Minerva Magazine
Mental Health Beyond Neurotransmitters: Hormones, Endocrinology, and Psychedelic Therapies in Modern Psychiatry
Dr. Linus Abrams, a psychiatrist with nearly 35 years of clinical experience, joins Peter Attia to explore how mental health care must evolve beyond the traditional neurotransmitter model to incorporate hormones, metabolism, circadian biology, and endocrinology. The conversation covers how estradiol, testosterone, progesterone, thyroid hormones, and cortisol deeply shape mood and cognition, why accurate diagnosis of bipolar vs. unipolar depression is critical for treatment, and what the emerging evidence on ketamine and psychedelics means for the future of psychiatry.
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Peter Attia opens by welcoming Dr. Linus Abrams to Austin and noting his unusual integration of psychiatry with endocrinology. Abrams explains that after approximately 30 years of practice he felt he had plateaued intellectually—he was enjoying his work but not learning at the rate he desired. This prompted a significant pivot toward endocrinology, a field he describes as still actively absorbing. He emphasizes that his goal is not to criticize psychiatry but to add an additional lens, calling his career deeply fulfilling because of the opportunity to understand human beings at a profound level. He frames his work as progressive layers of insight and ongoing reinterpretation of prior misunderstandings, underscoring that the nature of any individual patient always exceeds any clinician's capacity to fully comprehend them.
Peter and Linus discuss how psychopharmacology, despite its power, remains only as good as the diagnostic hypothesis underlying it. Abrams acknowledges that even when medications produce dramatic reductions in suffering, sustaining long-term adherence remains a persistent challenge, particularly in conditions like bipolar disorder that require chronic treatment. He argues that the subjective, relational experience of getting to know a patient in depth is not merely a soft skill but the primary vehicle through which accurate diagnoses are reached. Without that rich human story, the pharmacologic intervention rests on a weak foundation. He also notes that even among peers who would agree medications help enormously, there is a shared recognition that something frequently remains missing—full vitality and the complete human experience are often not restored even when symptoms improve.
Abrams provides a foundational overview of psychotropic pharmacology, explaining that historically these drugs have worked by modulating monoamine neurotransmitters—serotonin, dopamine, and norepinephrine. SSRIs selectively amplify serotonin signaling primarily by blocking its reuptake, which leaves more serotonin available in the synapse. However, a critical and often underappreciated consequence is that raising serotonin can suppress dopamine. This matters clinically because patients with attentional difficulties or low-energy depression who are already dopamine-deficient may find their symptoms worsened by an SSRI. SNRIs address this partially by adding norepinephrine reuptake inhibition to the serotonin effect, creating a more balanced monoamine profile. Abrams describes the drug class boundaries as a continuum rather than a hard categorical distinction—a drug is labeled an SSRI or SNRI based on where it falls on a spectrum of serotonin-to-norepinephrine selectivity. Escitalopram (Lexapro) is offered as one of the purest SSRIs, while drugs with broader monoamine profiles blur the line. He notes that many patients on SSRIs alone feel better symptomatically but report a persistent sense of blunting or lack of vitality—a consequence of dopamine suppression that the medication itself induces.
The conversation touches on specific diagnostic contexts where SSRIs perform particularly well. Dysthymia—a chronic, low-grade depressive state—and conditions in the OCD and anxiety spectrum tend to respond favorably to purely serotonergic agents, even without robust dopaminergic or noradrenergic support. Abrams notes this is somewhat counterintuitive given that dysthymia can feel like a pervasive flatness, yet pharmacologically it responds well to serotonin amplification alone. This reinforces the point that different symptom clusters have different neurochemical substrates, and matching the drug to the underlying biology of the specific condition is more important than applying a one-size-fits-all first-line protocol. The discussion also raises the practical consideration of when to choose an SSRI over an SNRI: the newer drug is not automatically superior—the right choice depends on the symptom profile, the presence or absence of attentional or energy-related complaints, and whether dopamine suppression would be harmful.
Abrams explains that the majority of patients who eventually receive a bipolar diagnosis come to him not knowing they have it—they present with depression. The most common form in his practice is bipolar 2, characterized by hypomania rather than full mania. Hypomania can be highly adaptive: Abrams estimates that over his career roughly a third of his bipolar patients were exceptionally high-achieving individuals who harnessed hypomanic energy to build companies, generate ideas, and sustain remarkable productivity. The problem arises during depressive episodes, which respond differently to antidepressants than unipolar depression does. Giving an SSRI to a bipolar patient without a mood stabilizer can worsen cycling or precipitate instability. The correct pharmacologic approach for bipolar depression often involves mood stabilizers such as lithium or lamotrigine, both of which can treat the depressive pole effectively even as monotherapy. Lamotrigine in particular is highlighted as being frequently misunderstood—most people associate bipolar medications with treating elevated mood, but lamotrigine has strong evidence for the depressive side of the illness. Making the correct diagnostic distinction between unipolar and bipolar depression is therefore not merely academic; it directly determines which drug is appropriate and which might cause harm.
Peter raises the evolutionary question of why depression persists as a heritable condition if it is so debilitating. Abrams offers a nuanced evolutionary framework. He suggests that certain features of depression—such as diurnal variation in mood and hypersomnia—may have been conserved because they once served survival functions. Spending more time sheltered during low-resource seasons, conserving energy, and emerging only during productive daylight hours could have conferred survival advantages. He is careful to distinguish clinical depression from the ordinary depressive experiences of everyday life, noting that clinical depression is genuinely harmful: it is lethal in some cases, increases risk for multiple medical conditions, and exacts an enormous toll. At the same time, from a psychological vantage point, a severe depressive episode can function as a radical reappraisal of one's prior beliefs and models of the world—a disruptive but sometimes ultimately reorganizing experience. He notes the parallel with atherosclerosis: some conditions exist outside the reach of natural selection's purview, making the evolutionary lens useful but not definitive.
The conversation turns to why mental health appears to be worsening despite material improvements in living standards. Abrams and Attia explore the paradox that the least wealthy person in the United States today lives in more physical comfort than medieval royalty, yet rates of depression and anxiety have risen sharply. The key distinction they identify is relational: what modernity has disrupted is not material wellbeing but the density and quality of human connection. Digital devices and social media have made isolation not only possible but structurally easy in a way that was literally impossible for most of human history. Ten thousand years ago, social isolation was effectively a death sentence; today it is a viable lifestyle. Attia argues that this means individuals must now make deliberate, active efforts to do things that were once automatic defaults—being outdoors, maintaining face-to-face relationships, limiting information overload. Peter explicitly argues that the price of modernity is that formerly automatic behaviors (going outside, connecting with others) must now be consciously chosen and effortfully sustained, and that failure to do so silently erodes mental health resilience.
Abrams briefly situates insomnia within a similar evolutionary framework—wakefulness and hypervigilance at night may have served ancestral protective functions, making modern insomnia a mismatch between evolved biology and a safe contemporary environment. Peter then introduces his 'window analogy' for distress tolerance, a model he describes using in his own life. He conceptualizes distress tolerance as a window of varying width: when the window is wide open, a person can absorb significant stress, conflict, and irritation without reaction; when the window narrows, even minor provocations—a child's behavior, a spouse's comment, an employee's mistake—trigger irritability. The critical insight is that the width of that window is not primarily a product of willpower or psychological discipline. It is determined by biological factors: whether you slept adequately, whether you exercised, what you ate, what your hormonal status is, and whether you are under chronic stress. This model frames irritability not as a character flaw but as a biological signal that foundational physiology is compromised.
Building on the distress tolerance window model, Abrams affirms that foundational biological factors—nutrition, exercise, sleep, and hormonal health—are not peripheral lifestyle considerations but core determinants of psychiatric resilience. He agrees with Peter that adaptive capacity, the ability to self-regulate in response to internal and external threats, is continuously shaped by these inputs and changes dynamically throughout life. Abrams describes this adaptive capacity as always in flux, never static. The conversation frames these factors as the substrate upon which all pharmacologic interventions operate: no medication can fully compensate for chronically poor sleep, sedentary behavior, nutritional deficits, or hormonal dysregulation. This leads naturally into the central argument of Abrams's recent intellectual pivot—that psychiatry must evaluate and address these biological foundations rather than targeting neurotransmitters in isolation.
Abrams reflects on how his career spans the era before and after the Women's Health Initiative (WHI) study, which in the early 2000s led to a dramatic reduction in estrogen prescriptions for menopausal women based on concerns about cardiovascular and cancer risk. He observed directly in his practice that women who were taken off or denied hormones during menopause showed an erosion of adaptive capacity—their ability to self-regulate emotionally and cognitively declined in measurable ways. He describes a similar phenomenon in men whose declining testosterone went unaddressed, often dismissed as 'normal aging.' The WHI's influence cascaded through psychiatry by creating a generation of patients who were told hormones were dangerous while simultaneously receiving more psychotropic prescriptions for symptoms that were at least partially hormonally driven. Abrams frames this as an example of siloed medical thinking—psychiatry treating neurotransmitters while ignoring the hormonal infrastructure that regulates them.
Abrams delivers one of the most technically detailed sections of the conversation, explaining precisely how estradiol operates within the central nervous system. Estrogen does not merely influence mood indirectly through peripheral effects—it is, in his words, 'embedded and imbued' within the brain. There are well-characterized membrane estrogen receptors (alpha and beta) on neuronal membranes, and there are also estrogen response elements (EREs) within the genome itself, meaning estrogen regulates transcription at the most fundamental level of neuronal activity. Specifically: estradiol promotes serotonin synthesis by upregulating tryptophan hydroxylase through EREs; it promotes dopamine synthesis through tyrosine hydroxylase via the same mechanism; and it promotes acetylcholine synthesis through choline acetyltransferase. In other words, estradiol is not downstream of neurotransmitter systems—it is upstream, acting as a master regulator of the enzymatic machinery that produces the very neurotransmitters that psychiatric drugs target. Abrams finds this 'fascinating and remarkable,' and it forms the intellectual backbone of his argument that ignoring hormonal status while prescribing psychotropics is treating symptoms while ignoring the biological infrastructure generating them. The wide variability in how women experience estrogen withdrawal—from barely perceptible symptoms to complete cognitive and emotional incapacitation—is likely attributable to differences in receptor density, receptor sensitivity, and interactions with other hormonal and metabolic variables.
Abrams explains that men receive estradiol primarily through the aromatization of testosterone—testosterone functions as a prohormone for estradiol. Beyond this, testosterone directly modulates the dopamine system, particularly the mesolimbic pathway (governing reward salience and reward prediction) and the mesocortical pathway (governing executive function and working memory). Declining testosterone in men—andropause—is more gradual and insidious than female menopause, making it harder to identify. Clinically it can present as a dulling of drive and motivation, subclinical cognitive dysfunction, and ADHD-like symptoms in addition to the more familiar physical and libido-related effects. Peter then raises the question of clomiphene and enclomiphene as indirect methods of raising testosterone by blocking hypothalamic receptors for estradiol and testosterone, tricking the pituitary into producing more LH and FSH. Abrams confirms a critical clinical observation: clomiphene works by blocking estrogen and androgen receptors in the brain, meaning it raises serum testosterone while simultaneously depriving the central nervous system of the very hormonal signaling it needs. The result, consistent with Peter's clinical experience, is that lab values normalize but psychiatric and cognitive symptoms do not improve—the numbers are fixed, the person is not. This makes clomiphene an inferior choice for patients with mood, cognitive, or psychological complaints, even though it has other advantages such as preserving endogenous production and fertility.
Abrams explains the mechanism underlying both premenstrual dysphoric disorder (PMDD) and postpartum depression through the lens of progesterone dynamics. In the normal menstrual cycle, progesterone rises in the luteal phase to prepare the uterine lining for implantation; when implantation does not occur, the lining sheds and progesterone drops precipitously. Crucially, the psychiatric symptoms are not caused by the low level of progesterone itself—women feel fine during the follicular phase when progesterone is equally low. The trigger is the rate of decline, the rapid crash. The same mechanism applies after delivery: progesterone levels during pregnancy are extraordinarily high, and delivery causes an abrupt withdrawal that the brain must adapt to. Women who are sensitive to this rate of change—for reasons that remain incompletely understood—experience depressive and dysphoric symptoms disproportionate to what the absolute hormone level would predict. Abrams expresses genuine empathy for women navigating these challenges, acknowledging how profound and physiologically driven these experiences are. Postpartum psychosis, which occurs in less than 1% of deliveries, represents the most severe end of this spectrum and requires different acute management.
Abrams discusses the treatment landscape for postpartum depression, distinguishing between different severity categories and corresponding therapeutic approaches. For the most acute and severe presentations, synthetic neurosteroid medications (such as brexanolone/Zulresso) can provide rapid relief by directly modulating GABA-A receptors, essentially substituting for the progesterone metabolite allopregnanolone that the brain has been abruptly deprived of. This is a different pharmacologic category from standard antidepressants and works on a different timescale—days rather than weeks. For less severe presentations, standard treatment may involve SSRIs or other antidepressants, sometimes as monotherapy when the hormonal mechanism is clearly the driver. Abrams emphasizes the importance of setting appropriate expectations with patients about treatment timelines and the likelihood of being able to eventually taper off medications, noting that for hormonally driven episodes, the prognosis for discontinuation is generally more favorable than for chronic recurrent mood disorders.
Abrams presents a detailed clinical discussion of how thyroid dysfunction masquerades as depression, arguing that standard psychiatric and internal medicine evaluation of thyroid status is often inadequate. The typical approach—checking TSH and accepting any value within the broad 'normal' reference range—misses a significant subset of patients. Abrams explains that TSH is only an indirect signal from the pituitary to the thyroid and that a TSH in the upper half of the normal range (e.g., 2.5–5.0 on a scale of 0.8–5.0) may reflect a real, functionally meaningful thyroid hormone deficiency even if technically 'normal.' He argues that free T4 is a more important value because T4 serves dual roles: it is a prohormone that is converted to T3 both centrally (in the brain via one set of deiodinase enzymes) and peripherally (via a different set). If free T4 is suboptimal in a depressed patient, that warrants either an endocrine referral or direct thyroid supplementation. He further discusses the selective use of T3 alone in treatment-resistant depression, sometimes at doses starting as low as 2.5 mcg twice daily and potentially reaching 25 mcg twice daily, and distinguishes between the FDA-approved short-acting Cytomel and compounded time-release formulations. He shares case examples of patients who had failed multiple antidepressant combinations but achieved significant relief with T3 augmentation, hypothesizing that thyroid hormone may work through upregulation of catecholamine receptor sensitivity and through central mechanisms beyond simple hormone replacement.
The conversation addresses cortisol as perhaps the most pervasive and underappreciated hormonal contributor to psychiatric distress. Abrams and Peter agree that chronic elevation of cortisol—a state of hyperarousal that evolved for acute threat response but is now triggered chronically by modern stressors—likely underlies a significant proportion of the anxiety, mood instability, and cognitive dysfunction seen in clinical practice. A critical limitation distinguishes cortisol from other hormonal axes: unlike estradiol, testosterone, or thyroid hormone, chronically elevated cortisol cannot be directly pharmacologically corrected with a simple replacement or suppression strategy. The treatment must be indirect—lifestyle modification, stress reduction, sleep optimization, exercise, and sometimes therapy. Abrams notes that while he explains hormonal mechanisms to patients when prescribing estrogen or thyroid supplementation, the cortisol conversation is more nuanced because the treatment is behavioral rather than pharmaceutical. This makes it a harder sell and a harder problem to solve, but he believes that framing hyperarousal physiologically—rather than as a character weakness or psychological failing—helps patients engage with the necessary behavioral changes.
Abrams presents a particularly instructive clinical case: a perimenopausal woman who came to him requesting hormones, describing herself as someone who had always been emotionally strong and high-functioning but was now overwhelmed by menopause. When he probed her history more carefully, she described her twenties and thirties as 'chaotic'—she had started multiple companies, traveled extensively, spent impulsively, had racing thoughts faster than she could write them down. This history, recontextualized, pointed unmistakably to long-standing bipolar 2 disorder with hypomanic episodes that had never been diagnosed. The perimenopausal hormonal transition had stripped away the compensatory biological buffer that had allowed her to maintain relative stability, unmasking the underlying mood dysregulation. Abrams investigated her hormones and gonadotropins, confirmed the menopausal picture, but recognized that the organizing diagnosis was bipolar disorder, not simply hormone deficiency. He started her on lamotrigine, which produced a dramatic improvement. The case illustrates a broader principle: hormonal transitions—particularly perimenopause—can reveal latent psychiatric conditions that had been previously subclinical or misattributed to personality traits. The patient gained not only symptom relief but a coherent narrative framework for understanding the difficulties she had experienced throughout her adult life.
Abrams discusses ketamine as a tool for recalcitrant depression, noting that it works through a fundamentally different mechanism than traditional antidepressants—it is an NMDA receptor antagonist affecting glutamate signaling rather than monoamine reuptake. Ketamine is not related to MDMA and should not be confused with it; they act through completely different pharmacologic pathways. Clinically, ketamine is administered in controlled settings and produces a partially or sometimes fully dissociative experience during the treatment. Relief from depressive symptoms can follow, but the durability is variable—for the most severe cases, repeated treatments may be needed as the effects wear off. Abrams acknowledges that ketamine is time-consuming, expensive, and inconvenient, which limits its practical utility for many patients. He expresses some uncertainty about whether the degree of dissociation during the experience correlates with therapeutic outcomes, as it appears to in some psychedelic studies. He also raises concerns about recreational ketamine use, noting the risk of psychological dependency and the potential for harm outside of controlled clinical contexts. Compared to classic psychedelics, ketamine's mechanism does not rely on the same neuroplasticity-through-experiential-processing model, though both categories are being explored for depression that has not responded to conventional treatment.
Abrams discusses a notable case report involving a patient with severe, long-standing Alzheimer's disease who reportedly showed remarkable cognitive and behavioral improvement after receiving a therapeutic dose (5 grams) of psilocybin. Abrams is cautious about drawing broad conclusions from an N-of-1 case, particularly given the unusual clinical picture—a decade of severe Alzheimer's with incontinence and monosyllabic speech does not typically reverse—and raises the possibility that PTSD rather than true Alzheimer's may have been the primary underlying condition. He references Robin Carhart-Harris's REBUS (Relaxed Beliefs Under Psychedelics) model, which frames the therapeutic mechanism of classic psychedelics as the induction of a neuroplastic window during which maladaptive beliefs and prior models of the world become revisable. This window, when paired with appropriate therapeutic support, allows lasting change. Abrams draws a conceptual parallel between this psychedelic-induced neuroplasticity and the neuroplasticity promoted by optimal estradiol levels—both operate through BDNF, NMDA, and glutamate pathways. The implication is that hormones and psychedelics may share overlapping mechanisms of action at the level of neuroplasticity, which has interesting implications for how both should be studied and deployed clinically.
Peter shares his own experiences with psychedelics with unusual candor, describing both a profoundly positive and several devastating experiences. His most impactful positive experience occurred approximately a decade ago and involved what he describes as an out-of-body perspective—witnessing his own past from outside himself, but crucially, experiencing key moments from the vantage point of another person (a parent) rather than his own lived perspective. This generated a profound and durable sense of empathy and gratitude, reframing past frustrations as those of 'someone who has never fully appreciated' the sacrifices made on his behalf. The durability, he notes, has been lifelong—a decade later the insight remains vivid. In contrast, other experiences on psilocybin were brutal and prolonged: one involved hours of a recurring guillotine imagery with the blade perpetually approaching but never completing its fall, a form of psychological torture that took months to recover from. Another he described as 'Guantanamo Bay for my soul.' What he finds scientifically perplexing is that he cannot identify any meaningful difference in set, setting, dose, or delivery between the experiences that were transformative and those that were devastating, which he sees as the core unsolved problem in psychedelic research—the unpredictability of outcome.
The final major segment of the conversation addresses what role psychedelics might play in formal psychiatric practice over the next 10 to 20 years. Abrams expresses cautious optimism, noting that the evidence base for specific applications—PTSD, existential anxiety in end-of-life care, and treatment-resistant depression—is growing and scientifically coherent. He is particularly enthusiastic about MDMA for certain forms of PTSD where the empathogenic properties of the drug facilitate reconciliation of traumatic relational experiences, noting that PTSD is a heterogeneous category and MDMA may be especially well-suited to the subset where empathy and relationship repair are central. For end-of-life care, he argues that the risk-reward calculus shifts substantially—when someone is facing existential terror in the context of terminal illness, the potential risks of a psychedelic experience are more acceptable relative to the potential benefits. Abrams frames his 'Russian roulette' concept as a core limitation of current psychedelic medicine: the unpredictability of who will benefit and who will be harmed, and to what degree, remains the central unsolved problem. Both he and Peter agree that psychedelics are genuine drugs with genuine side effects and that the field must develop better predictive tools—whether biological, psychological, or experiential—to identify who should and should not receive them, and under what conditions. Peter expresses high confidence that psychedelic-assisted therapy will remain part of the psychiatric toolkit for the rest of his life.
Key Takeaways
- •Hormones like estradiol, testosterone, progesterone, and thyroid hormones directly regulate neurotransmitter synthesis at the genomic level, making endocrinology inseparable from psychiatry.
- •Bipolar 2 disorder is frequently misdiagnosed as unipolar depression; giving antidepressants without mood stabilizers to bipolar patients can worsen their condition.
- •The WHI-driven reduction in hormone replacement therapy had measurable negative psychiatric consequences, eroding women's adaptive capacity and emotional regulation.
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