant risks to those taking them. Particularly, atypical antipyschotics like those prescribed in this study can cause weight gain, increase the risk for type 2 diabetes, and lead to cardiovascular problems.

The off-label use of drugs is common, and legal. While the practice of prescribing drugs for indications other than those approved by the Food and Drug Administration (FDA) can lead to new discoveries and innovative clinical practice, off-label use of drugs lacks scientific support. The most commonly prescribed drugs for off-label indications include cardiac and psychiatric medications. Overall, up to one-fifth of all drugs may be prescribed off-label. Of psychiatric drugs, the proportion of off-label use may be closer to one-third. Surprisingly, surveys have found that physicians believe that the indications for which they prescribe many drugs are approved by the FDA. This raises concern about the marketing and promotion of the off-label use of prescription drugs, as well as physician knowledge and evidence base.

Treating mental illness is increasingly problematic, and when clinicians have exhausted available resources, it is understandable that they would search the armamentarium of drugs to try something new. This practice has certainly led to positive patient outcomes and new treatment discoveries in some instances. However, a substantial number of psychiatric medications — antidepressants, antipsychotics, and anti-anxiety drugs — carry considerable safety concerns and black-box warnings, not to mention substantial costs. Still, these drugs are commonly used off-label for the treatment of agitation, depression, obsessive-compulsive disorder, PTSD, Tourette’s syndrome, and autism.

The off-label use of antipsychotics among veterans is higher than the off-label use for other classes of drugs. Since these drugs carry significant risks, as well as expenses, and have limited evidence supporting their use even for approved indications, caution should be exercised with their use. Off-label use, while common, may compromise patient safety and epitomize wasteful medication use.

References

Copeland, L. (2003). Racial Disparity in the Use of Atypical Antipsychotic Medications Among Veterans American Journal of Psychiatry, 160 (10), 1817-1822 DOI: 10.1176/appi.ajp.160.10.1817

Radley, D. (2006). Off-label Prescribing Among Office-Based Physicians Archives of Internal Medicine, 166 (9), 1026-1026 DOI: 10.1001/archinte.166.9.1021

Vasterling, J., Verfaellie, M., & Sullivan, K. (2009). Mild traumatic brain injury and posttraumatic stress disorder in returning veterans: Perspectives from cognitive neuroscience Clinical Psychology Review DOI: 10.1016/j.cpr.2009.08.004

Baker DG, Heppner P, Afari N, et al. Trauma exposure, branch of service, and physical injury in relation to mental health among U.S. veterans returning from Iraq and Afghanistan. Mil Med. Aug 2009;174(8):773-778.

Chen, D., Wynia, M., Moloney, R., & Alexander, G. (2009). U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey Pharmacoepidemiology and Drug Safety DOI: 10.1002/pds.1825

Walton, S., Schumock, G., Lee, K., Alexander, G., Meltzer, D., & Stafford, R. (2008). Prioritizing Future Research on Off-Label Prescribing: Results of a Quantitative Evaluation Pharmacotherapy, 28 (12), 1443-1452 DOI: 10.1592/phco.28.12.1443

Leslie, D., Mohamed, S., & Rosenheck, R. (2009). Off-Label Use of Antipsychotic Medications in the Department of Veterans Affairs Health Care System Psychiatric Services, 60 (9), 1175-1181 DOI: 10.1176/appi.ps.60.9.1175

DXM is readily available, easily accessible, and inexpensive; it is safe and effective at clinical doses. However, when ingested in large quantities — usually greater than 2 mg/kg of body weight — the drug can display physical and psychological effects similar to ketamine and phencyclidine (PCP). Massive doses of DXM can cause increased heart rate, extreme high blood pressure, and respiratory depression. DXM can also cause the dissociative effects seen with hallucinogens. Treatment of DXM overdoses is primarily supportive, and antidotes to DXM have limited success in reversing the effects of an overdose.

The CHPA is responding to increased public awareness and concern for the issue of teen medicine abuse, but the effectiveness of the campaign remains to be determined. In addition to labeling all brand name and generic products containing DXM with the warning logo, which will begin appearing on pharmacy shelves later this year, the CHPA has also established a website (stopmedicineabuse.org) to educate consumers and parents about the risks of DXM abuse. The website offers handbooks and drug abuse resources, links to other organizations, access to newsletters, and connections to social networking sites. But, will allowing parents to download widgets and icons onto their Facebook or Twitter accounts really stop teens from misusing drugs?

The goal of the CHPA — to increase awareness and education about a growing public health concern — is admirable, but may be misdirected. Research concerning the effectiveness of warning labels is mixed, and some data suggests that people who read warning labels are already health conscious and attentive to health warnings. Factors influencing the effectiveness of warning labels include characteristics of the icon itself (font, color, size, etc.), consumer familiarity with the product, and the age of the consumer. And, even if warning labels reach teenagers, they may not influence the behavior, because younger audiences may not fully appreciate the risks associated with DXM abuse or be influenced to change their attitude or behavior. Other research has shown that the effects of health warnings on packaging labels cannot be differentiated from concurrent community education programs.

Warning labels are everywhere — cigarettes, alcohol, music, television; they have been put in place due to changing regulations, public safety concerns, and mounting lawsuits. Now, will another warning label be eye-catching and effective, or just another image to glance over in a society in which we are constantly overloaded with stimuli?

References

Argo, J., & Main, K. (2004). Meta-Analyses of the Effectiveness of Warning Labels Journal of Public Policy & Marketing, 23 (2), 193-208 DOI: 10.1509/jppm.23.2.193.51400

Engs RC. Do warning labels on alcoholic beverages deter alcohol abuse? J Sch Health. Mar 1989;59(3):116-118.

Ford, J. (2009). Misuse of Over-the-Counter Cough or Cold Medications Among Adolescents: Prevalence and Correlates in a National Sample Journal of Adolescent Health, 44 (5), 505-507 DOI: 10.1016/j.jadohealth.2008.10.140

Hassan, L., Shiu, E., Thrasher, J., Fong, G., & Hastings, G. (2008). Exploring the effectiveness of cigarette warning labels: findings from the United States and United Kingdom arms of the International Tobacco Control (ITC) Four Country Survey International Journal of Nonprofit and Voluntary Sector Marketing, 13 (3), 263-274 DOI: 10.1002/nvsm.328

Kaskutas LA, Greenfield TK. The role of health consciousness in predicting attention to health warning messages. Am J Health Promot. Jan-Feb 1997;11(3):186-193.

Lessenger, J., & Feinberg, S. (2008). Abuse of Prescription and Over-the-Counter Medications The Journal of the American Board of Family Medicine, 21 (1), 45-54 DOI: 10.3122/jabfm.2008.01.070071

Levine, D. (2007). “Pharming”: the abuse of prescription and over-the-counter drugs in teens Current Opinion in Pediatrics, 19 (3) DOI: 10.1097/MOP.0b013e32814b09cf

Romanelli, F., & Smith, K. (2009). Dextromethorphan abuse: Clinical effects and management Journal of the American Pharmacists Association, 49 (2) DOI: 10.1331/JAPhA.2009.08091

Schwartz, R. (2005). Adolescent Abuse of Dextromethorphan Clinical Pediatrics, 44 (7), 565-568 DOI: 10.1177/000992280504400702

Wilkinson C, Room R. Warnings on alcohol containers and advertisements: international experience and evidence on effects. Drug Alcohol Rev. Jul 2009;28(4):426-435.

To the uninitiated, doses that high would be lethal. To someone who had developed a tolerance to the medication, however, doses in that range may be necessary to achieve the desired effect. It seems to defy physiology that what would kill one individual would merely mellow out another, but therein lies the enigma of drug tolerance.

Certain medications, such as narcotic painkillers and sedatives such as Xanax, are known to create tolerance. In the case of opiate narcotics, this occurs at several levels within the body. Chronic use of opiate medications causes partial loss of function of its neural receptors’ ability to signal within brain cell. It also causes adjustment of the signaling systems within the cell, leading to alterations in its excitability. These changes, in turn, can indirectly affect the excitability of nerve cells throughout the body, further contributing to overall tolerance. Interestingly, the signaling systems involving cAMP also play a role in synaptic plasticity, leading to potential consequences of opiates on learning and memory. Combined, these changes lead to a blunting of the body’s response to a given dose of an opiate over time, and therefore an ever-escalating need for higher doses of opiates in order to achieve the same effect.

The development of tolerance to sedatives such as Xanax is less well understood, but may involve down-regulation of the benzodiazepine and GABA receptors within the brain. Reduction in the number of chloride channels within the cells and the resultant changes in the GABA receptors may also play a role. Chronic use may alter the gene regulation of the receptor itself. However tolerance to sedative medications occurs, it is known to occur swiftly, particularly with respect to their depressant effects.

While the amount of medications that Jackson was taking may seem shocking, it is a well-known consequence of chronic use of these medications. Unfortunately, while tolerance to the sedative effects of these medications may occur, tolerance to some of their other effects may not, frequently leading to illness, and in some cases, death.

References

Christie, M. (2008). Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction British Journal of Pharmacology, 154 (2), 384-396 DOI: 10.1038/bjp.2008.100

Bateson, A. (2002). Basic Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal Current Pharmaceutical Design, 8 (1), 5-21 DOI: 10.2174/1381612023396681

Miller LG. Chronic benzodiazepine administration: from the patient to the gene. J Clin Pharmacol. 1991 Jun;31(6):492-5.

Hutchinson, M. (1996). The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs Progress in Neurobiology, 49 (1), 73-97 DOI: 10.1016/0301-0082(96)00011-1

By contrast, the placebo’s darker cousin, the nocebo, is much less well researched and is rarely considered in clinical practice. The term nocebo is taken from Latin for “I will harm”^* and was first formalized in the 1960s to mean something that rationally should have no effect but actually causes a deterioration in health. The difficulty in researching the nocebo effect arises because ethics review committees tend to take a dim view of trials in which an intervention is likely to cause actual harm to the subjects.

There are many anecdotal examples of the nocebo effect at work. For example, a nocebo response may explain the phenomenon of the voodoo curse in which a victim dies only because a belief in the power of the witch doctor has been so ingrained that, after he has been hexed, the target simply cannot believe that he will live. Other cases have been reported in which a patient has died after having been given a terminal prognosis; only for a post-mortem to reveal no such fatal disease was present. A few scientific studies have also looked at the phenomenon, including one in which volunteers were told that the researchers were looking for a link between mobile phone usage and the incidence of headaches. Throughout the trial a number of users reported headaches, even when (unbeknown to them), the phone they were using was actually an empty shell.

Patients taking pharmaceutical drugs often report unwanted and nonspecific adverse effects that cannot be attributed to the pharmacological action of the medicine. In a review of studies examining the reported side effects from pharmacological treatments, several factors were found to be associated with an increase in the number of such reports, including the patient’s expectations of adverse effects at the outset of treatment; a patient’s prior experience with certain treatments; and particular psychological characteristics such as anxiety and depression.

Although poorly understood, physiological explanations of the nocebo effect have been proposed. It has been shown, for example, that a patient’s anticipation of worsening pain causes an increase in anxiety which triggers the activation of cholecystokinin that, in turn, facilitates pain transmission. This response generates a vicious circle of anxiety and pain which may be one explanation of the nocebo effect.

The nocebo effect has important implications for clinical practice, and there are several measures that physicians and other practitioners can adopt to limit its damaging effects. Health care professionals should try to identify in advance those patients most at risk of the nocebo effect, they should choose their language carefully in consultations with patients, so as not to generate any self-defeating attitude in the patient, and they should always consider that nonspecific side effects of drug treatments may be due to the nocebo effect, and manage accordingly.

Placebo and nocebo are two sides of the same coin. A strong relationship and effective dialogue between doctor and patient can take advantage of any placebo response while mitigating any response from its darker and opposite number, the nocebo effect.

^*The term placebo, meaning “I will please,” dates back to the 18th century.

References

Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-7. DOI: 10.1001/jama.287.5.622

Colloca L, & Benedetti F (2007). Nocebo hyperalgesia: how anxiety is turned into pain Curr Opin Anaesthesiol, 20, 435-439 DOI: 10.1097/ACO.0b013e3282b972fb

Oftedal G, Straume A, Johnsson A, Stovner LJ. Mobile phone headache: a double blind, sham-controlled provocation study. Cephalalgia. 2007;27:447-55. DOI: 10.1111/j.1468-2982.2007.01336.x

Among the endogenous tasks performed by anandamide are pain control, memory blocking, appetite enhancement, the suckling reflex, lowering of blood pressure during shock, and the regulation of certain immune responses. These functions shed light on common hallmarks of cannabis withdrawal, such as anxiety, chills, sweats, flu-like physical symptoms, and decreased appetite. At Columbia University’s National Center on Addiction and Substance Abuse, where a great deal of National Institute for Drug Abuse (NIDA) funded research takes place, researchers have found that abrupt marijuana withdrawal leads to symptoms similar to depression and nicotine withdrawal.

What the NIDA has learned about cannabis addiction, according to the principal investigator of a recent NIDA study, was that “we had no difficulty recruiting dozens of people between the ages of 30 and 55 who have smoked marijuana at least 5,000 times. A simple ad in the paper generated hundreds of phone calls from such people.” (This would be roughly equivalent to 14 years of daily pot smoking.)

Here is a sampling of comments from dependent marijuana smokers, gathered from my blog, Addiction Inbox :

Comment 1

I’m 55 and I’ve been smoking pot off and on for the last 30 years… I had no idea of the withdrawal I would experience. Two days in, I thought for sure I had some dreaded disease. One minute I would be freezing, the next sweating. The loss of appetite doesn’t bother me because pot always helped me keep on an extra 5-10 lbs from the munchies and sweet tooth. Not sure how long it will take, but I do look forward to the day when this has all passed.

Comment 2

As far as symptoms, the worst for me so far has been insomnia, on day nine I was awake for 28 hours, a hallucinatory experience itself….The temperature regulation thing is very real, I’m freezing, I’m burning, I’m sweating. Starting to get hungry once a day.

Comment 3

The cravings have pretty much subsided but not completely. When I get bored is when it is the strongest. I have experienced the sweating, severe diarrhea, migraine headaches and sleeplessness…. I have hidden this addiction from family for so long and it’s nice to not have to worry if someone is going to stop by and smell it and catch me.

Comment 4

I have been smoking pot since I was 17, I am now 34, happily married with a child. I smoked at least once a day, up to 4 joints a day by myself. I stopped smoking a week ago but I am completely miserable…. I am always dreaming of using, I wake up in sweats and search the whole house for a roach sometimes when I am desperate but at the same time I feel proud that I have not called my dealer or visited my using friends, this time I might as well do it.

Comment 5

It’s been 2 weeks since I vaporized my last bowl, and since then I’ve gotten so desperate I’ve been smoking resin. Last night I used rubbing alcohol to get the resin out of my bong and smoked the resin after the alcohol evaporated. It tasted awful and barely got me high, but tonight I did it again, and I was so impatient that I put the resin-alcohol solution in the oven to help it evaporate! This is how desperate I’ve become – I’ve risked burning down my house in order to get marginally high.

Comment 6

After using heavily for the past 7 years, and basically all day every day for the last 6 months my side effects are major. i still cant sleep properly although at least now im getting 6 hours which isnt too bad. nausea every day. i have a bad stomach to begin with but i usually dont get sick every day. hot and cold sweats. im freezing right now but about half an hour ago i was boiling. i havent eaten properly since i stopped. the thing i dont like is that i feel spaced out constantly. i feel like im bent even when im not. and not bent in a calm relaxing way either.

Comment 7

I am a researcher at a university and have studied the effects of drugs, particularly alcohol, on the brain for the last decade or so. Like many of my friends and colleagues, I consider marijuana to be a relatively low-risk drug when used in moderation by responsible adults. However, I am now forced to admit that my view of the discontinuation syndrome was naïve and that I was completely unprepared for it myself:

Week 1: Despite missing my evening smoking session and feeling some mild irritability, I felt fine.

Week 2: Mild flu-like symptoms, which I assumed to be viral in nature though it did not exactly feel viral. No real desire to smoke marijuana. I assumed I was out of the woods and had gotten off easy.

Week 3: Sudden onset of incredibly intense and vivid dreams. Profuse sweating at night. Difficulty discerning dreaming from waking state. Lack of energy. Upset stomach. Absolutely no appetite. Unable to focus. Saw my primary care physician. All labs normal.

Week 4: This is where the real problems began for me. Sudden onset of intense, full body anxiety…. This led to complete insomnia for days. A very deep feeling of dread and a sense that I was going completely insane. Crying spells that came from nowhere….

Week 5: The intense anxiety slowly began to dissipate… was able to sleep for 4-6 hours a night, which is approaching normal for me. Appetite slowly came back but the thought of eating was unpleasant. Feeling of confidence began to return. Feelings of hopelessness and of going crazy began to diminish.

References

Budney, A. (2004). Review of the Validity and Significance of Cannabis Withdrawal Syndrome American Journal of Psychiatry, 161 (11), 1967-1977 DOI: 10.1176/appi.ajp.161.11.1967

Lichtman, A.H. and Martin, B.R. (2002) Marijuana withdrawal syndrome in the animal model. Journal of Clinical Pharmacology, 42, 20S-27S.

Vandrey, R., Budney, A., Kamon, J., & Stanger, C. (2005). Cannabis withdrawal in adolescent treatment seekers Drug and Alcohol Dependence, 78 (2), 205-210 DOI: 10.1016/j.drugalcdep.2004.11.001

WILSON, D., VARVEL, S., HARLOE, J., MARTIN, B., & LICHTMAN, A. (2006). SR 141716 (Rimonabant) precipitates withdrawal in marijuana-dependent mice Pharmacology Biochemistry and Behavior, 85 (1), 105-113 DOI: 10.1016/j.pbb.2006.07.018

The authors claim that NSAIDs do not prevent the onset of dementia, but may simply delay it, leading to an increased appearance of dementia in older patients. The study participants included more than 3000 adults aged 65 years or older. Approximately 25% of the subjects were over 80 years old. At baseline, all participants showed normal cognitive function. Their cognitive function was evaluated every two years for 12 years using the Cognitive Abilities Screening Instrument. The researchers also collected data on each subject’s NSAID use, and divided the drug exposure into light or no use, moderate use, or heavy use categories.

During the study period, 476 patients developed dementia. (Of these, 356 patients were diagnosed with AD.) Heavy NSAID use was associated with a 66% increased risk for dementia, compared to the light or no NSAID use group. While this seems contradictory to many popular opinions, the authors claim that it may, in fact, reinforce other theories of dementia prevention with NSAID use. Most other studies have used younger populations to assess NSAID use and dementia onset, but the current study had a much older population. Therefore, the authors conclude that heavy NSAID use may not prevent –- but delay — dementia onset. And, in traditionally late-in-life disease onset such as dementia and AD, delay could masquerade as prevention. Other studies with younger populations may have inaccurately observed a delayed onset of dementia as complete prevention.

The exact mechanism of how NSAIDs influence dementia are not well understood, but may be due to the anti-inflammatory properties of the drugs. NSAIDs reduce inflammatory markers in the brain, and may also reduce the deposits of amyloid proteins in the brain. (These protein deposits are believed to play a role in the pathogenesis of dementia.)

Dementia is a prevalent health concern among elderly people around the world. AD is the leading cause of dementia, accounting for 50 to 70% of cases worldwide. Its precise cause is not known, but is likely a combination of diverse genetic and environmental factors. Unfortunately, treatment options for dementia remain unpredictable. The bottom line of all of these studies is that no one knows the real relationship between NSAIDs, aging, and dementia. If practitioners want to change their prescribing habits of NSAIDs in the elderly, well-designed clinical trials are needed to investigate true clinical indications for preventing or treating dementia. NSAID use in the elderly is highly prevalent for a host of conditions, and continued examination of the neuroprotective effects of NSAIDs will lead to a better understanding of the risks and benefits of NSAID use.

References

BREITNER, J. (2003). NSAIDs and Alzheimer’s disease: how far to generalise from trials? The Lancet Neurology, 2 (9), 527-527 DOI: 10.1016/S1474-4422(03)00498-8

Breitner, J., Haneuse, S., Walker, R., Dublin, S., Crane, P., Gray, S., & Larson, E. (2009). Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort Neurology, 72 (22), 1899-1905 DOI: 10.1212/WNL.0b013e3181a18691

Cacabelos, R. (2008). Pharmacogenomics and therapeutic prospects in dementia European Archives of Psychiatry and Clinical Neuroscience, 258 (S1), 28-47 DOI: 10.1007/s00406-007-1006-x

Hayden, K., Zandi, P., Khachaturian, A., Szekely, C., Fotuhi, M., Norton, M., Tschanz, J., Pieper, C., Corcoran, C., Lyketsos, C., Breitner, J., Welsh-Bohmer, K., & , . (2007). Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study Neurology, 69 (3), 275-282 DOI: 10.1212/01.wnl.0000265223.25679.2a

. (2008). Cognitive Function Over Time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): Results of a Randomized, Controlled Trial of Naproxen and Celecoxib Archives of Neurology, 65 (7), 896-905 DOI: 10.1001/archneur.2008.65.7.nct70006

Szekely, C., Breitner, J., Fitzpatrick, A., Rea, T., Psaty, B., Kuller, L., & Zandi, P. (2008). NSAID use and dementia risk in the Cardiovascular Health Study*: Role of APOE and NSAID type Neurology, 70 (1), 17-24 DOI: 10.1212/01.wnl.0000284596.95156.48

Vlad, S., Miller, D., Kowall, N., & Felson, D. (2008). Protective effects of NSAIDs on the development of Alzheimer disease Neurology, 70 (19), 1672-1677 DOI: 10.1212/01.wnl.0000311269.57716.63

What these researchers and others before them have done is taken a representative swath of humanity and labeled them as “healthy.” The JUPITER trial, for example, looked at using a statin for so-called “healthy” individuals and found that it reduced their risk of cardiovascular events. However, these people weren’t healthy. Average, yes; representative of the United States population, yes. Healthy, no. Seventy-five percent of the subjects in the JUPITER trial were overweight or obese and also had a blood test abnormality. Similarly, in the TIPs study the subjects did not have pre-existing cardiovascular disease but did have type 2 diabetes, increased waist-to-hip ratio, abnormal lipids, high blood pressure, or a history of recent smoking. In other words, not “healthy.” Notable, too, is the fact that each and every one of the things that renders these individuals unhealthy is almost entirely preventable with lifestyle modifications.

The fact that legitimate research is being conducted on this “polypill” is a sad commentary on the faith that the healthcare industry has in people to save themselves. Although the researchers in the TIPS trial point out that their medication is not intended to be a substitute for diet and exercise, as Dr. Clyde Yancy, medical director of the Baylor Heart Institute in Dallas, was quoted in Clinical Endocrinology News, “There is nothing more effective than modifying lifestyle, but people may tend to dismiss that concept if they believe a pill is lowering their risk of heart disease.”

In a few years, we’ll get the final results on the TIPS trial. I predict that it will show a benefit. I also predict that the drug will be heavily marketed to people who have had the power to lower their risk of cardiovascular disease in their own hands all along. It is up to us to decide if we want our health to be determined by our own efforts or those of the pharmaceutical industry.

References

Xavier, D., Pais, P., Sigamani, A., Pogue, J., Afzal, R., & Yusuf, S. (2008). The need to test the theories behind the Polypill: rationale behind the Indian Polycap Study Nature Clinical Practice Cardiovascular Medicine, 6 (2), 96-97 DOI: 10.1038/ncpcardio1438

Ridker, P., Danielson, E., Fonseca, F., Genest, J., Gotto, A., Kastelein, J., Koenig, W., Libby, P., Lorenzatti, A., MacFadyen, J., Nordestgaard, B., Shepherd, J., Willerson, J., Glynn, R., & , . (2008). Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein New England Journal of Medicine, 359 (21), 2195-2207 DOI: 10.1056/NEJMoa0807646

The most popular, and the least studied — not a prescription for rational decision making from a public health point of view. A variety of influences combined to force marijuana research off the table years ago, but the birth of “receptorology,” as molecular scientist Candace Pert once called it, and a more relaxed grip on federal funding has refueled the research.

Why did cannabis research lag behind that of other drugs of abuse? For decades, the prevailing belief among users and clinical researchers alike was that marijuana did not produce dependency and therefore could not produce major withdrawal symptoms. Nonetheless, heavy marijuana users were claiming that tolerance does build. And when they withdraw from use, many report strong cravings. Marijuana withdrawal, which typically affects only heavy smokers, has not been well characterized by the research community.

Back in the fall of 1988, pharmacology professor Allyn Howlett and her colleagues at St. Louis University Medical School came up with strong evidence for the specific brain receptor to which the THC molecules were binding. However, the nature of the organic chemical itself — the compound in the brain that was meant to bind to those reported sites — remained unidentified until 1992. That year, William A. Devane, one of the researchers at Hebrew University in Jerusalem, along with Rafael Mechoulam and others, identified the body’s own form of THC in pulverized pig brains. The substance that stuck to the THC receptors was known as arachidonyl ethanolamide. Devane christened the substance “anandamide,” after the Sanskrit ananda, or bliss. It was left for animal physiologist Gary Weesner of the U.S. Department of Agriculture (USDA) to ask the burning question: “How do pigs use their anandamide?” In a study of the possibility of using anandamide as a safe sedative for animals, Dr. Weesner discovered that pigs treated with anandamide tended to show lower body temperature, slower respiration, and less movement — all indicators of a calmer porcine state of mind.

THC and its organic cousin make an impressive triple play in the brain: They effect movement through receptors in the basal ganglia, they alter sensory perception through receptors in the cerebral cortex, and they impact memory by means of receptors in the hippocampus. However, there has been little evidence in animal models for tolerance and withdrawal, the classic determinants of addiction. To the early researchers, it did not look like cannabis should be addictive. And for at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome.

Nevertheless, some people appear to exhibit a classic pattern of dependency. By the year 2000, more than 100,000 Americans a year were seeking treatment for marijuana dependency, by some estimates. Marijuana Anonymous, an organization modeled on the principles of Alcoholics Anonymous, had become a robust recovery organization. What was going on?

Some of the mystery of marijuana’s effects was resolved after researchers demonstrated that marijuana definitely increased dopamine activity in the limbic area of the brain, as do all other addictive drugs. Tanda, Pontieri, and Di Chiara demonstrated that dopamine levels in the nucleus accumbens doubled when rats received an infusion of THC. It appears that marijuana also raises dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors.

In 2004, a study group at the University of Vermont undertook a critical review of all major relevant studies of marijuana withdrawal. The meta-review appeared to bear out the theory that there are heavy marijuana users who suffer a verifiable and often vivid set of withdrawal symptoms when they try to quit. The most common clinically significant symptoms of abrupt withdrawal in heavy pot smokers, according to the research group, were

anxiety, decreased appetite/weight loss, irritability, restlessness, sleep problems, and strange dreams. These symptoms were associated with abstinence in at least 70% of the studies in which they were measured. Other clinically important symptoms such as anger/aggression, physical discomfort (usually stomach related) depressed mood, increased craving for marijuana, and increased sweating and shakiness occurred less consistently.

These are not trivial issues. As one long-time heavy cannabis user put it: “It’s not suicidal ideation but it’s the feeling that life will just never ‘be right’… when you suffer from symptoms that you’ve been told don’t exist, you are left looking for the wrong cause. So, if you’re told that marijuana withdrawal does not increase anxiety, anger, or ‘hopelessness,’ you want to look for a cause of those things… I went through withdrawal periods where I was inappropriately angry at the wrong thing, thinking that specific people were upsetting me when they were not.”

In the final post of this series, we will hear from more heavy marijuana users, in their own words. Personal observations and selected case histories of frequent marijuana users were gathered from anonymous, unedited comments posted on a blog site maintained by the author.

References

Hanson D. “Marijuana Withdrawal: A Survey of Symptoms.” In The Praeger International Collection on Addictions. Ed. by Angela Browne-Miller. Westport, Connecticut: Praeger, 2009. Vol. 2 pp.111-124.

Budney, A. (2004). Review of the Validity and Significance of Cannabis Withdrawal Syndrome American Journal of Psychiatry, 161 (11), 1967-1977 DOI: 10.1176/appi.ajp.161.11.1967

Kouri, E., & Pope, H. (2000). Abstinence symptoms during withdrawal from chronic marijuana use. Experimental and Clinical Psychopharmacology, 8 (4), 483-492 DOI: 10.1037/1064-1297.8.4.483

Rodriguez de Fonseca, F. (1997). Activation of Corticotropin-Releasing Factor in the Limbic System During Cannabinoid Withdrawal Science, 276 (5321), 2050-2054 DOI: 10.1126/science.276.5321.2050

Tanda, G. (1997). Cannabinoid and Heroin Activation of Mesolimbic Dopamine Transmission by a Common µ1 Opioid Receptor Mechanism Science, 276 (5321), 2048-2050 DOI: 10.1126/science.276.5321.2048

One of the curious things about lithium is its effect on the brain. Patients who have bipolar disorder and are being treated with lithium often have imaging studies of their brain as part of their routine management. Radiologists noticed that patients on lithium develop hypertrophy of their brain, meaning that their brains are denser than average. Scientists began to wonder if somehow the lithium was causing new brain cells to grow, and thought there might be an application for diseases that cause cell death in the central nervous system.

One of the more severe examples of such a disease is amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s Disease. ALS produces a progressive degeneration of the nerve cells in the central nervous system that supply the muscles of the body, leading to progressive weakness, paralysis, and eventually death. The causes of ALS are largely unknown, and there is no known cure. The average span from time of diagnosis to death is 3 to 5 years, making it a devastating disease. The only current treatment option for ALS is a medication called riluzole, which functions as a neuroprotectant meaning it delays the degenerative process. Even this medication only adds a few months of time, and slightly prolongs the time to requiring a ventilator to breathe.

Because the prognosis for ALS is so poor, many trials are underway for substances that may serve as a better neuroprotective agent. Lithium is one of the chemicals that holds a fair amount of promise. In February 2008, scientists from Italy published a study in the Proceedings of the National Academy of Sciences where they took 44 patients with ALS and divided them into two groups: one receiving riluzole, and the other receiving riluzole plus lithium. The two groups were case matched, meaning the researchers tried to make them as equal as possible in terms of severity of disease. The groups were tested for their functional level at the beginning of the trial, and then followed up 15 months later to repeat their testing. Of the patients who received riluzole, about a third of them had died, and the remainder had significant functional decline during the interim. By contrast, of the patients receiving riluzole and lithium, not a single patient had died, and the entire group had only a mild decrease in their functional level.

The results of this study were astonishing, and scientists are now hopeful that lithium may play a role in many neurodegenerative diseases. Clinical trials are already underway for the use of lithium in diseases like Parkinson’s disease, Huntington’s disease, spinal cord injury, and even Alzheimer’s dementia. If the results of the 2008 study can be reproduced and translated into additional disease states, this old medication may be able to provide millions of patients with neurodegenerative disorders with a new lease on life.

References

F. Fornai, P. Longone, L. Cafaro, O. Kastsiuchenka, M. Ferrucci, M. L. Manca, G. Lazzeri, A. Spalloni, N. Bellio, P. Lenzi, N. Modugno, G. Siciliano, C. Isidoro, L. Murri, S. Ruggieri, A. Paparelli (2008). Lithium delays progression of amyotrophic lateral sclerosis Proceedings of the National Academy of Sciences, 105 (6), 2052-2057 DOI: 10.1073/pnas.0708022105

Recently, researchers discovered that fear memories in rats are not permanent, as once thought, but change when retrieved. When a memory is retrieved, it activates new protein synthesis and alters the release of neurotransmitters in the basolateral amygdala. Propranolol can apparently disrupt this so-called “reconsolidation” of fear memories, shortly after the period of memory retrieval and reactivation, leading to a change in how the fear memory is expressed.

To investigate if the same process applied to humans, the authors of the current study induced a conditioned fearful response in 40 human volunteers. The subjects were given a mild shock when shown pictures of spiders on day 1 of the study. Their fear response was measured as the eyeblink startle reflex to a loud noise. On day 2 of the study, the memory reactivation phase, the study volunteers exhibited the same response to the fearful stimuli (the spider pictures) as on day 1. On day 3, 20 of the subjects were given 40 mg of propranolol, and the remaining 20 were given a placebo. Next, the entire group was exposed to the fearful stimuli. The propranolol group did not exhibit the same startle response as on previous days. The placebo group showed no change in startle response compared to days 1 or 2. The authors conclude that the administration of oral propranolol before reactivation of a fearful memory reduced the expression of a fearful memory and virtually eliminated the fear response.

The authors note that the propranolol did not alter the knowledge or declarative memory of the association between the stimuli and response, but this knowledge did not produce an emotional response. Propranolol acts on the beta-receptors in the amygdala during emotional information processing in humans and other animals, and may disrupt the protein synthesis that takes place during the reconsolidation of memories.

Several previous studies have reported related findings using midazolam, a short-acting benzodiazepine that reduces anxiety, and produces sedation and muscle relaxation. Benzodiazepines may also cause amnesia and impair memory. NMDA receptor antagonists have also been shown to interfere with memory reconsolidation in rats, but many of these studies have not been generalized to humans. Both of the drugs have shown variable results, depending on the age of the fearful memory and the length and number of memory reactivation sessions.

Understanding memory formation and maintenance — particularly fearful and traumatic memories — is important to the effective treatment of psychological and anxiety disorders propagated by harmful and maladaptive memories. This current study needs to be expanded and conducted on a larger scale, but may have significance for patients suffering from emotional disorders.

References

Silvia G Bustos, Héctor Maldonado, Víctor A Molina (2008). Disruptive Effect of Midazolam on Fear Memory Reconsolidation: Decisive Influence of Reactivation Time Span and Memory Age Neuropsychopharmacology, 34 (2), 446-457 DOI: 10.1038/npp.2008.75

Merel Kindt, Marieke Soeter, Bram Vervliet (2009). Beyond extinction: erasing human fear responses and preventing the return of fear Nature Neuroscience DOI: 10.1038/nn.2271

J. L. C. Lee (2006). Reconsolidation and Extinction of Conditioned Fear: Inhibition and Potentiation Journal of Neuroscience, 26 (39), 10051-10056 DOI: 10.1523/JNEUROSCI.2466-06.2006

Stephen Maren, Gregory J. Quirk (2004). Neuronal signalling of fear memory Nature Reviews Neuroscience, 5 (11), 844-852 DOI: 10.1038/nrn1535

Shirley Zhang, Jacquelyn Cranney (2008). The role of GABA and anxiety in the reconsolidation of conditioned fear. Behavioral Neuroscience, 122 (6), 1295-1305 DOI: 10.1037/a0013273

Search the literature for reasons why this is happening and you’re likely to stumble across an array of sources that point the finger at over-prescribing physicians and misbehaving patients who don’t take their antibiotics as prescribed. Certainly these two factors play a significant role. But what is frequently overlooked is how drug resistance may be fostered outside the hospital and doctor’s office.

Take, for example, factory farming. Each year in the United States, the farming industry uses 25 million pounds of antibiotics, representing 70% of America’s antibiotic usage, not just to treat infections, but also to prevent them so that their livestock can survive their feedlots long enough to get to slaughter. In 2001, the AMA issued a statement opposing this practice. In 2004, the FDA officially discouraged this practice but backed off from this position in July of 2008.

Then there’s the issue of lax oversight of production and disposal of antibiotics. There was a recent article documenting the presence of ciprofloxacin, a broad-spectrum antibiotic that was once one of the medical community’s “big guns”, in the effluvia of a medication production plant in India in concentrations high enough to treat 90,000 people. When the companies that utilized this plant were questioned about this finding, they stated that the issue of pollution in India was “not within the scope of the activities” of their group. And an Associated Press investigation last year found not only the antibiotic tetracycline, but also blood pressure medications, steroids, cholesterol medications, and antidepressants in Philadelphia’s drinking water, presumably due to the practice of flushing unused medications down the toilet.

Finally, the pharmaceutical industry shifted its attention elsewhere. Research and development funds began being diverted away from the realm of antibacterials in the 1980’s, focusing more on anti-retrovirals for the newly emerging HIV epidemic and higher-order cardiovascular medications. Only in recent years has the attention once again swung back to developing medications to attack the resilient bacteria that have rendered antibacterial efforts of previous decades obsolete.

So while both physicians and patients need to exercise caution in the prescription and consumption of antibiotics, a true attack on drug-resistant bacteria may require a more comprehensive approach addressing not only medical, but also environmental, societal, and industrial factors.

Reference

J. Stephenson (1998). Antibiotics and Livestock JAMA: The Journal of the American Medical Association, 280 (7), 594-594 DOI: 10.1001/jama.280.7.594-a