The benzodiazepines can produce a wide variety of abnormal mental responses and hazardous behavioral abnormalities, including rebound anxiety and insomnia, mania and other forms of psychosis, paranoia, violence, antisocial acts, depression, and suicide. These drugs can impair cognition, especially memory, and can result in confusion. They can induce dependence and addiction. Severe withdrawal syndromes with psychosis, seizures, and death can develop. The short-acting benzodiazepines, alprazolam and triazolam , are especially prone to cause psychological and behavioral abnormalities. The sources of data (...) to support these observations and conclusions are discussed in regard to the scientific method. These adverse drug effects can wreck havoc in the lives of individuals and their families. (shrink)

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding (...) the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. (shrink)

Philosophical and empirical research on bodily awareness has mostly focused so far on bodily disorders – such as anorexia nervosa, somatoparaphrenia, or xenomelia (body integrity dysphoria) – and bodily illusions induced in an experimental setting – such as the rubber hand illusion, or the thermal grid illusion. Studying these conditions can be illuminating to investigate a broad range of issues about the nature, function, and etiology of bodily experience. However, a number of psychoactive compounds can also induce a remarkably (...) wide variety of bodily effects that have received little attention despite their relevance to these issues. Some of these effects are similar to those associated with bodily disorders or experimental bodily illusions, while others appear to be unique. The purpose of this chapter is to provide an overview of these lesser known bodily effects of psychoactive compounds, and outline some ways in which they can bear on recent debates regarding bodily awareness and bodily ownership. (shrink)

The placebo drug reactions from controlled trials were studied for the first time systematically for efficacy and the safety in drug data pooled from randomized, placebo-controlled, multicentre studies. Results: The efficacy of placebo on clinical symptoms and outcome varied between the therapeutic indications. However, no placebo effects on laboratory values, as e.g. blood glucose or Hb1c in diabetics, were noted. The frequency and type of placebo-induced adverse reactions also varied between indication groups. The placebo side (...) effect profile was largely similar to the side effect profile of the active treatment. The mechanisms of placebo effects are manyfold and varied (e.g. endorphin release, conditioning), much lacks explanation. Conclusion: Since the prescription of non-evidence based medicines (= pseudoplacebos) may clearly also result in serious adverse effects, such practice may not only be non-beneficial but may even be harmful. In clinical research, the judicious use of placebo remains essential to establish the efficacy and safety, safeguarding that patients receiving placebo will not be subject to harm and are fully informed. (shrink)

Two meta-analyses of pharmacological research are presented, demonstrating that psychoactive drugs have consistent effects on EEG and sleep outside of their effects on REM sleep, and demonstrating that drugs other than those affecting sleep neurotransmitter systems and REM sleep can also alter reported nightmare occurrence. These data suggest that the neurobiology data terrain outside activation-synthesis may include sleep and dream electrophysiology, cognitive reports of dreaming, effects of alterations in consciousness on dreaming, immunology and host defense, and clinical (...) therapies for sleep disorders. (shrink)

We examine the ethical, social, and regulatory barriers that may hinder research on therapeutic potential of certain controversial controlled substances like marijuana, heroin, or ketamine. Hazards for individuals and society and potential adverse effects on communities may be good reasons for limiting access and justify careful monitoring of these substances. Overly strict regulations, fear of legal consequences, stigma associated with abuse and populations using illicit drugs, and lack of funding may, however, limit research on their considerable therapeutic potential. (...) We review the surprisingly sparse literature and address the particular ethical concerns pertinent to research with illicit and addictive substances, such as undue inducement, informed consent, therapeutic misconception, and risk to participants, researchers, and institutions. We consider the perspectives of key research stakeholders and explore whether they may be infected with bias. We conclude by proposing an empirical research agenda to provide an evidentiary basis for ethical reasoning. (shrink)

Current health care standards, in many countries, Australia included, are regrettably poor. Surprisingly, practitioners and treating teams alike in mental health and disability sectors, in particular, make far too many basic care-related mistakes, in addition to the already abundant diagnostic mistakes that cause and amplify great harm. In part, too many practitioners also fail to distinguish adverse effects for what they are and all too often treat adverse effects, instead, as comorbidities. Diagnostic failures are dangerous, the (...) result of which generates and perpetuates harms that are extremely costly in terms of patient welfare, in addition to the financial burden placed on everyone. In this essay, I contend that the authority bestowed upon psychiatry is misplaced. Subsequently, this misplaced authority affects the governing and investigatory institutions reliant and informed by psychiatry. The examination process undertaken in this investigation traces the metaphysics of psychiatric disorders relative to the Diagnostic-Statistical-Manual (DSM) in all its iterations and to the epistemological construction process that serves to underpin the fundamentals of psychiatric practice. There exists a crisis of confidence in psychiatric practice and I urge drastic reform be undertaken to arrest the damage. (shrink)

There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the (...) kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other hand, it suggests that ordinary conscious experience might involve a minimal kind of self-awareness rooted in multisensory processing, which is what appears to fade away during DIED. (shrink)

The placebo drug reactions from controlled trials were studied for the first time systematically for efficacy and the safety in drug data pooled from randomized, placebo-controlled, multicentre studies. Results: The efficacy of placebo on clinical symptoms and outcome varied between the therapeutic indications. However, no placebo effects on laboratory values, as e.g. blood glucose or Hb1c in diabetics, were noted. The frequency and type of placebo-induced adverse reactions also varied between indication groups. The placebo side (...) effect profile was largely similar to the side effect profile of the active treatment. The mechanisms of placebo effects are manyfold and varied (e.g. endorphin release, conditioning), much lacks explanation. Conclusion: Since the prescription of non-evidence based medicines (= pseudoplacebos) may clearly also result in serious adverse effects, such practice may not only be non-beneficial but may even be harmful. In clinical research, the judicious use of placebo remains essential to establish the efficacy and safety, safeguarding that patients receiving placebo will not be subject to harm and are fully informed. (shrink)

Exposure of man to chemical agents can occur intentionally, as in the treatment of disease, or inadvertently because the environment contains a wide range of synthetic or naturally occurring chemicals. The alkylating agents are a diverse group of compounds (Fig. 1) and comprise a good example of such xenobiotics, since much is known about their occurrence, and their biological effects include carcinogenicity, mutagenicity, toxicity and teratogenicity.Exposure to potentially carcinogenic alkylating agents such as nitrosamines may occur occupationally, from cigarette smoke, (...) from certain foodstuffs and even endogenously through the ingestion of the appropriate precursor chemicals.1 At the other extreme, the cytotoxic effects of agents such as the chloroethylating nitrosamides or mustards have been exploited in the design of certain antitumour drugs.2 The effectiveness of antitumour agents and the other, mostly adverse, biological effects of alkylating agents have been ascribed to their ability to damage cellular macromolecules, in particular DNA. This review concentrates on investigations carried out over the past two years on the role of DNA damage in carcinogenesis, but we shall see how recent advances in this area of research have also led to a better understanding of the mechanisms of the cytotoxic effects of alkylating antitumour agents. (shrink)

Drug recalls and lawsuits against pharmaceutical manufacturers are accompanied by announcements emphasizing harmful drug side-effects. Those with elevated health anxiety may be more reactive to such announcements. We evaluated whether health anxiety and financial incentives affect subjective symptom endorsement, and objective outcomes of cognitive and physiological functioning during a mock drug recall. Hundred and sixty-one participants reported use of over-the-counter pain medications and presented with a fictitious medication recall via a mock Food and Drug Administration (...) website. The opportunity to join a class-action lawsuit was manipulated. We assessed health anxiety, recalled drug usage, blood pressure, heart rate, and performance on a computerized Trail Making Test. Symptom endorsement was strongly predicted by health anxiety. When combined, three health anxiety measures explained 28.5% variance. These effects remain strong after controlling for depression and anxiety. Litigation condition did not predict symptom endorsement. Blood pressure and heart rate were modestly predicted by health anxiety, but not by litigation condition. TMT performance was consistently predicted by health anxiety, with higher scores associated with poorer performance. Although there were no main effects for litigation, interactions consistently emerged for the TMT, with generally poorer performance for those with higher health anxiety in the non-litigation condition; whereas health anxiety was unrelated to performance for the litigation condition. All but one participant joined the litigation when given the opportunity, despite a healthy sample and minimal use of pain medication. Subsequent data from 67 individuals with no mention of the FDA scenario or litigation showed that health anxiety still significantly predicts symptom endorsement, but the explained variance is less than half that obtained in the FDA scenario. The findings suggest that health anxiety plays a significant role in adverse symptom reporting, beyond anxiety or depression, and this effect is independent of the presence of the FDA recall. The lack of differences for health anxiety and symptom endorsement between litigation and non-litigation conditions rules out malingering. Although it is general practice in drug recalls to list potential adverse side effects caused by medications, this may elicit unintended symptom experiences and health anxious individuals may be more susceptible. (shrink)

The underreporting of suspected adverse drug reactions remains a primary issue for contemporary post-market drug surveillance or ‘pharmacovigilance.’ Pharmacovigilance pioneer W.H.W. Inman argued that ‘deadly sins’ committed by clinicians are to blame for underreporting. Of these ‘sins,’ ignorance and lethargy are the most obvious and impactful in causing underreporting. However, recent analyses show that diffidence, insecurity, and indifference additionally play a major role. I aim to augment our understanding of diffidence, insecurity, and indifference by arguing these sins (...) are underwritten by value judgments arising via epistemic risk. I contend that ‘evidence-based’ medicine codifies these sins. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an (...) open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

A study of the international pharmaceutical industry discusses the uses and abuses of prescription drugs and details the dangers and adverse impact of disease treatment with drugs.

After the US Supreme Court’s reversal of Roe v. Wade, a number of states have immediately banned abortion. Pro-choice activists are responding by promoting medication abortions – a do-it-yourself form of abortion. Women can take pills at home to induce an abortion in the first few weeks of pregnancy. -/- The Biden Administration [1] has backed the abortion pill, too. Attorney-General Merrick B. Garland and Health and Human Services Secretary Xavier Becerra both issued statements endorsing it. -/- “We stand ready (...) to work with other arms of the federal government that seek to use their lawful authorities to protect and preserve access to reproductive care,” said the Attorney-General. “In particular, the F.D.A. has approved the use of the medication mifepristone. States may not ban mifepristone based on disagreement with the F.D.A.’s expert judgment about its safety and efficacy.” -/- As the New York Times [1] has noted, this sets the scene for legal battles. The obvious one is: will anti-abortion states prosecute medication abortions? -/- But – based on experience in the United Kingdom - the use of the abortion pill could give pro-life doctors headaches as well. -/- In the past year, UK has witnessed the saga of two Catholic doctors who have been brought in front of the professional regulator, the General Medical Council, after accusations of professional misconduct. Their crime? They had supplied abortion pill reversal (APR) treatment to women. Accusations of this misconduct have been brought forward by pro-choice organisations [2]. -/- The problem is that some women might panic when they discover that they are pregnant or are pressured to make a rash decision. They obtain abortion pills, often without seeing a doctor faceto- face, and soon after taking the first pill, they regret their decision. -/- Is it too late for them to save their pregnancy? Not necessarily. -/- A treatment developed in the US works about half the time. It involves the woman taking progesterone after the first abortion pill to counteract the abortifacient action of the drug. -/- Seventy-three women in the UK are reported to have taken a full APR course, of whom, 38 – more than half — successfully remained pregnant. Admittedly, the procedure is controversial [3], with pro-choice writers denouncing it as unproven, unscientific, and unethical. This has triggered some healthcare practitioners and scholars to analyse the commitments of the pro-choice movement to APR. In a recently published paper in The New Bioethics [4], two colleagues, Dominic Whitehouse and Steven Bow, and I argue that those espousing a pro-choice worldview should actually support abortion pill reversal and that the current evidence indicates that they should actually be doing it. -/- While some pro-choice activists might be happy simply to expand women’s reproductive choices, some might also want to ensure that these choices are safe and effective at achieving the desired outcome, which in principle includes maintaining a pregnancy. -/- We then review the scientific evidence with respect to the ability of APR to halt an abortion, look at the potential impact of APR on mental health, as well as its procedural safety. While highlighting that gold-standard evidence is lacking, we note that APR is associated with about two times higher rate of embryo survival compared to not completing the full early medical abortion course, that there is large agreement in the literature that women who are ambiguous about abortion are at risk of poorer mental health outcomes after abortion (and argue that women who request APR fall into this category), and highlight that there is no evidence that APR is more dangerous than abandoning an initiated early medical abortion. -/- The latter fact is important, as the results of the only randomised-controlled trial of APR have been at times misrepresented in the media [5.6], creating the impression that APR is not safe while most of the adverse effects occurred in the study group that did not receive APR. As our paper argues, with respect to APR the two UK doctors were “champions of women’s choice and should be congratulated, not condemned, by pro-choice advocates”. -/- While the cases against the two doctors have now been dropped (and there have even been accusations against a member of one of these pro-choice organisations that they pressurised a patient into complaining about one of the doctors and twisted the patient’s experience of the treatment [7]), we argue that it is important to set-up systems to facilitate the future provision of APR to protect both patients and healthcare staff. -/- Our conclusion is that, while being open to any change in evidence, those espousing a pro-choice outlook should “support calls for an APR framework that will protect women and the healthcare professionals caring for them” “and certainly not oppose” APR. -/- The debate over abortion pill reversal will be heading to the United States soon. It is quite possible that it will be denounced as dangerous misinformation. It’s not. But pro-life defenders should be prepared to defend their ground. -/- This article was first published by Mercatornet. (shrink)

This paper examines the culture, the dynamics and the financial underpinnings that determine how medical research is being conducted on children in the United States. Children have increasingly become the subject of experiments that offer them no potential direct benefit but expose them to risks of harm and pain. A wide range of such experiments will be examined, including a lethal heartburn drug test, the experimental insertion of a pacemaker, an invasive insulin infusion experiment, and a fenfluramine "violence prediction" (...) experiment. Emphasis, however, is given to psychoactive drug tests because of the inherent ethical and diagnostic problems involved in the absence of any objective, verifiable diagnostic tool. Effort is made to provide readers comprehensive reference sources to evidence-based reports about the serious risks these drugs pose for adults and children so that the reader may judge whether the benefits (if any) outweigh the risks for children. The first ethical issue raised by these experiments is: did the severity of illness in these children justify their exposure to short and long-term risks? The ethics of the experiments will be evaluated by referring to existing codes of medical research ethics-the Nuremberg Code, the Declaration of Helsinki, and the federal Code of Regulations. The thirteen cases presented will demonstrate that children are being used in ever more speculative experiments, often in the absence of a therapeutic intent, but a significant chance for causing harm and / or discomfort. Some of the experiments were designed to explore the mechanisms of pathology and pharmacological interventions, or the response of neurological brain receptors to chemical provocation ("challenge"). Others were designed to test the safety or efficacy of new drugs, even to test these drugs on healthy children who were hypothesized to be "at risk." Children and adolescents have been subjected to "forced dose titration" experiments that induced a spectrum of severe adverse effects, including insomnia, extreme restlessness, agitation, (akathisia) and self-injurious behavior. FDA reports show that suicide is a significant issue in psychotropic drug trials-in pediatric trials the problem is even greater. The paper aims to demonstrate how the enactment of the Better Pharmaceuticals for Children Act (incorporated into the Food and Drug Administration Modernization Act, FDAMA), set in motion a radical shift in public policy by providing huge financial incentives to pharmaceutical companies to test new or patented drugs in children. Federal policy shifted from one aimed at protecting children by setting limits on permissible research risks, to a policy aimed at broadening the inclusion of children as test subjects. It will be shown how the FDA and the Department of Health and Human Services lifted regulatory restrictions to permit research involving greater than minimal risk to be conducted on healthy children, claiming that all children are potentially "at risk" of a future condition. Children were in this way deprived of regulatory protections. An argument will be made that the approval of nontherapeutic, harmful experiments-such as exposure of toddlers to lead poison-under the current gate keeping system raises serious doubts about the sustainability of institutional review boards (IRBs) as protectors of human research subjects. Children, who are precluded from exercising the adult human's right to informed consent, are being exploited as commodities for commercial ends. It is the position of the author that nothing less than the enactment of a federal law mandating a radical overhaul of the current research review system, with independent checks and balances, will provide children the legal protections they need. Ten specific recommendations are offered to protect children from harmful experiments. (shrink)

IntroductionResponsive neurostimulation is an evolving therapeutic option for patients with treatment-refractory epilepsy. Open-loop, continuous stimulation of the anterior thalamic nuclei is the only approved modality, yet chronic stimulation rarely induces complete seizure remission and is associated with neuropsychiatric adverse effects. Accounts of off-label responsive stimulation in thalamic nuclei describe significant improvements in patients who have failed multiple drug regimens, vagal nerve stimulation, and other invasive measures. This systematic review surveys the currently available data supporting the use of (...) responsive thalamic neurostimulation in primary and secondary generalized, treatment-refractory epilepsy.Materials and MethodsA systematic review was performed using the following combination of keywords and controlled vocabulary: OR ) OR [responsive neurostimulation AND thalamus AND ]. In addition, a search of the publications listed under the PubMed “cited by” tab was performed for all publications that passed title/abstract screening in addition to manually searching their reference lists.ResultsTen publications were identified describing a total of 29 subjects with a broad range of epilepsy disorders treated with closed-loop thalamic neurostimulation. The median age of subjects was 31 years old. Of the 29 subjects, 15 were stimulated in the anterior, 11 in the centromedian, and 3 in the pulvinar nuclei. Excluding 5 subjects who were treated for 1 month or less, median time on stimulation was 19 months. Of these subjects, 17/24 experienced greater than or equal to 50%, 11/24 least 75%, and 9/24 at least 90% reduction in seizures. Although a minority of patients did not exhibit significant clinical improvement by follow-up, there was a general trend of increasing treatment efficacy with longer periods on closed-loop thalamic stimulation.ConclusionThe data supporting off-label closed-loop thalamic stimulation for refractory epilepsy is limited to 29 adult and pediatric patients, many of whom experienced significant improvement in seizure duration and frequency. This encouraging progress must be verified in larger studies. (shrink)

Institutional corruption is a normative concept of growing importance that embodies the systemic dependencies and informal practices that distort an institution’s societal mission. An extensive range of studies and lawsuits already documents strategies by which pharmaceutical companies hide, ignore, or misrepresent evidence about new drugs; distort the medical literature; and misrepresent products to prescribing physicians. We focus on the consequences for patients: millions of adverse reactions. After defining institutional corruption, we focus on evidence that it lies behind the epidemic (...) of harms and the paucity of benefits. (shrink)

A relatively healthy forty-six-year-old woman with mild hypertension receives a prescription for an antihypertensive medication. One of the medication's adverse effects is its potential to cause severe depression. Four months later, she is diagnosed with anxiety, an early manifestation of depression. An antianxiety drug is prescribed, but her anxiety worsens. Her physician then diagnoses her as having a depressive disorder, and prescribes a new antidepressant medication. She is still on the same antihypertensive.A seventy-two-year-old man is given furosemide (...) and digoxin to control a mild case of congestive heart failure and hypertension. Because furosemide deletes potassium from the body, his physician also places him on a potassium supplement. Six months later, the physician tells the patient to stop taking the furosemide and prescribes an angiotensin converting enzyme inhibitor. An effect of ACE inhibitors is to reduce the body's excretion of potassium thereby reducing the digoxin's effectiveness. (shrink)

A relatively healthy forty-six-year-old woman with mild hypertension receives a prescription for an antihypertensive medication. One of the medication's adverse effects is its potential to cause severe depression. Four months later, she is diagnosed with anxiety, an early manifestation of depression. An antianxiety drug is prescribed, but her anxiety worsens. Her physician then diagnoses her as having a depressive disorder, and prescribes a new antidepressant medication. She is still on the same antihypertensive.A seventy-two-year-old man is given furosemide (...) and digoxin to control a mild case of congestive heart failure and hypertension. Because furosemide deletes potassium from the body, his physician also places him on a potassium supplement. Six months later, the physician tells the patient to stop taking the furosemide and prescribes an angiotensin converting enzyme inhibitor. An effect of ACE inhibitors is to reduce the body's excretion of potassium thereby reducing the digoxin's effectiveness. (shrink)

Children who experience well-being are engaging more confidently and positively with their caregiver and peers, which helps them to profit more from available learning opportunities and support current and later life outcomes. The goodness-of-fit theory suggests that children’s well-being might be a result of the interplay between their temperament and the environment. However, there is a lack of studies that examined the association between children’s temperament and well-being in early childhood education and care, and whether this association is affected by (...) ECEC process quality. Using a multilevel random coefficient approach, this study examines the association between toddlers’ temperament and well-being in Norwegian ECEC and investigates whether process quality moderates this association. Results reveal an association between temperament and well-being. Staff-child conflict moderates the association between shyness and well-being, and between activity and well-being. Moreover, high emotional behavioral support moderates the association between activity and well-being. Extra attention should be paid by the staff to these children’s needs. (shrink)

We use the format of a hypothetical case study to review issues related to pharmaceutical product approval and physician prescribing practices. In this case, a new FDA-approved drug is recommended for a patient who subsequently experiences an adverse event that may or may not be related to the prescription. This case raises a number of ethical and legal considerations physicians routinely face when deciding whether to recommend such drugs for their patients. Despite the need for ongoing observation by (...) the regulatory apparatus, physicians should be cognizant of the limitations of the drug approval system and the post-approval prescription drug surveillance system. We discuss physicians’ ethical obligations when faced with a newly approved drug, including seeking out independent sources of learning, reporting adverse effects, and notifying patients about limitations in available knowledge about therapeutic recommendations. (shrink)

Despite the remarkable achievements of novel targeted anti‐cancer drugs, most therapies only produce remission for a limited time, resistance to treatment, and relapse, often being the ultimate outcome. Drug resistance is due to highly efficient adaptive strategies utilized by cancer cells. Exogenous and endogenous stress stimuli are known to induce first‐line responses, capable of re‐establishing cellular homeostasis and determining cell fate decisions. Cancer cells may also mount second‐line adaptive strategies, such as the mutator response. Hypermutable subpopulations of cells may (...) expand under severe selective stress, thereby accelerating the emergence of adapted clones. As with first‐line protective responses, these strategies appear highly conserved, and are found in yeasts and bacteria. We hypothesize that evolutionarily conserved programs rheostatically regulate mutability in fluctuating environments, and contribute to drug resistance in cancer cells. Elucidating the conserved genetic and molecular mechanisms may present novel opportunities to increase the effectiveness of cancer therapies. (shrink)

Background Thorough information of the patient is an integral part of the process of shared decision making. We aimed to investigate if detailed information about medication may induce nocebo effects. Methods We conducted a randomized, single-blind, pilot-study including n = 51 psychiatric in-patients aged between 18 and 80 years with a depressive disorder and accompanying sleeping disorders. In the intervention group we provided thorough information about adverse effects, while the control group received only a simple consent procedure. (...) In both groups, patients received an open-label placebo pill instead of their sleeping medication. Results No statistically significant differences between the intervention group and the control group were found regarding the main outcome parameter. Conclusion In this study, we were not able detect an effect of informed consent vs. simple consent on the emergence of placebo or nocebo effects. This finding is contrary to most assumptions and publications about this topic. Trial registration Trial registration number: DRKS00017653, registered August 30th 2018. Retrosprectively registered. (shrink)

The principle of informed consent obligates physicians to explain possible side effects when prescribing medications. This disclosure may itself induce adverse effects through expectancy mechanisms known as nocebo effects, contradicting the principle of nonmaleficence. Rigorous research suggests that providing patients with a detailed enumeration of every possible adverse event—especially subjective self-appraised symptoms—can actually increase side effects. Describing one version of what might happen (clinical “facts”) may actually create outcomes that are different from what would (...) have happened without this information (another version of “facts”). This essay argues that the perceived tension between balancing informed consent with nonmaleficence might be resolved by recognizing that adverse effects have no clear black or white “truth.” This essay suggests a pragmatic approach for providers to minimize nocebo responses while still maintaining patient autonomy through “contextualized informed consent,” which takes into account possible side effects, the patient being treated, and the particular diagnosis involved. (shrink)

Usage of psychotropics during pregnancy and lactation has always been a topic of debate and controversy. The debate stems from the potential adverse effects on the growing fetus or infants due to the transfer of psychotropic drugs through placenta or breast milk of mothers receiving them; and the problem of discontinuing psychotropics in lactating mother considering chances of relapse. However, most of the psychotropics are found to be relatively safe when used cautiously during the lactation phase. This article (...) describes available data on the use of psychotropics in lactating mothers, in particular, in relation to the safety profile of infants. (shrink)

Market participants continue to demand greater transparency from boards of directors, yet little is known about the effect of increased transparency on director decisions. Using a sample of practicing board members, our first experiment provides evidence that increased transparency via disclosure may license directors to make more biased decisions. Guided by rich insights provided by these directors, we examine whether considering a company’s ethical values can deter disclosure-induced licensing by activating a morality mindset. In two additional experiments, we find (...) that exposure to a code of conduct that includes an ethics component does not mitigate the licensing effects we observed; however, considering a separate, concise ethics statement does mitigate these effects. Our findings highlight important differences between the code of conduct and ethics statement for decision-making which can help organizations to mitigate adverse effects of disclosure. Implications for users of financial information and regulators are also discussed. (shrink)

Objectives: To report the attitudes and opinions of subjects in US clinical trials about whether or not, and why, they should receive post-trial access (PTA) to the trial drug, care and information. Design: Focus groups, short self-administered questionnaires. Setting: Boston, Dallas, Detroit, Oklahoma City. Participants: Current and recent subjects in clinical trials, primarily for chronic diseases. Results: 93 individuals participated in 10 focus groups. Many thought researchers, sponsors, health insurers and others share obligations to facilitate PTA to the trial (...) drug, if it benefited the subject, or to a therapeutic equivalent. Some thought PTA obligations include providing transition care (referrals to non-trial physicians or other trials, limited follow-up, short-term drug supply) or care for long-term adverse events. Others held, in contrast, that there are no PTA obligations regarding drugs or care. However, there was agreement that former subjects should receive information (drug name, dosage received, market approval date, long-term adverse effects, trial results). Participants frequently appealed to health need, cost, relationships, reciprocity, free choice and sponsor self-interest to support their views. Many of their reasons overlapped with those commonly discussed by bioethicists. Conclusion: Many participants in US trials for chronic conditions thought there are obligations to facilitate PTA to the trial drug at a “fair” price; these views were less demanding than those of non-US subjects in other studies. However, our participants’ views about informational obligations were broader than those of other subjects and many bioethicists. Our results suggest that the PTA debate should expand beyond the trial drug and aggregate results. (shrink)

Despite the recent discovery that thalidomide causes limb defects by targeting highly angiogenic, immature blood vessels, several challenges still remain and new ones have arisen. These include understanding the drug's species specificity, determining molecular target(s) in the endothelial cell, shedding light on the molecular basis of phocomelia and producing a form of the drug that is clinically effective without having side effects. Now that the trigger of thalidomide‐induced teratogenesis has been uncovered, a framework is proposed, incorporating (...) and uniting previous models of thalidomide action, explaining how thalidomide causes not just limb defects, but also all the other defects it induces. (shrink)

ABSTRACT In this paper, I support the claim that placing certain restrictions on public access to possible new treatments is morally problematic under some exceptional circumstances. Very ill patients may find that all available standard treatments are unacceptable, either because they are ineffective or have serious adverse effects, and these patients may understandably be desperate to try something new even if this means stepping into the unknown. Faced with certain death, it is rational to want to try something (...) new and to chance a dire outcome. Restricting possible new treatments to research trials may put these treatments scientifically, geographically or economically out of reach of these patients. For those who can get access, research restrictions could weaken, though not necessarily eliminate, the value of consent participants of such trials are able to give. Some participants may therefore be exploited for scientific purposes in the name of public interest. There are nonetheless compelling reasons for keeping some restrictive regulation in this area. (shrink)

While pharmaceutical industry involvement in producing, interpreting, and regulating medical knowledge and practice is widely accepted and believed to promote medical innovation, industry-favouring biases may result in prioritizing corporate profit above public health. Using diabetes as our example, we review successive changes over forty years in screening, diagnosis, and treatment guidelines for type 2 diabetes and prediabetes, which have dramatically expanded the population prescribed diabetes drugs, generating a billion-dollar market. We argue that these guideline recommendations have emerged under pervasive industry (...) influence and persisted, despite weak evidence for their health benefits and indications of serious adverse effects associated with many of the drugs they recommend. We consider pharmaceutical industry conflicts of interest in some of the research and publications supporting these revisions, and in related standard-setting committees and oversight panels. We raise concern over the long-term impact of these multifaceted involvements. Rather than accept industry conflicts of interest as normal, needing only to be monitored and managed, we suggest challenging that normalcy, and ask: what are the real costs of tolerating such industry participation? We urge the development of a broader focus to fully understand and curtail the systemic nature of industry’s influence over medical knowledge and practice. (shrink)

Corporate social responsibility (CSR) concerns the realm of business behavior in which the firm tries to effectively manage its business and non-market environment interface. Coerced CSR refers to taking socially responsible action in response to or in anticipation of retaliation in some form (boycott, adverse publicity, introduction of regulatory laws, etc.) from interest groups who are not directly part of the market to which the firm caters. In contrast, strategic CSR or altruistic CSR refers to socially responsible activities undertaken (...) out of enlightened self-interest. The focus of this paper is to understand whether the impact of coercion is different for government-owned organizations and privately owned firms in developing countries. Activities that are in response to or in anticipationof threats by interest groups are identified and compared across publicly and privately owned firms, against the backdrop of weak enforcement of fairly stringent environmental regulation. We then generalize our observations and attempt to distinguish the intensity of pressures felt by public and privately owned firms and their speed of response. As a result of this understanding, we attempt to suggest specific policy mixes for various types of industry, depending on whether they are dominated by the public sector or private sector. (shrink)

Considerable hope surrounds the use of disease‐specific pluripotent stem cells to generate models of human disease allowing exploration of pathological mechanisms and search for new treatments. Disease‐specific human embryonic stem cells were the first to provide a useful source for studying certain disease states. The recent demonstration that human somatic cells, derived from readily accessible tissue such as skin or blood, can be converted to embryonic‐like induced pluripotent stem cells (hiPSCs) has opened new perspectives for modelling and understanding a (...) larger number of human pathologies. In this review, we examine the opportunities and challenges for the use of disease‐specific pluripotent stem cells in disease modelling and drug screening. Progress in these areas will substantially accelerate effective application of disease‐specific human pluripotent stem cells for drug screening. (shrink)

The simian virus 40 chromosome, a model for the mammalian replicon, is a uniquely powerful system for the study of drugs and treatments which target enzymes of the mammalian replication apparatus. High resolution gel electrophoretic analysis of normal and aberrant viral replication intermediates can be used effectively to understand the molecular events of replication failure. These events include breakage of replication forks, aberrant topoisomerase action, failure to separate daughter chromosomes, protein‐DNA crosslinking, single and double strand DNA breakage, alterations in topology (...) and inactivation of replication intermediates. The SV40 replication system can also be used to study the recombinational events which often follow drug‐induced replication failure. (shrink)

Side effects are ubiquitous in medicine and they often play a role in treatment decisions for patients and clinicians alike. Philosophers and health researchers often use side effects to illustrate issues with contemporary medical research and practice. However, technical definitions of ‘side effect’ differ among health authorities. Thus, determining the side effects of an intervention can differ depending on whose definition we assume. Here I review some of the common definitions of side effect and highlight their issues. (...) In response, I offer an account of side effects as jointly (i) unintended and (ii) effects due to the causal capacities or invariances of an intervention. I discuss (i) by examining the intentions or reasons behind therapeutic interventions, and I discuss (ii) by appealing to a manipulationist model of causation. The analysis here highlights that side effects are conceptually distinct from related outcomes like adverse events, adverse drug reactions, and placebo effects. The analysis also allows for reflection on the utility of ‘side effect’ as a technical term in medical research and practice. (shrink)

Different immunotherapeutic approaches are in the pipeline for the treatment of drug dependence. “Drug vaccines” aim to induce the immune system to produce antibodies that bind to drugs and prevent them from inducing rewarding effects in the brain. Drugs of abuse currently being tested using these new approaches are opioids, nicotine, cocaine, and methamphetamine. In human clinical trials, “cocaine and nicotine vaccines” have been shown to induce sufficient antibody levels while producing few side effects. Studies in (...) humans, determining how these vaccines interact in combination with their target drug, are underway. However, although vaccines can become a reasonable treatment option for drugs of abuse, there are several disadvantages that must be considered. These include i) great individual variability in the formation of antibodies, ii) the lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice, and iii) the lack of an effect on the drug desire that may predispose an addict to relapse. In addition, a comprehensive overview of several crucial ethical issues has not yet been widely discussed in order to have not only a biological approach to immunotherapy of addiction. Overall, immunotherapy offers a range of possible treatment options: the pharmacological treatment of addiction, the treatment of overdoses, the prevention of toxicity to the brain or the heart, and the protection of the fetus during pregnancy. So far, the results obtained from a small-scale experiment using vaccines against cocaine and nicotine suggest that a number of important technical challenges still need to be overcome before such vaccines can be approved for clinical use. (shrink)

Corporate social responsibility (CSR) concerns the realm of business behavior in which the firm tries to effectively manage its business and non-market environment interface. Coerced CSR refers to taking socially responsible action in response to or in anticipation of retaliation in some form (boycott, adverse publicity, introduction of regulatory laws, etc.) from interest groups who are not directly part of the market to which the firm caters. In contrast, strategic CSR or altruistic CSR refers to socially responsible activities undertaken (...) out of enlightened self-interest. The focus of this paper is to understand whether the impact of coercion is different for government-owned organizations and privately owned firms in developing countries. Activities that are in response to or in anticipationof threats by interest groups are identified and compared across publicly and privately owned firms, against the backdrop of weak enforcement of fairly stringent environmental regulation. We then generalize our observations and attempt to distinguish the intensity of pressures felt by public and privately owned firms and their speed of response. As a result of this understanding, we attempt to suggest specific policy mixes for various types of industry, depending on whether they are dominated by the public sector or private sector. (shrink)

Healthcare professionals such as nurses faced a tough time during the pandemic. Despite the personal and professional challenges, they contributed immensely during the pandemic. However, there were variations in nurses’ work engagement during the pandemic. One reason could be their personality, especially neuroticism. Neuroticism represents individuals’ proneness to distress in stressful situations, such as COVID-19. Hence, understanding how and in which conditions neuroticism influences work engagement is crucial. We used the Job Demand-Resource model to test the association between neuroticism and (...) work engagement. As neuroticism represents the stress-proneness of an individual, we further investigated if stress mediates the neuroticism-work engagement link. For the nurses, patient interaction is an integral part of their job. Based on the data collected from the nurses, we tested if contact with patients alleviates the adverse effect of neuroticism on work engagement. During COVID-19, there was an intense need for nursing support. Hence, avoiding duty when society is looking for support might induce a fear of stigmatization among the nurses. We examined if the perceived stigma of duty avoidance would affect the neuroticism-engagement relationship. Our results indicated that higher patient contact alleviated the adverse effect of neuroticism on work engagement. On the other hand, higher fear of stigma exacerbated the adverse effect of neuroticism on work engagement. We further checked the combined effect of beneficiary contact and fear of stigma on neuroticism-work engagement relationships. The findings highlighted the importance of societal factors and policymakers in enhancing nurses’ work engagement. (shrink)

The facilitation of tight regulatory frameworks necessary to ensure that new drugs are safe and effective have yet to be effectively applied within the paediatric population. Utilization of unlicensed and off-label drugs in children results in a variety of problems ranging from inefficacy, adverse reactions and in some cases death. This ethically questionable behaviour has led the European government to legally force pharmaceutical companies to propose paediatric applications and carry out clinical studies at early stages of drug development. (...) The new European Paediatric Regulation implemented in 2007 opens a new era of paediatric drug development and will offer the opportunity to vastly improve children's health. However, this brighter outlook for the paediatric community might encourage potentially unethical behaviour in a pharmaceutical industry that finds itself in economically unstable times. The article records the gradual evolution of the US Paediatric Exclusivity Plan and the underlying principle of the newly introduced European Paediatric Regulation. It discusses some of the potential drawbacks and detrimental consequences of implementing the new European regulation, and the prospects of avoiding these by critically evaluating the difficulties experienced by the US. (shrink)

We reply to the Ioannidis's paper "Effectiveness of antidepressants; an evidence based myth constructed from a thousand controlled trials." We disagree that antidepressants have no greater efficacy than placebo. We present the efficacy from hundreds of trials in terms of the percentage of patients with a substantial clinical response (a 50% improvement or more symptomatic reduction). This meta-analysis finds that 42-70% of depressed patients improve with drug and 21%-39% improve with placebo. The response benefit of antidepressant treatment is 33%-11% (...) greater than placebo. Ioannidis argues that it would be vanishingly smaller because systematic biasing in these clinical trials would reduce the drug-placebo difference to zero. Ioannidis' argument that antidepressants have no benefit is eroded by his failures of logic because he does not present any evidence that there are a large number of studies where placebo is substantially more effective than drug. (To reduce to zero, one would also have to show that some of the unpublished studies find placebo better than drug and have substantial systematic or methodological bias). We also present the empirical evidence showing that these methodological concerns generally have the opposite effect of what Ioannidis argues, supporting our contention that the measured efficacy of antidepressants likely underestimates true efficacy.Our most important criticism is Ioannidis’ basic underlying argument about antidepressants that if the existing evidence is imperfect and methods can be criticized, then this proves that antidepressant are not efficacious. He presents no credible evidence that antidepressants have zero effect size. Valid arguments can point out difficulties with the data but do not prove that a given drug had no efficacy. Indeed better evidence might prove it was more efficacious that originally found.We find no empirical or ethical reason why psychiatrists should not try to help depressed patients with drugs and/or with psychotherapeutic/behavioral treatments given evidence of efficacy even though our treatment knowledge has limitations. The immense suffering of patients with major depression leads to ethical, moral, professional and legal obligations to treat patients with the best available tools at our disposal, while diligently and actively monitoring for adverse effects and actively revising treatment components as necessary. (shrink)

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, (...) L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

Recent research offers good reason to think that various psychedelic drugs—including psilocybin, ayahuasca, ketamine, MDMA, and LSD—may have significant therapeutic potential in the treatment of various mental health conditions, including post-traumatic stress disorder, depression, existential distress, and addiction. Although the use of psychoactive drugs, such as Diazepam or Ritalin, is well established, psychedelics arguably represent a therapeutic step change. As experiential therapies, their value would seem to lie in the subjective experiences they induce. As it is the only way for (...) trainee psychedelic therapists to fully understand their subjective effects, some have suggested that firsthand experience of psychedelics should form part of training programs. We question this notion. First, we consider whether the epistemic benefits offered by drug-induced psychedelic experience are as unique as is supposed. We then reflect on the value it might have in regard to the training of psychedelic therapists. We conclude that, absent stronger evidence of the contribution drug-induced experiences make to the training of psychedelic therapists, requiring trainees to take psychedelic drugs does not seem ethically legitimate. However, given the potential for epistemic benefit cannot be entirely ruled out, permitting trainees who wish to gain first-hand experience of psychedelics may be permissible. (shrink)

BackgroundEnhancement involves the use of biomedical technologies to improve human capacities beyond therapeutic purposes. It has been well documented that enhancement is sometimes difficult to distinguish from treatment. As a subtype of enhancement, neuroenhancement aims to improve one’s cognitive or emotional capacities.Main bodyThis article proposes that the notion of neuroenhancement deserves special attention among enhancements in general, because apart from the notion of treatment, it also overlaps with other concepts such as prevention, pain relief, and pleasure seeking. Regarding prevention, patients’ (...) mental endurance can be enhanced when a patient is prescribed a selective serotonin reuptake inhibitor for the purpose of preventing the relapse of depression following a stressful situation. As for pain relief, psychiatrists use medication to alleviate distress in patients who experience various types of anxiety; the alleviation of distress is equal to psychological pain relief, but is also an enhancement of the patient’s temperamental traits. Regarding pleasure seeking, insidious transition exists between neuroenhancement and pleasure seeking when using psychotropic drugs. It is well known that people use psychostimulants for recreational purposes and to induce overconfidence in one’s performance. The polysemy of psychotropics derives from their effects on human sensibility. Therefore, when using psychotropic agents, psychiatrists should pay close attention to what the agent is used for on each patient in each situation, and explicitly share the continuity and overlap in the purpose of prescribing a medication with the patients to make a better clinical decision.ConclusionsThe notion of neuroenhancement overlaps not only with the notion of treatment, but also with other concepts of prevention, pain relief, and pleasure seeking. The continuity between those concepts makes the issues concerning the prescription of psychotropic drugs subtler. Psychiatrists should explicitly share the continuity with the patients to make a better clinical decision. (shrink)

Sartre's experimentation in February 1935 with the drug mescalin has been well documented by Simone de Beauvoir in her book The Prime of Life. 1 She recalls that Sartre experienced under the influence of the drug not exactly hallucinations, ‘but the objects he looked at changed their appearance in the most horrifying manner:’ [POL 209]. The residual effects of this nightmarish experience left Sartre, not only for several days ‘in a state of deep depression’ [POL 210], but (...) also produced moods that ‘recalled those that had been induced by mescalin.’. (shrink)

Sartre's experimentation in February 1935 with the drug mescalin has been well documented by Simone de Beauvoir in her book The Prime of Life.1 She recalls that Sartre experienced under the influence of the drug not exactly hallucinations, ‘but the objects he looked at changed their appearance in the most horrifying manner:’ [POL 209]. The residual effects of this nightmarish experience left Sartre, not only for several days ‘in a state of deep depression’ [POL 210], but also (...) produced moods that ‘recalled those that had been induced by mescalin.’. (shrink)

The COVID-19 pandemic has pressed a pause button on global economic development, and induced significant mental health problems. In order to demonstrate the progressed relationship between the pandemic, economic slowdown, and mental health burden, we overviewed the global-level gross domestic product changes and mental problems variation since the outbreak of COVID-19, and reviewed comprehensively the specific sectors influenced by the pandemic, including international trade, worldwide travel, education system, healthcare system, and individual employment. We hope to provide timely evidence to (...) help with the promotion of policymakers’ effective strategies in mitigating economic losses induced by the pandemic; we suggest different governments or policy makers in different countries to share information and experience in dealing with COVID-19-induced economic slowdown and promote COVID-19 vaccine popularization plan to protect every individual worldwide against the coronavirus essentially; and we appeal international information share and collaboration to minimize stigmatization related to adverse mental consequences of COVID-19 and to increase mental health wellbeings of people all over the world. (shrink)

This Article studies the Israeli courts’ approach to choice of law in securities class actions against dual-listed companies, and its unexpected adverse effects on Israeli shareholders. Israeli courts apply American law to dual-listed companies, as an inducement for companies to list their shares for trade on the Tel Aviv stock exchange. However, one of the outcomes of this choice was to enable American attorneys to include Israeli-traded shares in American securities class actions. The Article claims that this outcome (...) might undermine Israeli shareholders’ rights and reduce their expected compensation. (shrink)