Abstract: In the twenty-first century, biology faces a problem that has previously vexed other disciplines such as physics, namely the prospect that its knowledge domain could be used to generate biological agents with altered properties that enhanced their weapon potential. Biological weapons bring the additional dimension that these could be self-replicating, easy to manufacture and synthesized with commonly available expertise. This resulted in increasing concern about the type of research done and communicated, despite the fact that such research often has direct societal benefits, bringing the dual-use dilemma to biology. The conundrum of dual use research of concern was crystallized by the so-called "gain-of-function" type of experiments in which avian influenza viruses were endowed with new properties in the laboratory such as increased virulence and the capacity for mammalian transmission. After more than a decade of intensive discussion and controversy involving biological experiments with dual-use potential, there is no consensus on the issue except for the need to carry out such experiments in the safest conditions possible. In this essay, we review the topic with the hindsight of several years and suggest that instead of prescribing prohibitions and experimental limitations the focus should be on the importance of scientific questions at hand. We posit that the importance of a scientific question for medical and scientific progress provides a benchmark to determine the acceptable level of risk in biological experimentation.

Xavier Abad
Robbin Scott Weyant
Michael J Imperiale
Arturo Casadevall

A New Approach to evaluating the risk-Benefit equation for Dual-Use and Gain-of-Function research of concern

The use of technology to gain an advantage in human conflict is ancient. Iron replaced bronze in weapons and history is replete with examples of how scientific and technological advances were adapted for war and the acquisition of power. In fact, all technologies are potentially dual use. This trend accelerated with the expansion of knowledge following the scientific and industrial revolutions and affected primarily the disciplines of physics and chemistry, domains of knowledge containing information that was then immediately useful in warfare. The application of biological knowledge to conflict came later even though biological warfare also has a long history. For example, the black death that devastated medieval European society may have begun by an act of biological warfare during the siege of Caffa in 1346  (Wheelis, 2002) . British settlers to North America brought smallpox-infested blankets as "gifts" to Native Americans  (Duffy, 1951) . However, it was not until the molecular biology revolution in the late twentieth century that the potential of biology, and in particular microbiology, in biological warfare and terrorism came into focus. These fears came true with a single act of terrorism involving the mailing of anthrax spores in the U.S. in 2001, which caused several deaths and considerable disruption to government facilities such as congressional offices and the postal system  (Bush and Perez, 2012) . This act of bioterrorism catalyzed a series of events that led to greater awareness of the potential of using biological knowledge in nefarious ways, new regulations in biological research in the U.S. such as the Select Agents and Toxins list, and heighted concerns about some types of microbiology research. One of the immediate effects of the post-2001 environment was increased scrutiny of published findings, and several papers were particularly noteworthy for eliciting discussion and concern.  In 2001, researchers  in Australia showed that insertion of the gene for IL-4 into the ectromelia virus genome defeated vaccine immunity  (Jackson et al., 2001) , a report that drew immediate concerns because of its possible implication for similar effects with variola major virus. Similarly, the finding that complement inhibition potentiated variola virus virulence suggested a mechanism for enhancing its pathogenicity  (Rosengard et al., 2002) . An analysis of the U.S. milk distribution system revealed vulnerable nodes where the introduction of botulinum toxin could lead to mass casualties  (Wein and Liu, 2005) , leading to an outcry about journals publishing research that could be exploited by terrorists. Advances in molecular biology led to the chemical synthesis of poliovirus  (Cello et al., 2002)  and the reconstruction of the 1918 pandemic influenza virus  (Tumpey et al., 2005) , which greatly heightened concern about the re-introduction of extinct, controlled, and new viruses to naïve human populations. In this environment, the U.S. Government created the National Science Advisory Board for Biosecurity (NSABB) in 2005 to provide guidance on issues relating to biological risk and security. Both authors of this article were inaugural members of the NSABB and served on that board for 9 years. When the NSABB first began their deliberations, one of the major early topics was that of dual-use research in the biological sciences. This issue had previously vexed the physics community in the twentieth century as advances in physics and associated technologies had led to radar, nuclear weapons, ballistic missiles, and other military hardware. However, there was little or no precedent for similar concerns in the biological research community, especially since biological weapons were outlawed by the Biological Weapons Convention in 1972. Moreover, the term dual use, which had meant civilian and military use in the physics arena, was redefined in its application to biology by an NRC report in 2004 to mean technologies and information that had both beneficial and maleficent use  (NR Council, 2004) . Nevertheless, among the early accomplishments of the NSABB was formulating a definition for dual use research of concern (DURC), which limited the scope of worrisome work to a small subset of biological research. The NSABB also generated a set of recommendations for communicating DURC in publications and other venues. The work of the NSABB proceeded quietly and in relative obscurity until 2011 when the U.S. government learned about two submitted manuscripts reporting that highly pathogenic avian influenza virus (HPAIV) could be made mammalian transmissible by laboratory passage in ferrets, and sought an opinion from the board as to whether publication should be permitted. the Great Gain-of-Function (GOF) controversy Before considering the GOF controversy involving influenza virus, it is worthwhile reviewing what is meant by "GOF" and the limitations of the lexicon in the controversy. At the most basic level, a GOF experiment, as the name implies, is one that gives a biological entity any new property. GOF experiments can be highly beneficial and can generate pest resistant crops, microbes expressing proteins for medical therapy such as recombinant human insulin, and new cancer therapies by enhancing lymphocyte function. The controversial aspects of GOF experiments in microbiology arise when microbes are modified to have new properties that can enhance their virulence and transmissibility because such experiments raise worries about new diseases, outbreaks, pandemics, biosafety, and biosecurity. In the experience of the authors, the NSABB probably did not anticipate what a problematic dual-use paper would look like until they had the opportunity to consider the two papers that reported the gain of mammalian transmissibility for HPAIV  (Herfst et al., 2012; Imai et al., 2012) . What made the two papers highly controversial was that they reported that only a few amino acid changes were sufficient to confer mammalian transmissibility to the H5N1 HPAIV, and there was concern that this information could be used to generate a virus capable of pandemic potential with high mortality by anyone with basic molecular biology and virology skills. The NSABB initially recommended redacting the sequence information, but this was considered not feasible given the legal framework in the U.S., and the two papers  (Herfst et al., 2012; Imai et al., 2012)  were eventually published in 2012 after some modifications to the text. The arguments, counterarguments, and events surrounding that episode are described in various publications  (Berns et al., 2012a,b; Fouchier et al., 2012a) , often by the participants themselves, and will not be repeated here. The major outcome of the great GOF controversy of 2012 is that it defined and crystallized some of the issues of dual-use research in biology by providing clear examples of experiments that were of great scientific value while also raising biosecurity and biosafety concerns. Although both papers were eventually published with full information, the debate and controversy did not solve the central questions of what work should be performed moving forward and how it should be reported. In fact, the controversy erupted again in the summer of 2014 following the publication of additional papers describing other GOF experiments (e.g.,  Watanabe et al., 2014)  as well as a series of biosafety lapses at U.S. government laboratories, which led the government to impose a pause on these types of experiments with certain viruses until the NSABB could formulate new recommendations and guidelines. The pause was lifted in mid-December, 2017, alongside policy guidance about how GOF funding decisions should be made going forward. 1
 Publication Quandaries One of the most vexing questions of the problem of dual-use research is publication of scientific findings. In the U.S., the research community is guided by National Security Decision Directive (NSDD) 189, formulated in 1985 by the Reagan admini stration, which states that all fundamental research results could be published freely. In other words, there was either open publication or classification, and nothing in between. Viewed from the context of NSDD-189 the papers involved in the 2012 GOF controversy were either to be published in their entirety or classified, with the latter alternative being impractical and unfeasible since the work had been carried out in an unclassified environment. With this binary policy, redacting papers because they might contain information useful for nefarious purposes is not an option unless export control regulations are invoked [for a full discussion of the legalities involved, see NAS EM DURC report (National Academies of Sciences Engineering and Medicine, 2017)]. Consequently, when faced with GOF papers containing information that could conceivably be used to enhance the pathogenicity or transmissibility of a virus, editors and journals have almost always opted for full publication, usually requiring more details from the authors about biosafety and biosecurity methods, and often publishing an accompanying editorial emphasizing the scientifically useful aspects of the research [for examples, see  Dermody et al. (2013 Dermody et al. ( , 2014a ]. Such decisions have sometimes elicited strong criticism from members of the virology community  (Dermody et al., 2014b; Wain-Hobson, 2014a) . A more recent situation illustrates the difficult issues faced by authors, editors, and journals when publishing papers that contain DURC. In 2013, the Journal of Infectious Disease faced the quandary of receiving a paper reporting a new botulinum toxin that was resistant to neutralization by the then-available antisera. In response, the journal took the remarkable decision of publishing the paper without the toxin sequence and vowed to keep the data confidential until an antidote was available  (Casadevall et al., 2013; Dover et al., 2013; Relman, 2013; Hooper and Hirsch, 2014) . A major factor in withholding the sequence data was the realization that this toxin could be easily produced using standard techniques if the toxin sequence was available and that the availability of such a toxin might pose a major public health risk. This decision was highly controversial since without the sequence information other investigators could not verify the findings reported in the publication or begin to develop medical countermeasures. In fact, subsequent work revealed that the new toxin was indeed neutralized by available sera, thus diminishing the initial concerns  (Enserink, 2015) . On one hand, withholding the sequence information from public scrutiny was the responsible action given the potential threat, while on the other hand, such an action delayed verification of the findings and the generation of countermeasures had the threat been real. Clearly, manuscripts containing DURC pose vexing problems for journals that often must make such decisions alone. At American Society for Microbiology journals, there are protocols in place for reviewing such manuscripts and the journals have available many individuals with microbiological and safety expertise who can provide input  (Casadevall et al., 2015) . Other situations are likely to pose different challenges, but it is clear that journals are often poorly equipped to handle the difficult problems involved in publishing DURC content. In this regard, we have argued for the need of a national board that can help journals make publication decisions  (Casadevall et al., 2014) , although to date no such body exists. Another major challenge to the control of DURC information is the emergence of preprint servers in biology that allow the posting of research findings before peer review and the proliferation of predatory open access journals that will publish essentially any paper for a fee. Consequently, there now exist alternative systems for publication even if standard journals decline to publish a particular article over DURC concerns. Bypassing traditional publication methods could also allow authors to avoid government scrutiny.
 the situation today It is not an exaggeration that the situation today regarding DURC and GOF experiments remains highly unsatisfactory. Experimental work involving GOF experiments on pathogens with pandemic potential is highly regulated with proponents of such work arguing that restrictions on experimental design are unwarranted  (Fouchier et al., 2012b)  while opponents of such experiments argue that such work cannot be justified (Wain-Hobson, 2014a,b). Proponents of GOF experiments have noted that data generated in such experiments is useful in epidemiological surveillance (Schultz-Cherry et al., 2014), whereas opponents have argued that such work cannot be morally justified because of its inherent risk  (Lipsitch and Galvani, 2014) . In the U.S., government-mandated pauses on certain types of experiments remain in effect for federally funded research but such prohibitions do not extend to other countries, or to work funded by other sources. Although the NSABB continues to analyze and debate the issues involved with DURC and GOF experiments in the U.S., there is no comparable body on the international scene, where much of this type of research is done. There is no consensus in the scientific community on whether the value of some experiments justifies the risks involved. The central problem in finding a consensus is that the value of the research cannot be measured in real time, while assessments of risk involve assumptions that can lead to widely divergent estimates. For example, some risk-benefit calculations have suggested that a high consequence accident is likely to occur in the near future  (Lipsitch and Bloom, 2012; Lipsitch and Inglesby, 2014) , while others have estimated such probabilities to be near zero  (Fouchier, 2015) . However, there is some evidence that the incessant debate, which shows no sign of resolution, is taking its toll on the virology community as shown by surveys suggesting that scientists in training may avoid these areas of research  (Pfeiffer, 2015) . This is of particular concern given that recent years have seen new viral threats in the forms of the West Africa Ebola outbreak, the emergence of Zika virus in the Americas, and Middle East Respiratory syndrome coronavirus in the Arabian peninsula, highlighting the importance of virology in human preparedness against pandemic threats  Casadevall, 2015a, 2016) . One of the most important developments in the past few decades has been a change in the zeitgeist of the field that concerns itself with DURC research and GOF experiments. In the early years of the twenty-first century, as the U.S. reeled from the 9/11 terrorist attacks, which were shortly followed by the anthrax spore attacks, the focus was primarily on biosecurity. At that time, the concern was that terrorists and state actors would use the tools of the molecular biology revolution to create new and more devastating biological weapons. However, as the years passed and no new attacks developed, combined with the attribution of the anthrax spores in mail attacks to a lone insider in a U.S. government laboratory  (Bhattacharjee and Enserink, 2008) , this security threat appeared to recede. At the same time, a series of unfortunate biosafety lapses in government laboratories heightened concerns about biosafety. Hence, today people (at least those outside the security community) appear to be more worried about an unintended release of a pathogen with pandemic potential than a deliberate biological attack. This change in emphasis from biosecurity to biosafety has developed slowly and could easily change if there is another deliberate biological attack or if becomes apparent that adversaries are developing biological weapons. A major problem contributing to the unsatisfactory nature of the current situation is that the NSABB definition of DURC does not work well in day-to-day practice. The NSABB defined DURC as "life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security. " Although the crafting of this definition was a major achievement at the time in being able to limit the scope of DURC to a relatively small portion of biomedical research, thus leaving most biological research to proceed unfettered, subsequent experience showed that the clause "reasonably anticipated" is so subjective in nature that it requires a risk assessment beyond the capabilities of most scientists, reviewers, and editors  (Casadevall et al., 2014) . In essence, the definition was helpful in keeping whole swaths of biological research outside the DURC category, such as cancer and immunology research, but it difficult to apply in determining what is included in the DURC definition. Also contributing to an unsatisfactory situation are concerns whether such regulations as the Select Agents and Toxins list help or hinder societal security. On one hand, placing great restrictions on the accessibility to a number of agents and toxins does increase security by making them more difficult to obtain, with the caveat that these are naturally occurring agents that could be obtained from nature by a determined actor. On the other hand, there is the concern that focusing on lists and a relatively short list of agents means that the overwhelming majority of microbial threats are not on the DURC radar screen. For example, Zika virus emerged as a pathogen of pandemic potential with little or no anticipation from experts. Hence, making lists and focusing attention on those agents in the list has the paradoxical potential to reduce biosecurity since regulations are tightened for listed agents, possibly hindering research, while other dangerous agents are neglected  (Casadevall and Relman, 2010) . A similar argument applies to the current DURC oversight policy of the U.S. government, which is focused on a specific list of agents. 2 This process, which is akin to searching under the lamppost, carries great danger because it ignores what could be significant threats. In this regard, it is noteworthy that fungal pathogens are seldom considered as biological threats despite the fact that members of this kingdom have significant weapon potential  (Casadevall and Pirofski, 2006; Casadevall, 2017) . Against this backdrop of dissatisfaction is the fact that science continues to progress very rapidly, introducing new technologies such CRISPR/Cas9, gene drives, and more efficient synthetic biology, each of which brings with it new possibilities for research that improves the human condition as well as new tools for nefarious purposes. Furthermore, as the technologies improve they are increasingly accessible to more individuals and countries for whom this type of research was previously beyond reach. Hence, the problem of DURC is likely to become significantly more urgent in the near future.
 the Way Forward In a world where new infectious agents that can rapidly spread among vulnerable populations are described on a regular basis, humanity needs a healthy research establishment focused on microbial threats. It is estimated that there are a minimum of 320,000 mammalian viruses  (Anthony et al., 2013) : some fraction of these are probably zoonotic events waiting to happen. As Ian Malcolm, the fictional character created by Michael Crichton in the novel Jurassic Park, stated, "Life finds a way. " Information and knowledge are the best defenses against these threats. In addition to terror from nature, a new crisis will almost certainly occur in the future arising from a deliberate attack, a new provocative paper, or another biosafety lapse. GOF experiments and DURC research are essential for preparedness and the question is not whether this research should be pursued but rather how to do it safely and mitigate risk. To date, each of the controversies has been reactive, with proponents and opponents of such experiments responding to a specific finding or study. After more than a decade of discussion on what constitutes DURC, benefits and risks of GOF experiments, regulations, pauses, and moratoriums, it is increasingly apparent that current approaches are inadequate for the challenges at hand. Given these limitations, we have proposed a new framework for DURC research that focuses on answering specific questions  (Imperiale and Casadevall, 2015b) . Hence, instead of prohibiting certain types of experimentation, we suggest that the way forward is to focus on specific scientific questions and the problems that need answers. For example, if there is a need to determine whether a particular feral virus pathogen has the capacity for mammalian infection and transmission, then GOF experiments performed in safe and controlled conditions can be justified. On the other hand, endowing HIV with new transmission properties is not a medically important GOF experiment (National Academies of Sciences Engineering and Medicine, 2017). All human activities that involve probing the unknown, ranging from space exploration to tissue culture procedures, carry some degree of risk, and it is nature of humanity to accept risk to attain progress. Opponents and proponents of this type of experimentation need to maintain open channels for continued discussion because the dialectic of ideas is likely to result in better decisions. Institutional bodies such as the NSABB need to be supported for they constitute important venues for such discussion and recommendations that mitigate risk. In fact, it is important to create similar institutions that can work at the international level since U.S.-based research is a small portion of all microbiological work done worldwide. Most importantly, we should remain optimistic that the research community can do the research necessary to obtain information critical to protect our species while minimizing the risks of such work. 			 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-071.html.
			 https://www.phe.gov/s3/dualuse/documents/us-policy-durc-032812.pdf.


Abstract: A recent article by Beard, Rowe, and Fox (BRF) evaluates ten methodologies for quantifying the probability of existential catastrophe. This article builds on BRF's valuable contribution. First, this article describes the conceptual and mathematical relationship between the probability of existential catastrophe and the severity of events that could result in existential catastrophe. It discusses complications in this relationship arising from catastrophes occurring at different speeds and from multiple concurrent catastrophes. Second, this article revisits the ten BRF methodologies, finding an inverse relationship between a methodology's ease of use and the quality of results it produces-in other words, achieving a higher quality of analysis will in general require a larger investment in analysis. Third, the manuscript discusses the role of probability quantification in the management of existential risks, describing why the probability is only sometimes needed for decision-making and arguing that analyses should support realworld risk management decisions and not just be academic exercises. If the findings of this article are taken into account, together with BRF's evaluations of specific methodologies, then risk analyses of existential catastrophe may tend to be more successful at understanding and reducing the risks.

Quantifying the probability of existential catastrophe: A reply to Beard et al

Introduction A recent article by  Beard, Rowe, and Fox (Beard, Rowe, & Fox, 2020; henceforth BRF)  surveys methods used to quantify the probabilities of global and existential catastrophes. BRF is a valuable contribution to the study of global catastrophic risk and existential risk. It documents the range of methods in use and evaluates their strengths and limitations, providing both a good resource for researchers wishing to get up to speed on the topic and constructive guidance for future work. In this article, I provide some further commentary on the quantification of the probability of global/existential catastrophe, making some points not made by BRF or other prior literature. At the outset, I wish to express my wholehearted agreement with BRF in the importance of sound methodology for quantifying the probabilities (and severities) of global and existential catastrophes. I regret that I share the view that "within the nascent field of Existential Risk research people have been insufficiently discriminating" in the selection and use of quantification methods (BRF, Section 7). The following remarks join BRF in seeking to improve this situation. 2. Some considerations related to severity 2.1. The definition of existential catastrophe BRF defines existential catastrophe as "the collapse of civilization or the extinction of humanity". This is a reasonable definition, but there are others. First,  Bostrom (2002)  defines existential catastrophe as an event that "would either annihilate Earth-originating intelligent life or permanently and drastically curtail its potential". This definition emphasizes long-term effects. The collapse of civilization would presumably have some long-term effects, though whether the effects would last into the distant future is a complex matter  (Baum et al., 2019) . Second,  Tonn and Stiefel (2013)  define existential catastrophe as human extinction, i.e. loss of the existence of the human species. This paper will use the BRF definition while noting the existence of other definitions for existential catastrophe, for related concepts involving large losses of value such as global catastrophe  (Morrison, 1992) , ultimate harm  (Persson & Savulescu, 2012) , and oblivion  (Tonn, 1999) , and for other concepts involving large-scale harm such as astronomical suffering  (Sotala & Gloor, 2017) .
 Probability vs. severity BRF focuses on methodology for quantifying the probability of existential catastrophe, with limited attention other factors including severity. (This focus was an explicit decision; see BRF, Section 1) That is not unreasonable for a first pass at the topic-there is plenty to say about the probability methodology. However, it is important to recognize the interplay between probability and severity. All quantifications of the probability of existential catastrophe require at least some attention to severity for the simple reason that existential catastrophe is a type of event defined by its severity. More precisely, existential catastrophe is generally defined in terms of some minimum severity threshold; in BRF, the minimum threshold is the collapse of civilization. To assess the probability of existential catastrophe is to assess the probability of a harm greater or equal to the collapse of civilization. In the terminology of catastrophe risk analysis, the probability of existential catastrophe is an "exceedance probability", i.e. the probability of harms exceeding some minimum threshold  (Grossi, Kunreuther, & Windeler, 2005) . Quantifying the probability of specific existential catastrophe events (such as a nuclear war or Earth-asteroid collision) requires additional attention to severity. The probability can be decomposed into two constituent parts as follows: = P P P * EC 1 2 (1) In Eq. (  1 ), P EC is the probability of existential catastrophe from some event; P 1 is the probability of the initial catastrophe event; and P 2 is the probability that the event will result in a harm greater or equal to the collapse of civilization. For example, P 1 could represent the probability of nuclear war and P 2 could represent the probability that nuclear war would result in the collapse of civilization or worse. The occurrence of the initial catastrophe event does not necessarily entail the collapse of civilization-that depends on how effectively the survivors can cope with the aftermath of the event. Calculating P EC via Eq. (  1 ) requires two distinct analyses: one for each of P 1 and P 2 . Analysis of P 1 is the analysis of the probability of initial events, and can follow many conventions of probabilistic risk analysis. In contrast, quantifying P 2 requires analysis of the severity, with attention to the success of catastrophe survivors. This is a rather different sort of analysis than is needed to quantify the probability of initial catastrophe events represented by P 1 . However, P 2 is not equivalent to severity. P 2 is a probability variable representing the probability that the severity will exceed a certain threshold. P 2 can be obtained by creating a probability distribution for the severity of an initial event and then calculating the portion of that distribution that exceeds the threshold for existential catastrophe: ∫ = ∂ ∞ P P S S ( ) 2 ST (2) In Eq. (  2 ), P 2 is as in Eq. (  1 ); S is severity of some initial event; and S T is the minimum severity threshold of existential catastrophe Fig.  1 . A depiction of the relationship between P 2 and the severity of an initial event. The graphic is for illustrative purposes only; no evaluation of the actual relationship is intended. (the collapse of civilization in BRF). Eq. (  2 ) is illustrated in Fig.  1 . The studies surveyed in BRF vary in terms of which probabilities they quantify. (BRF acknowledges this; see BRF, Section 1) Out of the 66 studies in BRF, only three-  Chapman (2004) ;  Rees (2003), and Wells (2009) -explicitly quantify the probability of civilization collapse (as obtained from a keyword search of BRF, Appendix A). Of the other 63 studies, some quantify P 1 , while others quantify something similar to P EC but with a different severity threshold.  Chapman (2004)  is the only one of these studies that quantifies P EC via something resembling Eq. (1).  Chapman (2004)  is a study of asteroid impacts. As with many asteroid risk analyses,  Chapman (2004)  quantifies impact probability as a function of asteroid diameter (see Fig.  1  of  Chapman, 2004) . This provides P 1 .  Chapman (2004)  then proposes that asteroids of 2−3 km diameter may qualify as "civilization destroyers", while noting that the "predictions of consequences are fraught with uncertainty" (p.11; see also  Baum, 2018) . This roughly amounts to postulating that P 2 ≈ 0 for asteroids smaller than 2−3 km diameter and P 2 ≈ 1 for asteroids 2−3 km diameter or larger. However, there is no reason to expect such an extreme discontinuity in P 2 at 2−3 km. A more careful analysis would likely display a distribution of severities (as in Fig.  1 ) across a range of asteroid sizes, finding a continuum of P 2 values that gradually increase as a function of asteroid size. Until such analysis is conducted, one cannot rigorously quantify P EC for asteroid impact. Given that impact probability varies widely as a function of diameter (smaller asteroids have a much higher impact probability), P EC for asteroid impact will be highly sensitive to the resilience of civilization to impact events of different sizes. Similar reasoning applies to other existential risks. The study of  Wells (2009) , p.84-90) is of note because it quantifies P EC directly, without considering P 1 and P 2 . It can do this because is quantifies the overall P EC , not P EC for specific events. The analysis uses a technique that quantifies the probability of something persisting based on how long it has already existed for. Given the current age of civilization, P EC can be calculated.  Wells (2009)  also uses this technique to calculate the probability of human extinction, as do several other studies including  Gott (1993) . Because this technique does not consider any particulars of the existential risks that civilization currently faces, it provides at most a very limited amount of guidance to how the risks can be addressed. The study of  Rees (2003, p.8 ) is more ambiguous. Rees provides a subjective estimate of P EC , stating "I think the odds are no better than fifty-fifty that our present civilization on Earth will survive to the end of the present century". The text does not explain how the estimate was made. The broader study presented by  Rees (2003)  includes reasoning similar to  Wells (2009)  and analysis of catastrophe scenarios similar to  Chapman (2004) . Perhaps the subjective estimate was made in consideration both approaches, but this cannot be discerned from the text. The studies that quantify P 1 are not studies of the probability of existential catastrophe: they are studies of the probability of events that might or might not result in existential catastrophe. For example,  Lipsitch and Inglesby (2014)  quantify the probability that a highly pathogenic influenza strain would escape a research laboratory and cause a pandemic.  Lipsitch and Inglesby (2014)  also quantify the severity of the pandemic, estimating 2 million to 1.4 billion fatalities. To calculate P 2 and in turn P EC , this range of severities would have to be evaluated in terms of the probability of exceeding S T .  Hellman (2008)  quantifies the probability of a "fullscale nuclear war" started from a crisis similar to the Cuban missile crisis.  Hellman (2008)  does not quantify the severity and would need to do so to obtain P 2 and P EC . For the studies that quantify something analogous to P EC , analysis of additional scenarios is needed to obtain P EC . For example,  Gott (1993)  quantifies the probability of human extinction; additional analysis would quantify the probability of civilization collapsing without humanity going extinct.  Pamlin and Armstrong (2015)  quantify the probability of the subset of civilization collapse scenarios in which there is no subsequent recovery of civilization; additional analysis would quantify the probability of scenarios in which civilization collapses and recovers. Here it is worth recalling the multitude of definitions of existential catastrophe. The studies of  Gott (1993)  and  Pamlin and Armstrong (2015)  could classify as quantifying P EC under non-BRF definitions.
 Fast vs. slow catastrophes Existential risks can be classified in terms of how quickly the catastrophe unfolds. Specifically, it is the initial catastrophe event that unfolds at different speeds. The initial catastrophe event is the phenomenon that causes the harm, such as a nuclear war or Earthasteroid collision; it is represented in P 1 in Eq. (  1 ). The overall catastrophe scenario also includes the aftermath of the initial event. All existential catastrophes could have long-lasting effects, especially if civilization is not quickly rebuilt after it collapses. Nonetheless, the speed of initial events can vary significantly between different existential risks. The risks included in BRF group into either fast or slow risks. Fast risks have initial events that occur within years or less. Fast risks included in BRF are nuclear war, pandemics, runaway artificial intelligence, asteroid impacts, nanotechnology, particle physics experiments, space weather, super-volcanic eruptions, and synthetic biology. Slow risks have initial events that persist for decades or longer. Slow risks included in BRF are climate change and ecological catastrophe (see BRF, Appendix A; note that the fast vs. slow distinction is my own and does not appear in BRF). This is overall a reasonable list of risks and broadly consistent with other studies of existential risk. The list is not without exceptions-for example, flood basalt volcanic eruptions consist of a series of large eruptions over a period of hundreds of thousands of years; if the eruptions are sufficiently large and frequent, they could cause more prolonged harm  (Schmidt et al., 2016)  and therefore rate as a slow catastrophe. As another example, studies of artificial intelligence sometimes consider that the event could unfold in a "slow takeoff" lasting on the order of "decades or centuries"  (Bostrom, 2014, p.63) . Regardless, for probability analysis, the distinction between fast and slow is important in several respects. (The distinction can also be important for other reasons beyond the scope of this paper, such as policy decision-making.) First, event probability P 1 can have a different meaning for slow risks. The probability of climate change is approximately 1 (i.e., it is virtually certain that climate change is occurring). The only meaningful uncertainty about climate change risk is about how severe the impacts will end up being, including whether they would amount to existential catastrophe. The same probably applies to the forms of ecological degradation that could result in ecological catastrophe, though the reference cited in BRF on ecological catastrophe  (Pamlin & Armstrong, 2015)  is unclear on this point. Second, slow catastrophes may be especially important when they interact with fast catastrophes. Climate change and ecological degradation may be unlikely to destroy civilization on their own. Instead, they could weaken civilization, making it less resilient to fast catastrophes. All else equal, climate change and ecological degradation may make it more likely that civilization survives a fast catastrophe (such as a nuclear war) if the fast catastrophe occurs in 2020 instead of 2050. (All else is not equal-other factors include, but are not limited to, economic and technological change.) In other words, climate change and ecological degradation increases P 2 for nuclear war (and other fast risks). They could also affect P 1 , such as by destabilizing international politics, or alternatively by providing a rallying point that brings rival nations closer together. Additionally, fast catastrophes could also affect slow catastrophes. For example, the 2011 Fukushima Daiichi nuclear disaster, caused by the Tōhoku earthquake and tsunami, has prompted a shift from nuclear power to fossil fuels, thereby worsening climate change  (Srinivasan & Rethinaraj, 2013) . While the Tōhoku-Fukushima event was only a local catastrophe, the episode is nonetheless indicative of potential impacts of fast catastrophes on slow catastrophes. The above implies that the probability of slow catastrophe can be linked to the probability of fast catastrophe. This applies to most of the risks in BRF. One potential exception is particle physics experiments, for which P 1 may not be meaningfully affected by the slow catastrophes and for which P 2 may 1 under any circumstances (it may be impossible to survive a particle physics catastrophe). Artificial intelligence could be another exception following the same reasoning, though it is conceivable that AI development could be altered by the desire to develop AI to address the slow catastrophes  (Baum, 2014) , or by effects of slow catastrophes on the context in which AI is developed, such as related to international cooperation and competition. But for most cases, quantifying the probability of slow catastrophes should account for their effect on fast catastrophes. It has been argued that the field of existential risk is insufficiently attentive to slow catastrophes, perhaps because slow catastrophes are too "boring" or "unsexy"  (Kuhlemann, 2019; Liu, Lauta, & Maas, 2018) . My own view is that yes, slow catastrophes have been at least somewhat neglected in studies of existential risk. But it is also the case that slow catastrophes pose distinct analytical challenges, as outlined above. Furthermore, the fields dedicated to studying slow catastrophes tend to not study them in terms resembling existential risk. For example, high-profile research on planetary boundaries identifies approximately ten major global environmental threats that are nominally supposed to be unacceptable to humanity, but are defined in the research strictly in biogeophysical terms and not in terms of impacts to humanity  (Baum & Handoh, 2014) . Likewise, almost all of the studies of slow catastrophes studied in BRF (Section 1) focus on biogeophysical metrics, in particular the magnitude of average global temperature increase from climate change. The one exception is  Pamlin and Armstrong (2015) , which is also probably the only of these studies that classifies within the field of existential risk. (BRF defines the existential risk research community as "those who are consciously seeking to align their research with the goal of understanding and managing such risks".) There is a major need for research that blends the traditions of global environmental change and existential risk to analyze, in human terms, the risks of slow catastrophes.
 Multi-risk catastrophes The preceding discussion of slow vs. fast catastrophes raises a more general point. The literature surveyed in BRF consists exclusively of quantifications of specific risks or quantification of the overall probability of existential catastrophe or similar catastrophe. However, some catastrophe scenarios involve multiple risks. These scenarios can require a different set of methods than those surveyed in BRF. One type of scenario involves multiple initial catastrophe events occurring together by coincidence. For example, there could be a volcano eruption that happens to occur as a pandemic is breaking out. The initial events may be independent-for example, there is no reason to believe that infectious diseases affect plate tectonics and vice versa-in which case their probabilities (P 1 in Eq. (  1 )) could be modeled as independent random variables, with the aggregate initial event probability calculated accordingly. However, the probability of existential catastrophe given the co-occurrence of these events (P 2 in Eq. (  1 )) is unlikely to be independent. For example, a volcano eruption can prompt mass evacuations that facilitate disease transmission. Analysis of the severity of co-occurring initial catastrophe events must be done on a case-by-case basis; ditto for the accompanying probability of of existential catastrophe. Another type of scenario involves causal relations between multiple fast catastrophes. For example, there could be a war or pandemic that causes a geoengineering termination shock  (Baum, Maher, & Haqq-Misra, 2013; Parker & Irvine, 2018) , an asteroid collision that causes a nuclear war  (Baum, 2018; Tagliaferri, Spalding, Jacobs, Worden, & Erlich, 1994) , or a war that induces risky technology development (as previously occurred in World War II with the development of nuclear weapons). These scenarios cannot be modeled as independent random variables. They can be modeled using fault trees or Bayesian networks, albeit with more complex models that account for the nuances of each catastrophe within the causal chain. In principle, they could be studied via aggregated opinion surveys, weighted aggregation, or enhanced solicitation, all of which derive from expert judgment. In practice, however, there may be a dearth of qualified experts, because experts tend to focus on one risk at a time and not on the causal relations between them. (The methods mentioned in this paragraph are described in Section 3) Finally, there are scenarios in which a fast catastrophe occurs during a slow catastrophe, as discussed in Section 2.3. Analysis of these scenarios could proceed by evaluating "baseline" values of P 1 and P 2 for the fast catastrophe, and then evaluating the effects of the slow catastrophe on the baseline P 1 and P 2 . Alternatively, it could proceed by calculating scenario probabilities directly without first considering baselines. Regardless, the analysis requires a nuanced understanding of the impacts of the slow catastrophe as they relate to the onset and impacts of the fast catastrophe. (Other slow factors, such as economic and technological change, can be factored into the analysis alongside slow catastrophes.) 3. On the methods surveyed by BRF BRF survey ten methods used for quantifying existential catastrophe: 1 Analytical approachesestimating probability from theory without incorporating specific evidence on the risks, such as in the "doomsday argument". 2 Extrapolation and toy modelingsimple models that derive probabilities from data on other events on the assumption of an inherent relationship between the probability of the other events and existential catastrophe (noting that no existential catastrophe has previously occurred). 3 Fault treeslogic trees that decompose types of catastrophe events (e.g., nuclear war) into a collection of sequences of precursor events and conditions that can lead to the catastrophe event. 4 Bayesian networkssimilar to fault trees, except also permitting interactions between precursor events (hence a "network" instead of a "tree"). 5 Adapting large-scale modelsthe models depict details of specific risks (e.g., models of the global climate system to study climate change risk); these models are adapted to study extreme cases of these risks. 6 Individual subjective opinionsubjective judgments of a single person. 7 Aggregated opinion surveyssubjective judgments of multiple people, averaged into a single probability estimate. 8 Weighted aggregationsubjective judgments of multiple people, combined into a single probability estimate using a weighted average, with weights set according to some measure of the quality of the judgment expected from each person. 9 Enhanced solicitationsubjective judgments of multiple people, in which effort is made to improve judgment quality via some combination of training people to provide better opinions and being more careful in how their judgments are obtained. 10 Prediction marketsplatforms for people to place financial bets on their best-guess parameter estimates.
 The tradeoff between quality and accessibility BRF evaluate probability quantification methods according to four criteria: (1) rigor, defined as how effectively the method makes use of available information; (2) uncertainty, defined as how effectively the method handles the considerable uncertainty about the probability of existential catastrophe; (3) accessibility, defined as how readily a research group can apply the method, especially the small interdisciplinary groups that often study existential risk; and (4) utility, defined as the value of the method's results for decisionmaking purposes. BRF presents ratings of ten methods according to each of the four criteria. (The ratings were performed subjectively by the authors. In my own view, their ratings are reasonable.) Ideally, a method would rate well across all four criteria. Unfortunately, none of the methods surveyed by BRF achieve this. The BRF ratings data show a trend in which rigor, uncertainty, and utility are similar to each other and dissimilar to accessibility. Fig.  2 . Rigor vs. accessibility of each method as rated by BRF (data from BRF, Table  1 ). This trend holds across all methods (see BRF, Table  1 ). To illustrate this trend, Fig.  2  plots rigor vs. accessibility. No method is rated high in both, and only weighted aggregation is rated low in both. (More precisely, weighted aggregation is rated medium-low in rigor.) The trend in the data is entirely understandable. Rigor, uncertainty, and utility are all aspects of the quality of the probability quantification produced by the application of a particular method. Obtaining higher-quality results generally requires incorporating more detail about the risk and more nuance in how the detail is processed, both of which tend to make the method less accessible. There can be methods that are low-quality and inaccessible, though one would hope that these have gotten weeded out of the collective risk analysis toolkit. Conversely, however, it may not be possible for a method to be both high-quality and accessible. Quality analysis may inevitably require a substantial investment. The same point applies to applications of a given method. Any method can be applied in ways that are of higher or lower quality. There can be applications of a given method that are low-quality and inaccessible: a lot of resources spent implementing a method poorly. Higher quality implementations of a given method will tend to be less accessible, requiring more effort on the part of the research team, and in some cases more funding to invest in expenses such as travel to interview experts in person (instead of via phone or other mode of remote communication) or rewards to incentivize participants in prediction markets.
 On the role of existential risk quantification
 Why quantify probability (and severity)? Underlying the tradeoff between quality and accessibility is the basic point that the probabilities of potential existential catastrophe scenarios are difficult to rigorously quantify. The scenarios involve complex and unprecedented global processes. Historical data are unreliable or nonexistent. Expert judgment is often unreliable as well-or, perhaps there are no experts. Obtaining quality quantifications requires applying difficult methods, which can be a resource-intensive process in a field in which resources are scarce. Perhaps it would be better to skip the matter entirely and focus on other activities. BRF identify two major reasons to quantify the probabilities and severities of existential risks. The first is the prioritization of efforts to reduce various risks. The second is the evaluation of actions that could decrease one set of risks but increase another (i.e., risk-risk tradeoffs). Both are situations in which actions could affect multiple risks, and in which identifying the best action requires comparing the size of the effect on one set of risks to the size of the effect on another. These sizes are typically measured in terms of the product of probability and severity. Therefore, to identify the best actions in these situations, it is necessary to know the effects of the actions on the probabilities and severities of the risks in question. Quantifying the probabilities and severities is an important first step. (Additional analysis is required to assess the effects of specific actions aimed at reducing the risks, as well as the costs associated with pursuing these actions.) Quantification is not always necessary. Some actions would only affect one risk, or would affect multiple risks in the same direction (increase or decrease). These actions pose no tradeoff and require no quantification to evaluate. Where possible, it can be more efficient to focus on these actions. Indeed, one approach to handling difficult quantification tradeoffs is to search for actions that avoid the tradeoffs.  Graham and Wiener (1995)  refer to these as "risk-superior" options, analogous to the concept of Pareto superiority in welfare economics. An "existential-risk-superior" option would be one that reduces all existential risks by at least as much as all other options, and reduces at least one existential risk by more than each other option, such that there is reason to favor the existential-risk-superior option and no reason to favor any other option, setting aside reasons unrelated to existential risk. If existential-risk-superior options are identified, there is no further need to quantify the options, because one option is clearly best. However, even then, some quantification may be needed to identify existential-risk-superior options. And in many other cases, there are no existential-risk-superior options. Tradeoffs are inevitable. Quantification is an important research task, however difficult it may be.
 Analysis vs. decision-making Some further perspective can be obtained from considering the relationship between analysis and decision-making. Arguably, analysis of the probability and severity of existential catastrophe should aim to improve the quality of decisions that affect existential risk. Otherwise, the analysis is of mere intellectual interest. Reducing existential risk is (again, arguably) a moral imperative, not an intellectual curiosity. Analysis can improve decisions by enabling the decisions to result in larger reductions in the risk. Phrased differently, the expected value of the action taken is larger with the analysis than without. This is the essence of the concept of the value of information (e.g.,  Barrett, 2017) . Analysis can be valuable even if the action taken is unchanged. As a toy example, perhaps heads would have been chosen in a coin flip anyway, but it would have been a lucky guess, and so there is value in analysis indicating that the coin was indeed going to land on heads. The same reasoning holds for analysis about more complex decisions, including those about existential risk. But decisions do not occur in a theoretical vacuum, and they do not necessarily conform to the ideals of expected value maximization. Decisions are psychological and (often, especially for the most important decisions) social processes. In order to be most useful for reducing the risks, methodology for quantifying probabilities and severities should be designed with the nuances of actual decision processes in mind. This point is captured somewhat by the BRF concept of method utility, but some further elaboration is warranted. A lot of risk analysis is commissioned by clients who seek to use the analysis in their own decision-making. The field of risk analysis has roots in industry, especially nuclear power  (Thompson, Deisler, & Schwing, 2005; Wilson, 2012) . Engineering risk analysis commonly seeks to guide in-house safety decisions of industrial risk managers or regulatory decisions by policy makers at agencies like the US Environmental Protection Agency and Nuclear Regulatory Commission. For this, quantifying the overall probability of some catastrophe can be less important than identifying the specific system components that are most implicated in the risk and likewise in greatest need of attention. This is one reason that engineering risk analysis has gravitated toward methods like fault trees that decompose risks into constituent parts and therefore produce results that help managers focus on specific problems. Existential risk research is less often commissioned by clients. Instead, it is often sponsored philanthropically, whether by private funders or government agencies. The funders do not seek results that they can use for their own decisions. Instead, they wish to support the cause of existential risk reduction and hope that the analysis will in some way be useful to that end. Without decisionmaker clients, existential risk analysis projects must take additional steps to ensure that their analysis improves decision-making, including identifying decision-makers to support. Because of this, there is a greater risk of the analysis working in an academic fashion, disconnected from practical decision-making and not having constructive impact on the risks themselves. (Existential risk is not the only domain in which research lacks decision-maker clients. Another example is research by industry and environmental public interest groups that seek to inform environmental policy; von  Winterfeldt, Kavet, Peck, Mohan, & Hazen, 2012.)  Nonetheless, even without built-in decision-maker clients, it is still important for existential risk analysts to bear in mind how their analysis could be used for decision-making. That means recognizing that there is more to risk management than just numbers for probability and severity. The details of the risks themselves must be understood, and how potential actions can affect the risks, and the psychological and social and institutional contexts in which decisions will be made. This is a lot to account for-as if the probabilities and severities were not a lot on their own-but it is essential for pursuing actual reductions in existential risk and not just academic studies. It can help to recognize that risk analysis can be valuable even if it does not produce any quantification of probability and severity. Often, simply having an analysis that pulls together information about the risk in an intuitive and well-organized fashion is sufficient for improving risk management. In other words, risk analysis can be of value by improving people's mental models of risks, in addition to providing information on the rating or ranking of decision options. Additionally, risk analysis can be of value by creating an opportunity for stakeholders and experts to share risk-related information with each other in a way that crosses typical organizational barriers. The opportunity for people in different groups to talk through key issues affecting risk can be of significant valuable for the practice of risk management, even regardless of formal risk analysis outputs. It is important to not let the pursuit of numbers (of probability, severity, the timing of future events such as AI milestones, etc.) serve as a distraction from the goals of evaluating decision options and improving our understanding and management of the risks. In sum, quantifying probability and severity should be at most only one part of an overall existential risk analysis and management portfolio. But it is still a part, and an important one at that. It is likewise important to use quality methodology in performing the quantifications.
 Conclusion This article has sought to build on the excellent contribution of BRF to provide further perspective on the quantification of the probability of existential catastrophe. This article finds that the probability of existential catastrophe is inherently linked to the severity of events that could result in existential catastrophe, that achieving a higher quality of analysis of the probability will in general require a larger investment in analysis, that analysis of the probability is sometimes but not always necessary for decisionmaking, and that analysis should be designed to support risk management and not just designed as an academic exercise. If these findings are taken into account, together with the analyses of specific methodologies by BRF, then it is believed that risk analyses of existential catastrophe will tend to be more successful at understanding and reducing the risks.


Abstract: In an increasingly complex information society, demands for cognitive functioning are growing steadily. In recent years, numerous strategies to augment brain function have been proposed. Evidence for their efficacy (or lack thereof) and side effects has prompted discussions about ethical, societal, and medical implications. In the public debate, cognitive enhancement is often seen as a monolithic phenomenon. On a closer look, however, cognitive enhancement turns out to be a multifaceted concept: There is not one cognitive enhancer that augments brain function per se, but a great variety of interventions that can be clustered into biochemical, physical, and behavioral enhancement strategies. These cognitive enhancers differ in their mode of action, the cognitive domain they target, the time scale they work on, their availability and side effects, and how they differentially affect different groups of subjects. Here we disentangle the dimensions of cognitive enhancement, review prominent examples of cognitive enhancers that differ across these dimensions, and thereby provide a framework for both theoretical discussions and empirical research.

Martin Dresler
Anders Sandberg
Christoph Bublitz
Kathrin Ohla
Carlos Trenado
Aleksandra Mroczko-Wąsowicz
○,◆ Simone Kuḧn
Dimitris Repantis

Hacking the Brain: Dimensions of Cognitive Enhancement

INTRODUCTION An increasingly complex world exerts increasing demands on cognitive functionsfunctions that evolved for a fundamentally different environment. Daily life in an information society and a postindustrial economy require cognitive skills that have to be acquired through slow, effortful, and expensive processes of education and training. Likewise, these skills can become obsolete as the world changes ever faster or be lost by the processes of aging. People also vary in their mental abilities, allowing them to acquire certain skills more quickly or slower, which may have significant effects on life outcomes. Strategies to improve the acquisition and maintenance of cognitive skills are thus increasingly important on both an individual and societal level. These challenges of our times have fostered the See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. exploration of strategies to enhance human brain function. While people have since time immemorial sought to improve their performance, the present era is unique in that not only the challenges are growing rapidly but so are technologies that promise to meet them. Just like the hacking culture in the realm of computer software and hardware, an increasing number of individuals experiment with strategies to creatively overcome the natural limitations of human cognitive capacityin other words, to hack brain function. This development has led to both enthusiasm and dread, as observers have sharply differing intuitions about the feasibility, utility, risks, and eventual impact of enhancement technologies on the world. One reason for the often polarized debates has been the lack of hard evidence. Without empirical findings, it is easy to maintain any position, as well as regard opponents as having unfounded views. A further essential source of disagreement and theoretical confusion is a tendency to view enhancement as a unitary phenomenon to be judged as a whole, rather than as a broad set of techniques with important differences and diverging implications. Only on the basis of a clear picture on how a particular enhancement strategy might affect specific cognitive processes in specific populations, along with side effects and costs to be expected, an informed theoretical debate can evolve and a promising empirical research designs to test the strategy can be proposed. In the following, we aim to elucidate seven essential dimension of cognitive enhancement, namely, (a) its mode of action, (b) the cognitive domain targeted, (c) personal factors, (d) its time scale, (e) side effects, (f) availability, and (g) social acceptance (see Figure  1 ). Further, we will review empirical data of prominent examples of cognitive enhancers that differ across these dimensions and thereby illustrate some of their nuanced implications. The aim of our Review is to sketch a general framework that will foster both theoretical discussions and empirical research.
 MODE OF ACTION A widely cited definition characterizes enhancement as interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health.  1  While the current bioethical debate on cognitive enhancement is strongly focused on pharmacological ways of enhancement, improving mental capabilities also by nonpharmacological means has to be considered as cognitive enhancement proper according to the given characterization. We have reviewed elsewhere the efficacy of a number of nonpharmacological enhancers.  2, 3  To systematize the vast variety of different approaches of cognitive enhancement, we suggest clustering enhancement strategies into three major areas according to their main mode of action. Even though boundaries are not strict, most cognitive enhancement strategies can be considered to work as either biochemical, physical, or behavioral interventions (Figure  2 ). In the following, we will give an overview on the different cognitive enhancement strategies within these clusters.
 Biochemical Strategies. The prototypical cognitive enhancers addressed in the public debate are biochemical agents. However, biochemical interventions are not restricted to pharmaceutical "smart drugs". Also application of ordinary substances such as oxygen has been shown to increase, e.g., memory processes  4, 5  and neural activation in memory-related brain regions.  6  Biochemical enhancers with the longest tradition in human history are strategies to make use of certain nutritional components. Most widely used are probably glucose  7  and caffeine,  8, 9  which both have demonstrated cognition-enhancing effects in numerous studies. In addition to coffee, other beverages from caffeine-bearing plants such as guarana have shown to enhance cognition.  10  While the noncaffeine components in caffeine-bearing plants might exert independent effects on cognition,  11  it has been doubted that industrially designed drinks contain cognitive enhancing components that go beyond caffeine, glucose, or guarana extract.  12  Further nutritional components with some evidence for cognitive enhancing effects are flavonoids, e.g., in cocoa,  13, 14  curry powder (most likely due to the curcumin that it contains,  15, 16  folic acid,  17  or omega-3 fatty acids.  18  Besides specific dietary supplements, also the absence of food might enhance cognition: some evidence has been reported that fasting and general caloric restriction might improve memory in elderly individuals.  19, 20  Also certain traditional natural remedies have been discussed as cognitive enhancers: besides herbs that also grow in Western regions such as salvia,  21  particularly traditional Chinese and
 ACS Chemical Neuroscience
 Review Indian herbal medicines such as Bacopa monnieri have been ascribed with cognitive enhancing effects.  22, 23  However, with ginseng and ginkgo biloba, the most prominent examples of such traditional Asian herbal remedies so far have failed to consistently show positive effects on cognitive functions in healthy individuals.  24, 25  A further biochemical intervention with a long history concerns drugs that are being used recreationally and that have demonstrated the potential to enhance certain cognitive functions. For example, nicotine improves attention and memory,  26−28  and even alcohol, despite impairing many cognitive functions, might enhance others such as creative processes  29, 30  or, retroactively, memory.  31  Pharmaceuticals are in particular by the public regarded as prototypical cognitive enhancers: synthetic stimulants such as amphetamine, methylphenidate, or modafinil, or antidementia drugs such as acetylcholinesterase inhibitors and memantine are at the core of public debate on cognitive enhancement. However, evidence for their efficacy for augmenting brain function and cognition in healthy subjects is often markedly lower than assumed in theoretical discussions.  32−37  Importantly, the lack of an objective effect on cognition can be accompanied by a considerable placebo effect: for example, users who believed to have received mixed-amphetamine salts subjectively rated themselves as performing better and even show minor objective performance increases, independent of actual medication state.  38  While pharmacological enhancers are typically designed to affect or mimic certain neurotransmitters, also neural signaling molecules themselves such as adrenaline,  39  GABA,  40  glucocorticoids,  41  ovarian hormones,  42  and different neuropeptides  43−45  have been suggested as cognitive enhancers. A further biochemical strategy for cognitive enhancement consists of genetic modifications, which have been demonstrated to augment several learning and memory processes in animal models.  46−51  Although progress has also been made in elucidating the genetic basis of cognitive traits in humans,  52  genetic modifications in humans still have to be considered as future strategies rather than currently available enhancement options. 2.2. Physical Strategies. The current most widely discussed physical strategies for cognitive enhancement include a number of brain stimulation technologies. Whereas the cognition enhancing effects of invasive methods such as deep brain stimulation  53, 54  are restricted to subjects with pathological conditions, several forms of allegedly noninvasive stimulation strategies are increasingly used on healthy subjects, among them electrical stimulation methods such transcranial direct current stimulation (tDCS  55  ), transcranial alternating current stimulation (tACS  56  ), transcranial random noise stimulation (tRNS  57  ), transcranial pulsed current stimulation (tPCS  58, 59  ), transcutaneous vagus nerve stimulation (tVNS  60  ), or median nerve stimulation (MNS  61  ). Details of the stimulation procedures appear to be crucial: commercial do-it-yourself electrical brain stimulators might impair rather than enhance cognition,  62  and systematic reviews have shed doubt on a clear and simple enhancing effect of electrical brain stimulation on different cognitive domains also under controlled laboratory conditions.  63, 64  Recent studies have even questioned if some of the most commonly used setups for electrical brain stimulation have neurophysiologically meaningful effects at all.  65−68  On this background, the development of noninvasive deep brain stimulation via temporally interfering electric fields might provide a more systematic and targeted mechanism compared to the currently used approaches.  68  Besides electrical stimulation methods, also for transcranial magnetic stimulation (TMS  69  ), optical stimulation with lasers,  70  and several forms of acoustic stimulation, such as transcranial focused ultrasound stimulation,  71  binaural beats,  72, 73  or auditory stimulation of the EEG theta rhythm  74  or sleep EEG slow oscillations,  75  a potential for cognitive enhancement has been reported. Physical enhancement methods that target brain processes more indirectly include whole body vibrations,  76  stochastic resonance motor control improvement,  77, 78  and several forms of neurofeedback, 79 with, e.g., EEG neurofeedback in the upper alpha band enhancing memory,  80  working memory,  81  and visuospatial skills.  82  Besides classical neurofeedback training that involves unspecific but active effort of the subject, also neurofeedback interventions that automatically feedback low energy currents in response to EEG activity have been developed, thereby allowing the subject to receive the training procedure passively.  83  Recently, the use of fMRI neurofeedback, utilizing multivariate pattern analysis, has shown the potential to increase sustained attention  84  or visuospatial memory.  85  Finally, humans have always deployed physical tools to assist cognitive functioning. In current developments that converge minds and machines, these tools become more closely integrated with the person.  86  Crowdfunding or biohacking communities have developed numerous novel technical devices to increase cognitive functions transiently with, e.g., wearable electronic memory aids or augmented reality gadgets,  87, 88  or more permanently as in the case of cognition enhancing or extending bodily implants.  88, 89  Neural implants or prosthetics have progressed; in controlled laboratory settings, implants could facilitate human memory.  90  In addition, Brain−Computer Interfaces connect the central nervous system with computers through wearable or implanted electrodes and may afford a range of applications that enhance cognitive functions or joint outputs of minds coupled with machines.  91, 92  2.3. Behavioral Strategies. Although not commonly recognized as such by the public, cognitive enhancers with the most wide use and longest history are probably behavioral strategies: a rapidly growing body of evidence shows that everyday activities such as sleep  93  or physical exercise  94−96  improve cognitive functioning. Also well-established cultural activities such as musical training,  97, 98  dancing, 99 or learning a second language  100  have been demonstrated to enhance cognition beyond the specifically trained skills. In addition to these natural and cultural standard activities, several behavioral strategies have been developed to enhance certain brain functions intentionally. Two strategies that reach back to ancient times are mnemonic techniques to enhance learning and memory  101, 102  and meditation training to enhance attention processes and mindfulness.  103, 104  In contrast, commercial video games  105, 106  and customized computer trainings  107  represent historically very recent developments that are targeted to enhance specific cognitive capacities and skills. In contrast to several years of enthusiasm and widespread commercial application, however, more recent controlled studies and meta-analyses have shed some doubt on the efficacy of computerized brain training programs,  108  particularly criticizing claims of "far transfer" of training gains to cognitive domains considerably different from the specifically trained skills.  109, 110  ACS Chemical Neuroscience Review
 COGNITIVE DOMAIN The human mind is not a monolithic entity, but consists of a broad variety of cognitive functions. Not surprisingly, no single cognitive enhancer augments every cognitive function. Instead, most cognitive enhancers have specific profiles regarding their efficacy for different cognitive domains. Memory is, e.g., strongly enhanced by mnemonic strategies, but not by meditation; attention, in turn, is strongly enhanced by meditation training, but not training in mnemonic strategies.  101, 103, 104  Sleep, in contrast, enhances both cognitive capacities.  111, 112  Some computerized cognitive trainings have been found to enhance memory, processing speed and visuospatial skills, but not executive functions or attention.  107  It is currently highly debated in how far specific training strategies exert transfer effects also to nontrained cognitive domains.  113  Different cognitive tasks require different optimal levels of receptor activation, thus requiring different doses of pharmacological enhancers targeting the respective neurotransmitter system depending on the cognitive domain targeted.  114  Of note, effects of pharmacological enhancement on different cognitive domains might even differ depending on the cognitive test battery used, illustrating the fragility of the respective effects.  115  Some interventions might even enhance one but impair another cognitive domain: Intranasal application of oxytocin has been shown to enhance social cognition and cognitive flexibility but impairs long-term memory.  116, 117  Methylphenidate improves the ability to resist distraction but impairs cognitive flexibility.  118  Computerized working memory training has been reported to enhance working memory, reasoning, and arithmetic abilities; however, it might deteriorate creativity.  119  Also for amphetamines and modafinil, potential impairments on creativity are discussed besides their enhancing effects on other domains.  120, 34  In contrast, alcohol might enhance creative processes while impairing most other cognitive functions.  29  The costs and benefits of a single cognitive enhancer might even change through slight changes in the application process: for example, electrical stimulation of posterior brain regions was found to facilitate numerical learning, whereas automaticity for the learned material was impaired. In contrast, stimulation on frontal brain regions impaired the learning process, whereas automaticity for the learned material was enhanced.  121  Brain stimulation has thus been suggested to be a zero-sum game, with costs in some cognitive functions always being paid for gains in others.  122  This implies that enhancement may have to be tuned to the task at hand, in order to focus on the currently most important cognitive demands.
 PERSONAL FACTORS The efficacy of cognitive enhancers does not only differ for different cognitive domains, but also for different users. An important factor in this regard are the cognitive skills of the individual prior to the enhancement intervention. Many pharmaceuticals, including amphetamine,  123  modafinil, and methylphenidate,  124  work mainly in individuals with low baseline performance. In some cases, even impairments in individuals with higher performance at baseline have been reported, e.g., in the case of amphetamine,  125  methylphenidate,  124  nicotine,  27  or acute choline supplementation.  126  The phenomenon of enhanced cognition in individuals with low baseline performance and impairments in those with high baseline performance can be explained by the classical inverted U-model,  127, 128  where performance is optimal at intermediate levels of the targeted neurochemicals and impaired at levels that are either too low or too high.  129−131  For some drugs such as methylphenidate, enhancement dependency on the baseline might even differ between cognitive functions, with performance in specific tasks being improved in low, while impaired in high, performers,  124  but showing the opposite pattern for other tasks.  132  The baseline-dependency of cognitive enhancement is not restricted to pharmaceuticals: also in the case of video games,  133  cognitive training,  134  or brain stimulation,  135, 136  individuals starting at a lower baseline performance benefit more than those with an already high performance at baseline. In contrast, sleep appears to improve memory particularly in subjects with a higher baseline performance of memory,  137  working memory  138  or intelligence.  139  Also mnemonic training appears to work particularly well in individuals with a higher cognitive baseline performance.  140  This has been interpreted in terms of an amplification model, in which high baseline performance and cognitive enhancement interventions show synergistic effects.  141  Cognitive enhancers can also affect individuals differently depending on basic biological, psychological, or social factors. For example, effects of training interventions on selective attention can depend on the genotype of the trainee;  142  effects of methylphenidate on creativity can depend on personality characteristics;  143  the cognition enhancing effects of sleep  144  or video games  145  are modulated by gender. In turn, such modulations of enhancement effects might reduce existing differences in cognitive profiles, as seen, e.g., in action video game training, that have the potential to eliminate gender differences in spatial attention and decrease the gender disparity in mental rotation ability.  146  Also the hormonal status of subjects affects how strongly they profit, e.g., from sleep  144−148  or brain stimulation.  149  Caffeine enhances working memory particularly in extraverted individuals,  150  and memory enhancement through sleep  151  or mnemonic training  140  has been reported to depend on the age of subjects. Health status affects how much users benefit from different kinds of cognitive enhancers, including pharmaceuticals, 3 mnemonics,  152  or sleep.  153−156  Finally, also socioenvironmental factors such as social resources, parental occupation, or family composition can modulate cognitive enhancement interventions, e.g., with cognitive training programs.  157
 TIME SCALE Interventions for cognitive enhancement differ in the specific time scale they require to achieve their aims. The prototypical "smart pill" discussed in popular accounts of cognitive enhancement needs practically no preparation time, exerts its effects within seconds or minutes, and lasts for several hours. While this is close to reality in the case of some pharmacological enhancers, the temporal pattern of most other enhancement strategies differs strongly from these time scales. In particular, the time needed for application and the duration of their effects markedly varies between enhancement interventions. Most pharmacological enhancers can be applied quickly and without further preparation; however, some drugs such as acetylcholinesterase inhibitors or memantine are thought to require longer periods of intake to be effective.  33  Also some nutritional enhancers such as glucose and caffeine exert their effects rather quickly, whereas other nutritional supplements have to be taken over extended periods to show an impact on cognition.  158, 18  Obviously, behavioral strategies like sleep,
 ACS Chemical Neuroscience Review exercise, video games or mnemonic training need hours or weeks to robustly enhance cognition. Some effects of meditation might even take years of training.  159  For brain stimulation methods, both immediate effects of acute stimulation, but also more delayed effects after repeated stimulation haven been observed.  55, 69  Technological gadgets or implants need some preparation to be installed and accommodated to, however then exert their cognition augmenting effects on demand. Enhancing effects of most quickly acting pharmacological or nutritional cognitive enhancers also wear off rather rapidly. In contrast to such transient effects, interventions such as brain stimulation,  160, 161, 57  sleep, 162 mnemonic strategies  163  or genetic modifications  46  have the potential for long-term up to chronic enhancement. However, in the latter case, the reversibility of the effects (and side effects) of an enhancement intervention might be a further aspect to be considered. Interventions can also differ regarding the time point of application relative to the situation when enhanced cognitive performance is needed. For example, application of stress hormones such as cortisol or adrenaline before or after memory encoding enhances memory, whereas application before retrieval impairs memory; 41 benzodiazepines impair memory when given before and enhance memory when given after encoding;  164  in contrast, caffeine before learning enhances memory under certain conditions but might impair memory when consumed afterward.  165, 9  Mnemonic strategies on the other hand work solely when taught/applied before/during encoding, but can hardly be applied afterward. Finally, some interventions can also influence the timing of cognitive performance itself: stimulants such as methylphenidate, modafinil, and caffeine might increase the time subjects take to perform a given task, with impairing effects under time pressure and potentially enhancing effects in the absence of temporal constraints.  166
 SIDE EFFECTS The pharmaceutical platitude that there is no effect without side effects holds true also for many nonpharmacological enhancement interventions. It appears obvious that cognitive enhancers differ in the severity and form of side effects: prima facie, deep brain stimulation or implants have higher risks for side effects than sleep or cognitive training. However, also more indirect enhancement strategies such as neurofeedback potentially bear the risk of side effects up to inducing epileptiform activity,  167  and even gentle intervention such as meditation training might exert negative effects on specific cognitive domains: a negative relationship between mindfulness and implicit learning  168, 169  and an increased susceptibility to false memory formation after mindfulness meditation  170  have been observed. Here, the intended training goal of nonjudgemental mindfulness opposes tasks where either a more critical or automatic mindset was needed. Further examples of side effects intrinsically associated with the enhancement goal are trade-offs between stability vs flexible updating of memory systems:  129  memories can also become "too stable" due to a memory enhancement intervention, as observed, e.g., for the anti-obesity drug rimonabant.  171  It has been suggested to differentiate enhancement strategies according to their level of invasiveness.  172, 173  However, while invasiveness has a more or less definite meaning in its original medical context, physically breaching the skin or entering the body deeply through an external orifice,  174  it is difficult to determine the level of invasiveness in the context of cognitive enhancement. Both nutritional supplements and pharmaceuticals enter the body, and thus could be considered invasive in a narrow medical sense, as might be certain forms of physical exercise due to the risk of bruises or scratches as common, e.g., in martial arts or a hike through the woods. Brain stimulation that does not break the skin would, by contrast, be classified as noninvasive. This taxonomy can be disputed for good reasons.  175  Besides known risks of these stimulation methods such as scalp burns from tDCS or seizures from TMS, the "known unknowns" have been suggested to pose potentially even greater risks: potential build-up effects across multiple sessions or in sensitive nontarget areas.  176  Of note, only few neuroscientists use brain stimulation on themselves for cognitive enhancement.  176  Given the still unclear risks and side effects of do-it-yourself brain stimulation use, it has been proposed to extend existing medical device legislation to cover also nonpharmacological and in particular physically acting cognitive enhancement devices.  177, 178  In contrast to strict medical definitions, the more intuitively assessed level of invasiveness of an intervention often seems to depend on familiarity and cultural traditions. This leads to the Western attitude according to which changing one's diet or performing exercise appears less invasive than taking pharmaceuticals or applying brain stimulation, independent of their actual effects on health. Related to the time scale dimension, side effects of short-vs long-term use of cognitive enhancers can be differentiated. For example, while side effects for the acute use of methylphenidate include increased heart rate, headache, anxiety, nervousness, dizziness, drowsiness, and insomnia, in the case of long-term use side effects such as abnormal prefrontal brain function and impaired plasticity have been reported.  179, 180  Also addiction is a well-known side effect for the long-term use of pharmacological enhancers, which is particularly detrimental to the aim of enhancement if combined with tolerance effects such that larger doses are needed to achieve the same effect (or prevent impairing withdrawal effects). Also behavioral addictions have been observed, e.g., physical exercise  181  or the use of technological gadgets.  182  A somewhat nonobvious negative effect of some cognitive enhancers is their illusional efficacy: users sometimes believe their performance to be enhanced by amphetamine in absence of any verified and objectively visible enhancing effects, even if administered in a double blind manner.  183, 184, 38  This is particularly counterproductive in cases of already highfunctioning individuals whose cognitive capabilities might be impaired rather than enhanced by amphetamine.  125, 184  Also for caffeine, under certain conditions higher subjectively perceived mental energy in the absence of objectively enhancing effects have been observed.  185  The often subtle effects of enhancers can be hidden or amplified by placebo effects.
 AVAILABILITY Cognitive enhancers differ in at least three aspects of availability: legal status, cost, and application time. In terms of legal regulation, different enhancement methods are regulated by sometimes drastically varying frameworks. Pharmaceuticals, for instance, are regulated by strict international control regimes that effectively prohibit nontherapeutic uses or by more lenient domestic drug laws. Brain-stimulation methods, by contrast, fall under medical device regulations, pertaining to basic safety standards in terms but not proscribing the uses to which they might be put.  177, 178  Behavioral strategies are usually not regulated at all. The regulatory landscape is thus vast and
 ACS Chemical Neuroscience Review possibly incoherent (for a review, see  ref 186) . Besides practical hurdles to the acquisition of illicit drugs for cognitive enhancement, the legal status appears to affect the motivation of users to decide which cognitive enhancers to take.  166  A common ethical argument in the enhancement debate concerns distributive justice: also legally available enhancers come with cost barriers, restricting individuals of low socioeconomic status from access.  187  A main factor in the costs of cognitive enhancers is their patentability, which is not restricted to pharmaceuticals.  188  However, in particular, behavioral enhancement strategies are typically not subject to patentability or other cost-driving factors: sleep, exercise, meditation, or training in mnemonic strategies are largely free of cost and, thus, in contrast to pharmaceuticals or technological strategies, are available independent from the financial background of the user. On the other hand, these behavioral strategies require some time and effort: the 24/7 working manager as the clichéuser of cognitive enhancement drugs might have the financial means to afford quickly taking his expensive smart pill between two meetings, but might be unable or unwilling to spend extended periods of time with sleep, meditation, or mnemonic training.
 SOCIAL ACCEPTANCE Largely independent from their specific enhancing effects on different cognitive capacities, social acceptance of cognitive enhancement interventions differs strongly depending on traditions, their perceived naturalness, and the perceived directness of their mode of action. Enhancement interventions with a tradition of thousands of years such as meditation and nutrition are typically much better accepted than many currently debated enhancement strategies such as brain stimulation and pharmaceuticals.  189  Also more "natural" interventions such as sleep or exercise are seen in a more positive light compared to technological innovations.  190  Moreover, in how far the mode of action is perceived as psychologically mediated or more biologically direct, affecting the brain indirectly through the senses or more directly through the cranium or metabolism, often plays a role for their social acceptance: if an enhancement intervention such as intense cognitive or physical training requires extended efforts or is seen as a quick and effortless shortcut to the same goal as in the case of smart pills or brain stimulation touches different intuitions about human virtues and is thus valuated differently. Even though views based on such purely intuitive aspects of tradition, naturalness, or directness often rely on cognitive biases rather than rational argument,  191  a negative social perception for whatever reason might generate indirect psychological costs for users, which in turn might influence also rational evaluations of the respective enhancement intervention.  192  Accordingly, one of the central points in the ethical controversy revolves around the question of whether enhancement strategies only relevantly differ with respect to their outcomes, i.e., their benefits and side effects,  193  or also with respect to their mode of operation.  194  Some argue that the relevant ethical distinction runs along the lines of enhancements that are active, in the sense of requiring participation, and those that work on persons more passively.  195  Not surprisingly, different views on cognitive enhancement prevail in different (sub)cultures, with, e.g., a more positive view on enhancement interventions in Asia  196  or in younger populations.  197  Empirical studies on attitudes toward cognitive enhancement interventions found medical safety, coercion, and fairness the most common concerns, with nonusers displaying more concerns regarding medical safety and fairness than users.  198  Sometimes readily available substances for cognitive enhancement such as caffeine, energy drinks, or herbal drugs are dubbed "soft enhancers"; 199 however, considering that prohibition of substances is not only based on their potential harm, but also on historical circumstances, this differentiation between soft and hard enhancers appears questionable. A further aspect that determines the social acceptance of cognitive enhancement is the aim of the given intervention. Taken by face value, the term cognitive enhancement denotes any action or intervention that improves cognitive capacities, independent from the specific aim of this improvement. The use of the term in the empirical, philosophical, and sociopolitical literature, however, varies with regard of the specific aim of enhancement interventions: people appear to be more tolerant toward enhancement of traits considered less fundamental to self-identity,  200  and also more tolerant toward enhancement in individuals with cognitive impairments or low performance baselines compared to enhancement of normal or high achievers.  201, 202  At least four different aims can be identified, each leading to different research strategies and different ethical evaluations of existing or potential enhancement strategies.  203  The least problematic concept of cognitive enhancement targets those everyday medical or psychological interventions that are meant to treat pathological deficiencies. Closely related are those cognitive enhancement interventions that aim to prevent or attenuate cognitive decline that is associated also with healthy aging.  204  Slightly less accepted appear to be those enhancement strategies that aim to improve cognition in completely healthy individuals, but still clearly stay within the normal limits of cognition. The probably most widely used and ethically most controversial concept of cognitive enhancement aims at the augmentation of cognitive capacities beyond normal function, as is represented in the clichéof high-functioning students or managers trying to further improve their performance by taking smart pills. Besides these differentiations between enhancement of impaired vs healthy cognition, another difference in the aims of cognitive enhancement touches the ultimate deed of the enhancement intervention: due to the central role of cognitive capacities in defining humans as a species, it is tempting to consider the improvement of these defining human capacities as a value in itself. However, most philosophical or religious approaches do not center on objective cognitive performance markers, but propose values only indirectly related to cognitive performance such as living a happier or more meaningful life in general. In this light, human enhancement in more general terms does not need to aim for individual cognitive or neural processes, but can also be achieved by sociopolitical reforms targeted at the population level.  205, 206  9. CONCLUSIONS Cognitive enhancement clearly is a multidimensional endeavor. However, not every dimension is important for every theoretical or empirical research question. For example, many empirical researchers of cognitive enhancement are primarily interested in the understanding of the neurobiological and psychological mechanisms underlying cognitive functions.  207  For this aim, the availability and social acceptance dimensions are largely irrelevant. In contrast, many theorists are interested in the social and ethical implications of cognitive enhancement,  208  where these dimensions might be of prime importance. Also side effects and temporal factors might be of secondary importance
 ACS Chemical Neuroscience Review to empirical researchers with an interest in the neural mechanisms of certain cognitive processes, whereas these would be highly relevant for users who ponder the question which cognitive enhancement strategy to choose for a certain aim. When comparing different cognitive enhancement strategies, different dimensions might thus be differently weighed or completely ignored, depending on the aim of the comparison. Up until now, direct comparisons between cognitive enhancement strategies with radically different modes of actions have rarely been made (but see, e.g., ref  165) , and more comprehensive comparisons across dimensions might be difficult: practical issues of information availability from the different dimensions aside, interventions typically differ on different dimensions and are thus difficult to compare globally. In addition, multiple interactions between different enhancers exist, which further complicates the situation. Interactions have been reported, e.g., for glucose and caffeine,  209  diet and exercise,  210  exercise and working memory training,  211  video games and sleep,  212  video games and brain stimulation,  213  exercise and brain stimulation,  214  and brain stimulation and sleep.  215, 216  Also different dimensions discussed here can interact in multiple ways, as, e.g., computerized cognitive training can differentially enhance different cognitive processes depending on personal factors such as age;  217  and social acceptance of different enhancement strategies depends on both the baseline performance of users and the cognitive domain targeted.  200, 201  Despiteor because ofthese complexities, in our opinion, both theoretical discussions and empirical research would strongly benefit from a more differentiated approach. Specific research questions might require the emphasis on some dimensions of cognitive enhancement over others, and for some research questions some dimensions might be entirely irrelevant. Nevertheless, keeping in mind that cognitive enhancement is not a monolithic phenomenon will help to solve and avoid a number of confusions and disagreements that are still present in the public debate on cognitive enhancement. This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. Downloaded via 205.240.4.254 on March 24, 2022 at 02:39:01 (UTC).
 Figure 1 . 1 Figure 1. Cognitive enhancement interventions differ across several interdependent dimensions.
 Figure 2 . 2 Figure 2. Cognitive enhancement interventions different in their mode of actions.