The Abolition of Suffering
A Revised Programme

When superhappiness.com launched in 2007, the genomic and neuroscientific basis for the abolitionist project remained largely speculative. The Human Genome Project was three years complete; CRISPR was six years away from its first application in mammalian cells; deep brain stimulation was still a curiosity; and the psychedelic renaissance had not yet begun. The claim that suffering has a precise molecular substrate — and that this substrate can be deliberately altered — was dismissed as science fiction by most academic philosophers and neuroscientists alike.

Nineteen years later, the empirical landscape is transformed. We can now identify thousands of common genetic variants that collectively explain a substantial fraction of variance in hedonic set-point, depressive tendency, and subjective wellbeing. We can edit the genomes of model organisms with single-nucleotide precision. We possess compounds — validated in randomised controlled trials — that demonstrably elevate mood within hours, not weeks. We can trace the activity of individual neurons in awake, behaving animals as they process reward and aversion. We have, in short, moved from speculation to mechanism.

This does not mean the project is complete, or near-complete. The obstacles remain formidable: the genetic architecture of wellbeing is immensely polygenic; the blood-brain barrier is an adversarial membrane; the regulatory apparatus for psychoactive compounds in most jurisdictions remains rooted in twentieth-century pharmacology; and the philosophical consensus on whether elevated hedonic tone is intrinsically good remains fractured. But the direction of travel has been established. What follows is an attempt to map the scientific state of play in 2026 — and to assess, as clearly as possible, the realistic prospects for a future without suffering.

The most consequential finding of the past two decades is the confirmation that hedonic set-point — the baseline level of subjective wellbeing to which individuals return following positive or negative life events — is substantially heritable. The estimate from large twin studies has stabilised at approximately 40–50% for positive affect and roughly 30–40% for negative affect. Individual differences in suffering, to a degree that would have seemed shocking to most psychologists as recently as 1990, are in large part a matter of DNA.

Genome-wide association studies (GWAS) in cohorts of hundreds of thousands have now identified thousands of common single-nucleotide polymorphisms (SNPs) associated with depression, anxiety, subjective wellbeing, and anhedonia. The largest of these studies — drawing on data from the UK Biobank, the Million Veteran Program, 23andMe research participants, and linked national health registries in Scandinavia — have produced polygenic scores that explain between 8% and 15% of phenotypic variance in depression liability. This remains modest by the standards of purely physical traits, but the theoretical maximum (given imperfect measurement of the phenotype) may be considerably higher.

More interesting than the aggregate statistics are the biological pathways implicated. Signals cluster around genes involved in glutamatergic and GABAergic neurotransmission, synaptic plasticity, the hypothalamic-pituitary-adrenal (HPA) axis, and circadian rhythm regulation. The classical monoamine targets — serotonin transporter SLC6A4, the MAOA gene — remain statistically significant but explain only a small fraction of heritable variance. The genetic story of suffering is not primarily a story about serotonin.

Perhaps the most practically significant genomic discovery has been the identification of rare coding variants — present in less than 1% of the population — that produce large, quantifiable shifts in hedonic baseline. Certain loss-of-function variants in the FAAH gene (encoding fatty acid amide hydrolase, the primary degradative enzyme for the endocannabinoid anandamide) are associated with dramatically elevated wellbeing, reduced anxiety, and enhanced fear extinction, without apparent cognitive cost. Individuals carrying two copies of these variants describe a subjective life that resembles, in its affective quality, what the classical philosophical literature might call eudaimonia — not a manic high, but a steady, robust, and apparently sustainable positive baseline.

Equally striking are rare gain-of-function variants in the mu-opioid receptor gene OPRM1 that appear, across multiple independent cohorts, to be associated with elevated positive affect and reduced susceptibility to depression, without the analgesic side effects or addiction liability of exogenous opioids. The mu-opioid receptor system — long stigmatised by its association with heroin and its derivatives — may turn out to be among the most important genetic levers for raising the hedonic floor of the species.

The therapeutic implication is clear, if still distant: if we can safely replicate, through gene therapy, base editing, or small-molecule pharmacology, the phenotype of individuals carrying these protective variants, we will have achieved something unprecedented. Not a cure for a specific disease, but an upward shift in the range of human wellbeing as such.

The pharmacological record since 2007 is one of genuine, if still partial, progress. The era of SSRIs as the default intervention for depressive illness is ending — not because SSRIs are ineffective, but because their effectiveness is modest, delayed, and confined to a subset of sufferers. What has replaced them is a considerably more diverse, mechanistically varied, and in several cases faster-acting suite of compounds.

The most consequential development was the FDA approval of esketamine (the S-enantiomer of ketamine, marketed as Spravato) in 2019 — the first genuinely new antidepressant mechanism approved in three decades. Esketamine, delivered intranasally, produces measurable antidepressant effects within hours in patients with treatment-resistant depression. Its mechanism — blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, particularly those containing the GluN2B subunit — initiates a cascade of downstream events including rapid synaptogenesis and elevated BDNF signalling. Ketamine and its derivatives have demonstrated what the monoamine hypothesis of depression always implied but never delivered: that the brain's emotional tone is not simply a function of synaptic serotonin or noradrenaline concentration, but of synaptic structure — the density and plasticity of connections in prefrontal and limbic circuits.

What unites the most effective of these new agents — ketamine, psilocybin, kappa-opioid antagonists, neuroactive steroids — is their action on what might be called the gain settings of the emotional system. Rather than incrementally adjusting neurotransmitter levels within the existing architecture, they appear to reset the architecture itself: restoring synaptic density, modulating the sensitivity of threat-detection circuits, or directly blocking the molecular substrates of dysphoria. This is a conceptual revolution, not merely a pharmacological one.

A crucial qualification: the compounds listed above are therapeutic in intent — aimed at alleviating clinical suffering. The abolitionist project requires something more ambitious: not the restoration of baseline hedonic tone in those who have lost it, but the upward shift of the baseline in the general population. This distinction is philosophically critical and practically underexplored. The regulatory machinery, the clinical research infrastructure, and — most importantly — the conceptual framework of medicine are not yet organised around the goal of making healthy people substantially happier. That framing, and the scientific programme it would require, remains largely undeveloped.

The most important conceptual shift in neuroscience since 2007 has been the reconceptualisation of depression — and perhaps of negative affect more generally — as a disease of synaptic atrophy rather than neurotransmitter depletion. The monoamine hypothesis, dominant from the 1960s to the 2000s, held that depression results from insufficient serotonin, noradrenaline, or dopamine at the synapse. This hypothesis was always imperfect (the pharmacological timecourse was wrong; direct depletion of monoamines did not reliably cause depression in healthy subjects), but it drove drug development for fifty years.

The rapid-acting antidepressant effects of ketamine and psilocybin — observable within hours, persisting for weeks — forced a different account. Both compounds produce rapid increases in synaptogenesis in the prefrontal cortex and hippocampus, measurable in rodents within 24 hours and inferred in humans from MRI-based estimates of synaptic density. Ketamine achieves this via disinhibition (blocking inhibitory interneuron NMDA receptors, releasing a burst of glutamate) and subsequent activation of AMPA receptors and BDNF signalling. Psilocybin achieves it via 5-HT2A agonism on pyramidal neurons, with downstream effects on TrkB (the BDNF receptor) that appear to be the active antidepressant mechanism rather than the psychedelic experience per se.

The synaptic plasticity hypothesis of mood — associated primarily with the research of Ronald Duman and subsequently refined by Alex Kwan, Eero Castrén, and others — holds that depression is characterised by a reduction in the density and function of synaptic connections in prefrontal and limbic circuits, and that effective antidepressant treatments reverse this reduction. Chronic stress is the primary driver of synaptic atrophy; rapid-acting antidepressants are, in this framework, essentially synaptic repair agents.

This reframing has significant implications for the abolitionist project. It suggests that the goal is not simply to flood the brain with more of some pleasant neurotransmitter, but to maintain the structural conditions under which the brain's regulatory circuits can do their work — keeping amygdalar threat signals in proportion, sustaining motivational tone, and preventing the synaptic deterioration that appears to underlie chronic suffering. Compounds that support this structure prophylactically — before suffering has induced atrophy — would represent a qualitatively different class of agent from any currently in clinical use.

Optogenetics — the technique of expressing light-sensitive ion channels in genetically defined neuron populations and then controlling their activity with implanted optical fibres — has transformed our understanding of the circuits that generate pleasure and suffering. Since its development in the mid-2000s, it has allowed researchers to activate or silence specific cell types in specific brain regions with millisecond precision, and to determine their causal role in behaviour and, by inference, experience.

The picture that has emerged from a decade and a half of optogenetic dissection is considerably more complex than the classical dopamine-as-reward account. Dopamine neurons in the ventral tegmental area (VTA) and substantia nigra do encode prediction errors — deviations between expected and actual reward — but the hedonic experience of pleasure appears to be generated in discrete "hedonic hotspots" within the nucleus accumbens, ventral pallidum, and parabrachial nucleus. These hotspots, enriched in mu-opioid and cannabinoid receptors, can be activated by microinjection of opioids or cannabinoids to produce behavioural signs of intense pleasure in rodents, even in the absence of any external reward.

Equally revealing has been the identification of the circuits generating aversion and suffering. The central nucleus of the amygdala, the bed nucleus of the stria terminalis, the lateral habenula, and the kappa-opioid receptor-rich regions of the ventral striatum form an interconnected network — sometimes called the "anti-reward" system — whose activity corresponds reliably to states of fear, pain, dysphoria, and withdrawal. Selective optogenetic activation of lateral habenula neurons, which project to and inhibit VTA dopamine cells, reliably induces helplessness, anhedonia, and behavioural despair in rodents. Conversely, their inhibition produces rapid antidepressant effects.

These circuit-level discoveries have practical implications. Deep brain stimulation (DBS) of the lateral habenula has produced remarkable, though still anecdotal, remission of otherwise intractable depression in small human cohorts. Closed-loop neurostimulation — devices that continuously monitor local field potentials and deliver targeted stimulation only when the "suffering signature" is detected — is in early human trials for depression, chronic pain, and PTSD. The technology, currently confined to patients with severe, treatment-resistant illness, represents in principle a direct prosthetic for hedonic set-point regulation.

The deeper significance of these circuit discoveries is philosophical as much as clinical. They establish, with considerable precision, what the neural correlates of suffering look like: elevated habenula and central amygdala activity, reduced prefrontal regulatory tone, depleted mesolimbic dopamine signalling, and heightened kappa-opioid system activity. This is not yet a complete theory of suffering — it says nothing about why these patterns feel bad — but it is a precise description of the neural machinery that would need to be altered to abolish the capacity for suffering. The target, in other words, is now known.

Any serious account of the abolitionist project must confront what remains the deepest unsolved problem in neuroscience and philosophy: the "hard problem" of consciousness, and its more tractable but still formidable cousin, the phenomenal binding problem. The hard problem asks why any physical process gives rise to subjective experience at all. The binding problem asks something more specific: why is experience unified? Why, given that the brain is a distributed system processing different features of perception and cognition in anatomically distinct regions, is the resulting experience the experience of a single, coherent subject?

The binding problem matters for the abolitionist project because suffering is not a local event in the brain — it is a phenomenally unified state. Pain in one's back does not feel like a localised disturbance in somatosensory cortex; it feels like something happening to a coherent experiencing subject who is having a bad time. To abolish suffering is to alter this unified state — which means understanding how it arises. A theory of suffering that treated the amygdala and habenula in isolation, without an account of how their activity contributes to a unified phenomenal state, would be incomplete in a practically significant way.

The most scientifically ambitious theories of phenomenal binding invoke quantum mechanical effects in neural tissue — specifically, the possibility that the neuronal cytoskeleton (and in particular microtubule networks) supports quantum superpositions that allow spatially separated processing events to become entangled and thus phenomenally unified. This view, associated with Roger Penrose and Stuart Hameroff and defended in a physicalistic idealist framework by David Pearce, remains unconfirmed but has received renewed attention following experimental reports of quantum coherence in warm biological systems. The majority view among neuroscientists favours classical binding mechanisms — synchronous gamma-frequency oscillations, thalamocortical loops — but the experimental evidence for these as sufficient explanations of phenomenal unity remains contested.

What can be said with confidence is this: whatever the correct theory of consciousness turns out to be, it will constrain what counts as a solution to the problem of suffering. If consciousness is a product of quantum coherence in microtubules, then interventions targeting classical neural circuitry may be incomplete. If it is a product of classical information integration, then the circuitry findings described above may be entirely sufficient. The stakes of this theoretical dispute, for the abolitionist project, are not merely academic.

The most transformative technological development since 2007 for pharmacological progress — more than any specific compound — is the maturation of AI-assisted molecular discovery. The release of AlphaFold 2 in 2021 (and its successors) made accurate three-dimensional protein structure prediction available to any researcher with internet access, eliminating a bottleneck that had constrained rational drug design for decades. The protein structures of the mu-opioid receptor, the NMDA receptor, the 5-HT2A receptor, and every other major mood-related target are now known to atomic resolution.

Generative molecular design — using large language models and reinforcement learning to propose novel molecules that satisfy specified pharmacological criteria — is now producing drug candidates at a rate that would have required orders of magnitude more time and resources in the pre-AI era. Companies such as Isomorphic Labs, Recursion, Insilico Medicine, and several academic groups have reported AI-generated lead compounds reaching Phase 2 clinical trials within timescales that compress the traditional pipeline by years.

The implications for the abolitionist pharmacopoeia are potentially enormous. The barrier to mood-brightening pharmacology has never primarily been the existence of suitable targets — the mu-opioid receptor, the FAAH enzyme, the kappa-opioid receptor, the lateral habenula's input receptors — but the difficulty of designing ligands that engage these targets with the required selectivity, oral bioavailability, CNS penetration, and absence of tolerance or dependence liability. AI-assisted design substantially accelerates progress on all these dimensions simultaneously.

Particularly promising is the application of AI to the design of functionally selective ligands — compounds that activate only a subset of the signalling pathways downstream of a given receptor. The mu-opioid receptor, for example, signals through both G-protein-coupled pathways (which mediate analgesia and mood elevation) and beta-arrestin-coupled pathways (which mediate tolerance, dependence, and respiratory depression). A G-protein-biased mu-opioid agonist would in principle deliver the hedonic effects of opioids without the addictive liability. Such compounds — TRV130/oliceridine, mitragynine pseudoindoxyl — are in development, and AI is now being deployed to generate improved variants with superior selectivity profiles.

The abolitionist project does not begin and end with Homo sapiens. If suffering matters morally — and it is difficult to articulate a coherent principle by which it matters in humans but not in other sentient organisms — then the suffering of non-human animals constitutes an ethical emergency of a scale that dwarfs the human case by several orders of magnitude. Conservative estimates suggest that the total number of vertebrates experiencing significant pain and distress at any given moment in wild and farmed contexts runs into the hundreds of billions.

The 2007 version of this document argued for what was then a radical proposition: that the suffering of wild animals is an appropriate target for moral concern and biotechnological intervention. This position has gained — slowly, tentatively, but measurably — within academic philosophy, conservation biology, and bioethics. The field now travels under various labels: "compassionate conservation," "wild animal welfare," "wildlife contraception." None of these programmes has yet confronted the full ambition of the abolitionist project as applied to non-human life, but they represent a conceptual beachhead.

The scientific developments that make non-human hedonic uplift conceivable — rather than merely imaginable — are the same ones that apply to humans: CRISPR gene editing (which can in principle be deployed via self-spreading viral vectors to modify the genomes of wild animal populations), polygenic scores for animal models of affect, and optogenetic characterisation of the circuits that generate fear, pain, and distress across taxa. Crucially, the mu-opioid hedonic hotspots identified in rodents are evolutionarily ancient and well-conserved — homologues are found across mammals and, in attenuated form, in birds and fish. The biology of suffering, at its circuit level, is remarkably shared.

The practical and ethical challenges of wild animal intervention are immense: ecological disruption, unintended evolutionary consequences, questions of consent and autonomy, the engineering complexity of gene drives capable of spreading desired variants through a wild population. No credible programme for wide-scale intervention exists today. But the intellectual groundwork — establishing that wild animal suffering is a moral concern, that its biological substrate is in principle addressable, that the engineering tools are at least theoretically available — is being laid, and it constitutes the most morally ambitious frontier of the abolitionist project.

The abolitionist project faces objections from multiple directions. They deserve to be taken seriously — and most of them, taken seriously, turn out to be arguments for caution, precision, and further research rather than arguments against the project in principle.

Any honest roadmap must acknowledge the difference between the time-horizon of science — which will produce the relevant tools — and the time-horizon of implementation, which depends on regulatory, political, cultural, and economic factors that are less tractable than the biology. What follows describes what might be achievable, under reasonable assumptions, across the coming decades.

The deepest philosophical objection to the abolitionist project — deeper than the concerns about motivation, creativity, or unforeseen consequences — is the objection from authenticity. The worry is not that happiness obtained through biological intervention is less pleasant, but that it is less genuinely one's own. That the self produced by hedonic uplift is a manufactured self, a curated self, a self that does not authentically confront the world as it is.

This objection deserves respect, but it ultimately collapses under scrutiny. Every human being is the product of a vast array of factors they did not choose: their genes, their early environment, their neurochemistry, the cultural matrix that shaped their values and emotional responses. The self that confronts the world "authentically" was produced by processes that were no more chosen than the processes proposed by the abolitionist programme. The distinction between "natural" suffering and "manufactured" happiness assumes a normative weight for the natural that it does not deserve — a form of what might be called the naturalistic fallacy applied to psychology rather than ethics.

More importantly, the objection assumes a fixed relationship between suffering and authenticity that is not supported by the phenomenology of human experience. People who undergo successful treatment for depression — including the most structurally transformative treatments, like psilocybin-assisted therapy — consistently report that they feel more themselves, not less. The depressed self, rigidly locked into threat-detection and self-critical rumination, is experienced as an alien imposition; the recovered self is experienced as the authentic one. If this subjective report has any weight — and it is difficult to see why it should not — then the objection from authenticity points in the opposite direction from what it intends.

The question of personal identity — whether the entity produced by radical hedonic uplift would be the same person who underwent the procedure — is similarly more tractable than it first appears. Personal identity is not constituted by a fixed emotional valence. A person who recovers from severe depression does not become a different person; they become a healthier version of themselves. If hedonic uplift is understood as a form of restoration to a healthier state — the state that evolution, with its indifferent optimisation for reproductive fitness rather than welfare, has systematically denied most organisms — then it is continuous with rather than a departure from the self that preceded it.

In 2007, the case for the abolitionist project rested primarily on philosophical argument: on the intrinsic badness of suffering, the absence of any convincing argument for its necessity or value, and the theoretical possibility of a biology in which it has been abolished. The science was consistent with this vision but could not yet be said to actively support it.

In 2026, the scientific situation is different. We have confirmed that hedonic set-point is substantially genetic and that its genetic architecture is beginning to yield to analysis. We have identified compounds that produce rapid, robust, and durable mood elevation through mechanisms that are now well understood at the circuit and molecular level. We have the computational tools to design new compounds at a rate that was inconceivable a decade ago. We have the gene-editing tools to, in principle, introduce protective hedonic variants into the genomes of future organisms. We have optogenetically characterised, with considerable precision, the circuits that generate suffering. The tools are being forged.

What remains is the harder part: the cultural, political, and moral work of establishing that the abolition of suffering is not a fantasy or a dystopia but an obligation — the central moral project of any civilisation that takes seriously the reality of sentient experience. This work is not scientific but philosophical, and it will require the same quality of rigorous, sustained argument that the scientific programme requires in its own domain.

The original Hedonistic Imperative (1995) ended with a vision: a world in which every sentient organism experiences a life whose hedonic tone lies somewhere between the mildly pleasant and the ecstatic — in which the capacity for suffering has not been eliminated as a matter of neural structure, in which pain signals still function as information, but in which the suffering dimension of experience — the protracted, existential, phenomenologically unbearable quality that characterises the worst of human and animal experience — has been made biologically impossible.

That vision is now closer. Not close — the obstacles are still immense and the timescale is generational. But the direction is clear, the tools are developing, and the moral case has never been stronger. The question that remains is not whether the abolition of suffering is achievable or desirable, but whether the civilisation that possesses the means to achieve it will summon the moral seriousness to do so.

This document is a living resource and will be updated as the science develops. It should be read in conjunction with The Hedonistic Imperative (1995), the Good Drug Guide, and the hedweb.com consciousness studies pages. The author welcomes correspondence and criticism.