Psychedelics for Moral Bioenhancement in Healthy Individuals—A Violation of the Non-Maleficence Principle?

Abstract

Several authors have advanced the idea that psychedelics such as psilocybin might be effective means for achieving moral bioenhancement (MBE). Here, I discuss some reservations on this assertion from both neuropharmacological and bioethical perspectives, and surmised that there is little, if any, good justification for such a claim. The indication of psychedelics for MBE is undermined by their hallucinogenic properties and the risk of adverse psychosis. There is also a lack of sound bioethical basis for using psychedelics to enhance morality. Based on our current understanding, the use of psychedelics specifically for MBE in healthy individuals would violate the ethical principle of non-maleficence. Unless there is unequivocal demonstration that psychedelics could enhance morality, or that new non-hallucinogenic derivatives become available, an indication for psychedelics in MBE would be untenable.

1. Introduction

Moral bioenhancement (MBE), a controversial and much debated topic [1,2,3,4] in bioethics, entails the use of biomedical means, which are either pharmacological (drugs, biologicals) or procedure-based (brain magnetic or current stimulations) treatments, to result in morally better motives and behaviors in individuals and to potentially eliminate projected harm from morally deficient individuals [5,6,7]. Other than moral philosophical reasons against MBE [2,4], particularly mandatory or involuntary forms of the latter, another line of dissent focused on a lack of known biotechnological or biomedical approaches [8,9] that can reliably and unequivocally bring about moral enhancement in the foreseeable near future.

Psychedelics are a class of strongly psychoactive hallucinogenic substances. A psychedelic “trip” has been described as a transformative experience [10] that produces changes in cognition, including alterations in mood, perception and the experience of a somewhat altered state of consciousness [11], commonly characterized by euphoria, happiness and hallucinations. Such acute and profound psychotropic effects could to a large extent be due to the ability of the psychedelic substances to disrupt neural network connections and thus desynchronize the brain [12,13,14] and could be accompanied by adverse psychosis (see further discussion below). These substances are illegal worldwide under the United Nations treaty of Convention on Psychotropic Substances of 1971, but recreational use of psychedelics is apparently common (the United States Drug Enforcement Administration classifies MDMA, psilocybin and other psychedelics under Schedule I drugs—substances, or chemicals that are defined as drugs with no currently accepted medical use and a high potential for abuse). Psychedelics such as 3,4-methylenedioxymethamphetamine (MDMA or commonly known as ecstasy) and psilocybin have been experimented as therapeutics against trauma and stress disorders as well as depression in psychotic or palliative settings [15,16,17,18,19,20]. Despite concerns and controversies [21], the Australian Therapeutic Goods Administration (TGA) has recently given approval for psychedelics to be prescribed by doctors for psychiatric conditions such as depression and post-traumatic stress disorder (PTSD) [22].

The use of psychedelics for MBE has been proposed by several authors [23,24,25]. More recently, investigations on the use of psychedelics for various neurological/psychiatric ailments have prompted louder calls for their use in MBE. For example, Vojin Rakić has argued that psilocybin, the psychoactive component of magic mushrooms, is a superior moral bioenhancer to non-psychedelic substances because it has a more direct effect on human morality and happiness, which are supposedly “in a circularly supportive relationship” [26]. Rakić has further asserted that psilocybin would have additional effects on moral enhancement and happiness if combined with meditation. Here, I examine whether these strong claims have evidential support and ponder on the whether the use of psilocybin specifically for MBE is in itself ethically prudent.

2. Psilocybin’s Mechanism of Action and Its Neuropharmacological Effects

Given the recent research advances, it is necessary to briefly review the neuropharmacology of psychedelics (for a more detailed review, readers are referred to comprehensive reviews by de Vos et al. [27] as well as by Jaster and González-Maeso [28], among others), particularly psilocybin. The compound is a prodrug that is metabolically dephosphorylated into psilocin, which is structurally analogous to the monoamine neurotransmitter serotonin or 5-hydroxytryptamine (5-HT). Psilocin is thus an agonist or partial agonist for members of the serotonin receptor family (psychedelics are known to interact promiscuously with a number of receptors within the family, and possibly also other signaling receptors), particularly 5-Hydroxytryptamine Receptor 2A (5-HT_2AR) [29,30,31,32]. There is a strong correlation between the psychedelic effects of psilocybin with 5-HT_2AR occupancy and plasma psilocin levels [30]; therefore, signaling from the receptor likely mediates most, if not all, of the drug’s psychedelic manifestation [33]. However, it is not completely clear why some agonists have a psychedelic effect while others do not. 5-HT_2AR is known for agonist-biased downstream signaling, in terms of ligand-bound conformation-dependent engagement of either Gq/11 or β-arrestin2, which might play a role in determining psychedelic potency. Psychedelics also target a wide range of neuronal cell types with varying expressions of their cognate receptors. Therein lies an apparent issue with the therapeutic use of psychedelics like psilocybin—the desirable anti-depressant and the less desirable hallucinogenic effects are apparently coupled as they originate from similar or shared signaling mechanism(s).

More recent works have provided additional important information on how psychedelics might act in the brain, particularly pertaining to its therapeutic potential as anti-depressants. Eero Castrén’s research group found in 2021 that both typical and fast-acting antidepressants bind directly to the transmembrane domain of the neurotrophin receptor tyrosine kinase receptor 2 (TRKB), thereby facilitating synaptic localization of TRKB and its activation by the neurotrophin brain-derived neurotrophic factor (BDNF). More recently, the group has further shown that the psychedelics lysergic acid diethylamide (or LSD) and psilocin also bind to TRKB, and with affinities that are a thousand-fold higher than those for other antidepressants [34]. Importantly, the effects of psychedelics on neural plasticity and antidepressant-like effect in mice depend on TRKB binding and allosteric promotion of endogenous BDNF signaling but are independent of HTR2A activation. On the other hand, the prototypical LSD-induced head twitch response (HTR), a hallucinogenic trait, is dependent on 5-HT_2AR but independent of TRKB binding (see Figure 1 for a diagrammatic summary).

These new findings suggest the possibility of uncoupling the antidepressant or anxiolytic effect from the hallucinogenic effect if one could design, or derive, a compound that no longer binds (or binds in a manner that enhance a particular downstream signaling) to 5-HT_2AR while retaining its allosteric effect on BDNF signaling through TRKB binding [35,36]. This has important implications for MBE. While the happiness-generating, anti-depression effect of psychedelics like psilocybin could potentially drive MBE, the accompanying hallucinogenic trip and associated adverse effects are obviously undesirable. Other studies have further augmented the possibility of uncoupling anxiolysis from a hallucinogenic trip. For example, Muir and colleagues have recently shown that psychedelic drove network-level activation of multiple neuron cell types in the medial prefrontal cortex of mice beyond just those expressing 5-HT_2AR [37]. Specific and targeted activation of psychedelic-responsive neurons that were genetically tagged recapitulated the anxiolytic effects of the psychedelic without triggering the hallucinogenic-like effects.

3. Issues with Psilocybin’s Adverse Effects

There are several well-known medical issues associated with the use of psilocybin. Firstly, psilocybin-induced states of mind share features with states experienced in psychosis, and psilocybin is in fact proposed to be useful in the modelling of early psychosis [38]. Precipitation of acute negative emotional states (such as fear, agitation, confusion and delirium) or psychosis by psilocybin, albeit rare, have been documented [39]. Secondly, psilocybin could cause syndromes that resemble a state of schizophrenia [40,41] and could be used for experimental animal models of this psychiatric disorder [42]. The question here is whether a drug-induced schizophrenic syndrome could persist in the longer term, as has been documented for MDMA [43,44], particularly for individuals with some degree of genetic or psychiatric predisposition or susceptibility. Finally, at least one long-term psychotic effect of psilocybin has been well documented—a condition of visual flashback or traumatic recall of an intensely upsetting experience known as hallucinogen-persisting perception disorder (HPPD) [45,46,47,48].

The above-described adverse effects of psilocybin stem from its hallucinogenic and psychotic potencies, which is likely mediated by the drug’s (or more precisely its active metabolite psilocin’s) interaction with 5-HT_2AR. Of course, most if not all drugs carry a degree of dose-dependent health risk, and any approved indication would be one in which the benefits clearly outweigh the risks. The use of psilocybin and other psychedelics in depression and PTSD has been well-researched and their effectiveness has substantial evidential support. The same, however, cannot be said for MBE, which is itself poorly defined. In fact, even if we can all come to an unambiguous consensus as to what exactly constitutes or count towards MBE, we might still be no closer to sanctioning the use of psilocybin in this regard.

4. Does Psilocybin Really Promote Morality or Alter Moral Mindsets?

Unlike investigations on the effectiveness of psilocybin and other psychedelics in depression, the effectiveness of psilocybin in enhancing morality has scarce support. In fact, a study which directly addresses the influence of psilocybin on moral decision-making has shown no effect [49]. The authors investigated the effect of an acute oral dose of psilocybin (0.215 mg/kg) in healthy human subjects on empathy and hypothetical moral decision-making with the multifaceted empathy test (n = 32) and moral dilemma task (n = 24). Psilocybin administration was found to increase emotional but not cognitive empathy compared with placebo. However, moral decision-making was unaffected by psilocybin. In an earlier study, Schmid and colleagues investigated the acute effects of MDMA (75 mg) and methylphenidate (40 mg) in comparison with a placebo in a suit of psychological tests including a multifaceted empathy test and a moral judgment task in a cross-over study with 30 healthy subjects. MDMA (but not methylphenidate) did exhibit some subjective empathogenic effects, such as closeness to others, openness and trust. However, neither drug influenced moral judgement [50].

There is therefore no concrete or unequivocal evidence that morality in the trial participants was substantially altered by psilocybin or MDMA. It appears that what psychedelics promote would be emotional empathy [49,50] and some degree of pro-sociality [51], as also discerned by other psychological tests. Rakić has argued that the feeling of happiness generated by psilocybin is critical for its MBE effect [26]. However, it does not appear that the perceived increase in emotional empathy and happiness affects the participants’ decisions when confronted with moral dilemmas.

One could compare these somewhat underwhelming results with those that have demarcated regions of the brain that are associated with clear changes in moral judgement or dishonesty [52,53]. For example, lesions to the ventromedial prefrontal cortex increased utilitarian-type moral judgement [54] and impairs judgement of harmful intent [55], whereas individuals with basolateral amygdala damage showed a breakdown of utilitarian sacrificial moral judgments [56], and a gradual escalation of self-serving dishonesty could be traced to an adaptive signal reduction in the amygdala with repetitive acts of dishonesty [57]. It is clear that moral judgements in a brain can be altered, but psilocybin did not show a discernible influence in this regard.

Of course, it might be argued that the use of moral dilemmas is not the best, or perhaps not even useful, for gauging changes in an individual’s morality. While such an argument attests to the broader difficulty in deciding how morality should be measured, it also suggests that the enhancement of emotional empathy and happiness by psilocybin is insufficient as indicators of enhanced morality.

5. The Use of Psychedelics Such as Psilocybin Specifically Only for MBE Is Unjustified

Given psilocybin’s adverse effects and a lack of clear deliverables in MBE, we could argue that the use of psilocybin for MBE is not (at least not yet) scientifically justified, nor ethically prudent. I shall further posit that two advances must be in place before the notion of “psilocybin for MBE” could become practical. The first would be the discovery or development of a compound that is based on (or derived from) psilocybin, which retains its potent allosteric influence on TRKB-mediated BDNF signaling underlying its anti-depressive effect but no longer has a high affinity for 5-HT_2AR, or that its binding does not illicit hallucinogenic effects or acute psychosis. Secondly, there should be some consensus on how enhanced morality could be effectively and robustly measured, and for psilocybin to meet the measures by these consensus yardsticks.

On the first point, one might question as to why psilocybin, with all its risks, is deemed fine for use in depression, but not MBE. It should be noted that its use for depression and PTSD is drastically different from its proposed use for MBE both in terms of urgency and permissiveness. The former are illnesses that require treatment with effective therapeutics, even if these come with some risks or side effects. To a patient suffering from treatment-resistant depression or one in palliative care for a terminal illness, relief from debilitating depression could effectively reduce mortality from self-harm or suicide, with the restoration of comfort, dignity and quality of life. As such, a prescription of psilocybin, even if the treatment is accompanied by hallucinations and psychosis, would be justified and treatment deemed desirable. Contrastingly, subjecting an otherwise healthy individual to MBE just to enhance one’s morality carries neither the urgency nor tangible health benefits that would justify the risks. On the other hand, should we now have a new compound or a derivative that carries no hallucinogenic and psychotic risk, their application to enhance empathy and happiness, even if this may not truly amount to enhanced morality, would appear to be more permissive.

Is MBE necessary and would it help solve the problems of today that are purportedly rooted in moral inadequacies or deficiencies? This main purpose of MBE as proposed by Persson and Savulescu [6,58] has been intensely reviewed and counter-examined by many authors [4,8,59,60,61], and it is not my intention here to revisit these pertinent points. We should indeed be more concerned with the technical point of what exactly constitutes MBE and more specifically, whether psilocybin could actually achieve MBE. Advances in neuroscience and neuropsychology tell us that moral judgement involves both emotion and cognitive processing [62,63]. Scientific evidence also suggests that there is no neural unification in moral judgment, as moral wrongness was sub-served by distinct neural systems underlying moral judgments of harm, dishonesty, and disgust [64]. Philosophers have called for objective standards to gauge the extent of MBE [65], but such objectivity could be confounded by the opposing meta-ethical theories that one subscribes to. Thomas Douglas, one of the original proponents of moral enhancement, stated the following: “… both what counts as a good motive and what counts as an improvement in one’s motives will be different for different people, or people performing different roles” [5]. As aptly summarized by Birgit Beck, “… there is no shared opinion among philosophers (or scientists) about the meaning, prospects, and ethical evaluation of moral enhancement” [8]. This lack of consensus does not help in gauging whether MBE has at any instance been achieved, or whether MBE could be effectively achieved by psilocybin.

As pointed out in the section above, experimental psilocybin treatment did not change participants’ disposition in moral dilemmas. If moral dilemmas are inadequate as indicators of MBE, what would be adequate? Several authors have debated which aspects of morality MBE would be possible to enhance. For example, Jebari has posited that MBE treatments could alter a person’s dispositions, emotions or behaviors in order to make that person more moral, and that emotional and dispositional changes would perhaps be more achievable [66]. Shook suggested that a moral enhancer would, in theory, affect one or more of five aspects—heightened moral appreciation, stronger moral decisions, correct moral judgements, improved moral intentions and more moral will power [67]. This “to-lookout-for” list might indeed suggest a way forward, for it is conceivable that a well-designed selection of psychological tests, perhaps illustrated through vignettes, could be utilized to test changes in each of the above aspects with an MBE treatment. However, until such tests are made available, proven to be robust and can practically differentiate a morally enhanced state from baseline, and that psilocybin treatment can achieve a credible score in these tests, we shall not be in any position to suggest that the drug could achieve MBE.

6. Attempts to Use Psilocybin Solely to Achieve MBE in Healthy Individuals Would Violate the Ethical Principle of Non-Maleficence

Without specific endpoints or measures to gauge the extent of enhancement, and in view of the undesirable risks and side effects, any involuntary use of psilocybin solely for MBE would appear to be unjustifiable and untenable. I posit that such use would be in violation of the ethical principle of non-maleficence [68], given that we should first cause no harm in administration of any treatment. From a Kantian perspective, such individuals would also have been used only as a means for experimentation without a firm sight of a good end for themselves, which does not align with Kant’s categorical imperative [69].

There are, however, arguments for MBE’s use as a form of criminal rehabilitation [70,71]. We would agree that a reliable form of MBE that could robustly enhance moral sense and judgement on the part of individuals who have demonstrated moral shortcomings as exhibited in their criminal offences, either as part of their medical rehabilitation or the administration of retributive justice, would be a good idea. However, I do not think that psychedelics are the way forward based on the arguments made in the sections above.

7. Concluding Remarks

In the discussions above, I outlined reservations against the use of psychedelics (with a focus on psilocybin) for MBE, which we think lacks both scientific justification and bioethical prudence at the moment. As such, any use of psilocybin on a healthy individual (i.e., not suffering from debilitating depression) would violate the ethical principle of inflicting no harm [68]. However, the recent discovery that psychedelics’ anti-depression effect could be potentially decoupled from the hallucinogenic effect suggests the possibility of pharmacological improvement of the drug. Furthermore, the approval of psychedelics for the treatment of depression, PTSD and other psychiatric ailments has now given us an unprecedented opportunity for some observational assessment of this class of drugs on morality and behaviors that are relevant to morality. Proponents advocating psilocybin’s use for MBE might benefit from the outcome of these new developments.