Addiction

Brain metabolism and drug addiction

Addiction is an organism's attempt, under metabolic distress, to return to homeostasis using substances or activities that provide temporary relief. Addictive behavior is the body's search for metabolic support once its own regulatory systems are compromised. A strong metabolism reduces susceptibility, because an organism with good cellular energy production has less need for external substances.

People with slower metabolism tend to smoke more deeply mainly to compensate for low CO2 production and poor glucose oxidation; the act briefly improves oxygenation and cellular stability. This "dirty" metabolic support comes bundled with toxins that worsen long-term health, which is part of why heavy smoking looks more dangerous than the underlying drive behind it.

Cravings and addictions reflect physiological distress rather than moral failure, and the euphoria from addictive substances reflects correction of an underlying imbalance rather than an artificial high. Supporting metabolic health directly makes recreational substances less harmful and less likely to become physiological crutches, because better tools already exist for the functions people are using them for: alertness, digestion, anxiety regulation.

The hormonal axis

Addiction is characterized by a dysregulation of the dopaminergic and serotonergic systems: downregulated dopamine production or desensitized dopamine receptors, overproduced serotonin or oversensitized serotonin receptors, and an overall shift toward serotonin dominance. The two systems are mutually antagonistic at the enzyme level: serotonin inhibits tyrosine hydroxylase, the enzyme that synthesizes dopamine, while dopamine inhibits tryptophan hydroxylase (TPH), the enzyme that synthesizes serotonin. Estrogen pushes the balance toward serotonin; progesterone pushes it back toward dopamine. Obese people run lower baseline dopamine, the same low-dopamine/metabolic-dysfunction pattern that shows up in addictive behavior generally.

Chronic stress creates a self-sustaining loop: low dopamine raises serotonin, which lowers dopamine further. Serotonin is the master controller of cortisol synthesis, regulating ACTH through the 5-HT2 receptor. In rats, stress lowered the dopaminergic effects of alcohol and increased drinking; cortisol antagonists abolished the increase and even stopped self-administration of alcohol outright. Alcohol briefly raises GABA activity, which briefly lowers cortisol, part of why stressed people gravitate toward it.

Prolactin is a reliable stress biomarker, elevated in virtually every form of substance abuse, especially alcohol and opioids, and it tends to stay elevated even after the abusive behavior stops. People often show elevated prolactin, cortisol, estrogen, or serotonin *before* an addictive episode, evidence they're already trying to suppress a chronic stress state the addictive behavior only continues.

Estrogen damages cortisol's own negative-feedback loop: with estrogen elevated, the body reads its cortisol supply as insufficient even when it's already adequate, pushing it toward a hypercortisol state. People who abuse alcohol run estrogen levels comparable to chemical castration. Estrogen dominance enables cocaine addiction specifically; progesterone treats it.

Key mediators

Endotoxin and the gut

Endotoxin (lipopolysaccharide) from gut bacteria drives addictive behavior, alcohol consumption most directly: the urge to drink peaks at night, exactly when dopamine is lowest and serotonin highest. Alcohol is itself a TLR4 (endotoxin receptor) agonist, so drinking stimulates more drinking in a direct feed-forward loop, with cortisol rising reactively to hold back the inflammation endotoxin causes. Naltrexone, a TLR4 antagonist, blocks alcohol-abuse behavior; the FDA already prescribes it off-label to curb drinking, under a different official mechanism, since the sanctioned story treats alcoholism as genetic. About 95% of the body's serotonin is produced in the intestine, and once endotoxin outpaces the gut's capacity to handle it, that serotonin surplus itself starts driving prostaglandin formation and nitric oxide release. If endotoxin really is the primary driver of alcohol abuse, antibiotics and charcoal should curb it too, and that prediction holds up.

Endorphins

Serotonin and endorphins get called "happy hormones," but both are primarily stress mediators. Aging lowers beta-endorphin; anything that causes pain, overexertion, or interferes with energy supply raises endorphins instead, while anything that feels good (a massage, for instance) protects against them. Endorphins in turn activate estrogen receptors, aromatase, and prolactin (itself an amplifier of estrogen's effect), compounding into more inflammation and lower energy production. Low-dose naltrexone (LDN) works therapeutically by lowering these harmful endorphins; anything genuinely pleasurable does the same, protecting against both endorphins and nitric oxide.

Thyroid and blood sugar

Hypothyroidism leaves the liver unable to store glycogen effectively, producing a direct craving for sugar and other fast-energy substances.

There's a natural tendency of people who have some hormone imbalance, especially hypothyroidism which makes your liver unable to store glycogen effectively. It causes a natural craving for sugar.

— Ray Peat

I was always extremely craving sugar and generally eating a lot until I took. I was probably about 40 years old when I first took thyroid and I suddenly had no more sugar cravings. I could go eight hours without getting terribly hungry or shaky or thinking about sweet things.

— Ray Peat

Thyroid hormone keeps blood sugar stable; when it's low, blood sugar regulation turns erratic, driving cycles of hypoglycemia that create cravings for sugar, alcohol, caffeine, and anything else that raises blood sugar or masks the symptoms of it. Thyroid hormone is required by the enzymes that run glycolysis and the Krebs cycle, so low thyroid means reduced glucose-oxidation efficiency on top of the erratic supply.

In rats, thyroid extract, thyroxine, or triiodothyronine reduced voluntary alcohol intake.

The thyroid, by keeping the blood sugar up, will stop the sugar craving and it even affects the cravings for salt. A hypothyroid woman, for example, suffers from both sugar and salt cravings premenstrually.

— Ray Peat

Cravings for sugar and sodium track real physiological need closely enough to work as biochemical indexes of it: the insulin/sugar combination is directly anti-inflammatory and suppresses nitric oxide and other inflammatory mediators. A diabetic can't oxidize sugar, so diabetes and hypoglycemia both promote the same inflammatory cytokines by opposite routes, either blocking sugar's use (diabetes) or letting blood sugar drop too far. Sugar has a measurable anti-stress effect on the hypothalamus, lowering CRH synthesis and release; the brain registers glucose fast enough that a sweet mouth rinse alone (no swallowing) can relieve fatigue in runners.

Sugar is even a mild anesthetic for a baby. Getting injections and such, a dose of sucrose is demonstrably calming and actually stops the pain and it lowers adrenaline. So, it's actually not getting enough sugar that makes kids get hyperactive. The immediate effect of sugar is quieting.

— Ray Peat

Behavioral addiction: hypersexual disorder

Men diagnosed with hypersexual disorder ("sex addiction") showed signs of HPA-axis dysregulation. After a low dose of dexamethasone, which normally shuts down the morning cortisol signal, they more often failed to suppress cortisol and kept higher ACTH than healthy men, and the difference held after adjusting for their higher childhood trauma scores. Within the patient group, more severe hypersexual symptoms went with lower baseline cortisol. The study measured one point in time, so it cannot say whether the stress axis change drives the behavior or follows it.

Substance-specific mechanisms

Alcohol

Alcohol addiction runs through the endotoxin and cortisol systems: alcohol is a TLR4/endotoxin agonist that feeds forward on itself, RU486 (a cortisol antagonist) strongly cuts alcohol seeking and craving in alcoholics, and its GABA-boosting effect temporarily lowers cortisol the same way clinical GABA agonists are used for Cushing's hypercortisolemia.

Social context changes the dose response directly: socially connected animals feel alcohol's inebriating effect at much lower doses than isolated ones, since serotonin (elevated in isolation) blunts alcohol's pro-GABA effect. This is also why anti-serotonin drugs like cyproheptadine have worked for treating alcohol abuse and its withdrawal symptoms.

Caffeine and coffee

Caffeine stands apart from the other substances on this page: it functions as genuinely protective rather than compensatory, what Ray Peat called a "vitamin-like nutrient" or adaptogen. Coffee drinkers run a lower incidence of thyroid disease (including cancer) and suicide; caffeine protects the liver against alcohol and acetaminophen, and protects against cancer caused by radiation, chemical carcinogens, viruses, and estrogens.

Serotonin excess causes several of the features of depression, such as learned helplessness and reduced metabolic rate, while coffee stimulates the uptake (inactivation or storage) of serotonin, increases metabolic energy, and tends to improve mood. In animal studies, it reverses the state of helplessness or despair, often more effectively than so-called antidepressants.

— Ray Peat

Caffeine synergizes with progesterone directly, raising its blood and tissue concentration; women spontaneously drink more coffee premenstrually, which reads as a rational, self-directed form of self-medication rather than a coincidence. Caffeine raises brain pregnenolone and progesterone in a dose-dependent way; at the highest dose tested in one rat study, 100 mg/kg, pregnenolone rose 188% and progesterone 388%. Coffee withdrawal headaches relate to elevated nitric oxide in a low-thyroid state; caffeine itself lowers nitric oxide by 10-20%. A cup of strong coffee carries roughly 40 mg of magnesium (dry instant coffee runs close to 0.5% magnesium by weight), on top of nutrients like vitamin B1.

Caffeine has remarkable parallels to thyroid and progesterone, and the use of coffee or tea can help to maintain their production, or compensate for their deficiency.

— Ray Peat

Nicotine

Nicotine inhibits aromatase, lowering estrogen, which may explain part of its appeal for people in hyperestrogenic states. As with smoking generally (see Introduction), the deeper drive is compensation for low CO2 production and poor glucose oxidation rather than nicotine itself; addressing the underlying thyroid/CO2 deficiency reduces the drive to smoke. Women's naturally rising progesterone phase of the menstrual cycle raised the odds of successful smoking cessation on nicotine patches by about 37% in a clinical study. See Progesterone, Nicotine.

Cocaine and other stimulants

Cocaine and stimulants work primarily through dopamine, offering temporary relief from the low-dopamine state of chronic stress, but the stimulant effect rebounds into depletion and rising tolerance. Pregnenolone and progesterone lower cortisol, reduce cravings, and restore normal thyroid function, addressing the underlying deficiency directly rather than pushing the dopamine system itself.

Crash and withdrawal. Abrupt discontinuation of chronic amphetamine use leads to depression, anhedonia, dysphoria, fatigue, and anxiety. In mice, nitric oxide synthase inhibitors and an NMDA-receptor antagonist mitigated the depressive-like behavior of amphetamine withdrawal, which implicates the nitric oxide and NMDA pathways. After the stored norepinephrine has been released and metabolized, these drugs no longer stimulate nerve activity until the body makes more, and depression is common while the supply is low. Amphetamine, like other stressors, depletes rat brain norepinephrine stores without significantly changing dopamine concentrations, and it enhances the toxicity of several other stressors.

Excitotoxicity and thyroid. Pregnenolone and progesterone protect nerves against the excitotoxic amino acids, while estrogen and cortisol act through them to destroy nerves. Excitotoxins destroy dopaminergic and cholinergic nerves and spare noradrenergic ones, paralleling the changes of aging. Amphetamine and caffeine can lower TSH, so TSH can appear normal or low while a real hypothyroidism is present.

Cardiovascular and dopamine data for cocaine and for prescribed stimulants are on the Cocaine and Methylphenidate pages.

Cannabis (THC)

THC administration raises tissue pregnenolone 30-fold, which may account for much of its anxiolytic, stress-relieving effect: pregnenolone is the precursor to every steroid hormone and directly blocks cortisol's action at the cellular level.

Cannabis is antiandrogenic or estrogenic, but it can be protective in some situations. Protein, thyroid, sugars, and saturated fats are protective against both.

— Ray Peat

Cannabis's protective effects trace largely to that pregnenolone stimulation; its potential harms trace to its antiandrogenic and estrogenic properties instead.

Opioids

Opioid addiction runs on elevated prolactin that persists even after the abusive behavior itself stops. Cyproheptadine, an anti-serotonin drug, terminates morphine withdrawal symptoms, addressing the serotonin excess that characterizes withdrawal directly. The endogenous opioid system is itself activated by stress and energy deficit; external opioids relieve that temporarily but deepen dependence by suppressing the body's own endorphin production and disrupting the stress-hormone axis. Naltrexone (including the extended-release form, Vivitrol) blocks opioid receptors, reducing the rewarding effect of both opioids and alcohol through the same shared reward pathway.

Psychedelics (LSD, psilocybin)

Despite acting on serotonin receptors, psychedelics function as anti-serotonin agents overall.

Over the last 40 years, there have been many papers published showing that, starting back with the LSD research, they saw that LSD counteracted the effects of serotonin on smooth muscle, and then finally they showed an antagonistic effect where it inhibits the serotonin nerves in the brain.

— Ray Peat

LSD and related compounds inhibit a subset of serotonin receptors in a way that shuts off serotonin-producing neurons through negative feedback. One of the earliest therapeutic applications discovered was migraine relief, since chronic migraines were already understood as a serotonin-excess problem by the 1950s. Peat also linked the same anti-serotonin action to anti-tumor and anti-inflammatory effects, improved learning, and protection against nerve damage from serotonergic excitotoxicity.

Serotonin constricts, limits perspectives, and LSD, by blocking that, tends to restore perspectives. In excess, LSD creates too many imaginary perspectives, but it illustrates the negative effect on consciousness of too much serotonin.

— Ray Peat

When the US government campaign against LSD-type drugs took hold, drug companies rebranded chemically similar compounds like bromocriptine and lisuride, both of which lower serotonin, as "pro-dopamine" drugs rather than anti-serotonin ones, avoiding any association with the newly demonized hallucinogens. Doses as low as 10 micrograms can deliver anti-serotonin benefits without hallucinogenic effects, though other more accessible options exist for the same effect.

Environmental and social factors

Social isolation

The "Rat Park" effect shows how much social context alone changes addiction susceptibility: isolated animals need far more of an intoxicant than socially connected ones to reach the same effect, since isolation itself raises serotonin, and serotonin blunts alcohol's pro-GABA "drunk" effect. Isolated people aren't reaching for alcohol out of weakness; their neurochemistry genuinely blunts its effect, so it takes more to get there.

Light and circadian rhythm

The urge to drink peaks at night and in darkness, exactly when dopamine is lowest and serotonin highest. Darkness independently stimulates both aggression and eating in animal studies, tracking with the same serotonin rise. Adequate daytime bright light helps hold dopamine up and serotonin down, working against the same addictive drive from the light-exposure side.

Nutritional deficiencies

Several nutrient gaps predispose toward addiction directly: magnesium deficiency tracks with stress, anxiety, and addictive behavior (coffee itself is a significant magnesium source); vitamin B1 (thiamine) is a standard treatment for acute alcohol intoxication and lowers cortisol; adequate protein supports the liver function hormone metabolism depends on; and calcium alongside sugar helps blunt cortisol and cravings under stress. In nutrient-scarce regions of Peru, coca-leaf chewing is common and stops once nutrition improves, The habit may compensate for a real nutritional gap, beyond any stimulant craving.

Treatment

Pregnenolone and progesterone

These two neurosteroids address addiction at its foundation by opposing stress hormones directly and supporting cellular energy.

Progesterone cures essentially everything, trauma, all of the degenerative and stress-related diseases.

— Ray Peat

Pregnenolone blocks cortisol's effects by preventing the cortisol-bound glucocorticoid receptor from translocating into the cell nucleus, and stabilizes damaged mitochondria directly. In experiments, rats given 10 grams per dose of pregnenolone showed no harmful effects beyond normalizing their stress-hormone production. Unlike most hormone supplementation, which suppresses the body's own production, pregnenolone and progesterone support it instead. A clinical trial found pregnenolone reduced stress- and cue-induced craving and anxiety specifically in cocaine use disorder. Even a low-cost behavioral route raises the same neurosteroids: ejaculation measurably increases pregnenolone and DHEA.

You can correct [dopamine deficiency] most safely with progesterone and testosterone or the precursor of both of those, pregnenolone. Because when you try to push the dopamine system, you tend to increase oxidative damage and it is safe to work at the anti-stress level rather than pushing the end product of dopamine.

— Ray Peat

Progesterone destroys estrogen receptors, directly opposing estrogen dominance, and a single dose or two can sometimes be enough to reset the body's own production if thyroid, vitamin A, and cholesterol are otherwise adequate.

Thyroid support

Optimizing thyroid function addresses the metabolic root of the craving cycle directly, restoring anti-stress metabolism, lowering adrenaline and cortisol, and letting tissues metabolize normally; in some cases supplementation eventually restores the body's own thyroid function. Someone with years of accumulated PUFA in their tissues may need thyroid supplementation for several years while diet gradually changes their tissue fat composition.

Neurotrophic factors: BDNF vs GDNF

The two major neurotrophic factors implicated in addiction have opposite regional effects. BDNF (brain-derived neurotrophic factor) elevation in the ventral tegmental area and nucleus accumbens core during withdrawal drives incubation of drug craving and increases relapse vulnerability, whereas GDNF (glial cell line-derived neurotrophic factor) signaling in the same reward circuitry opposes drug-induced adaptations: it normalizes dopamine deficits, reduces alcohol and psychostimulant self-administration, and attenuates relapse across multiple drug classes, making it a candidate anti-addiction target rather than BDNF.

Anti-serotonin agents

Cyproheptadine has treated alcohol abuse and its withdrawal symptoms, terminated morphine withdrawal, and resolved psychotic symptoms in carcinoid or serotonin-syndrome patients. Vitamin D works the same direction by inhibiting TPH and raising dopamine synthesis, alongside dopamine agonists (which inhibit tryptophan hydroxylase directly) and adequate protein/B-vitamin intake to support normal serotonin metabolism.

Low-dose naltrexone works by lowering the harmful endorphins and endogenous opiates the body produces under stress:

The naloxone or naltrexone low dose treatment has a wide range of anti-stress effects, including protection against promotion of cancer.

— Ray Peat

Naltrexone also functions as a TLR4 antagonist, which may explain part of its effect on drinking beyond its action on opioid receptors specifically.

Nutritional approaches

Keeping blood sugar adequate is central: the sugar/insulin combination suppresses inflammatory mediators including nitric oxide, and cravings themselves ease once glycogen is full, youth hormones are high, and stimulation is adequate. Adequate protein supports the liver function that hormone metabolism and estrogen clearance both depend on. Saturated fats protect against PUFA accumulation and support mitochondrial function, and are specifically protective against the estrogenic effects of both alcohol and cannabis. Potassium (plentiful in fruit juice) has an insulin-like action that helps convert sugar to glycogen without the glycemic swings of other carbohydrate sources.

Reducing endotoxin burden helps directly, since it's the primary driver of at least alcohol addiction: raw carrots stay antibacterial through the whole intestine and can bind and carry out toxins via their fiber; resistant starches that human enzymes can't break down but gut bacteria can feed a disturbance of serotonin and nitric oxide (in rats, this manifests as anxiety and aggression); antibiotics and activated charcoal should curb endotoxin-driven alcohol abuse specifically, following the same logic; and fruit digests quickly enough that its sugars and minerals are largely absorbed before reaching the bacterial part of the intestine at all.

Anecdotes and case studies

Extreme caffeine use

A 61-year-old man with hallucinations, paranoia, dementia, and chronic pain had used high-dose caffeine (325-1,300 mg daily) and aspirin (4-17 g daily) since childhood to manage the pain and stress, plausibly staving off degeneration symptoms from underlying hypothyroidism.

A 90-year-old man drank 20-30 cups of coffee daily with cream and sugar and maintained full function and deep sleep, illustrating that high caffeine intake paired with adequate sugar and fat doesn't reliably produce the harms usually blamed on coffee alone.

Diabetics and sugar cravings

[Diabetics with a two-month life expectancy were fed] a regular diet of beef and potatoes and milk... as well as any amount of sugar that they craved, they would generally eat 12 ounces a day of white refined sugar, as well as their regular diet. And instead of dying in a month or six weeks, they recovered, went back to work, no longer diabetic.

— Ray Peat

Keeping blood sugar up to match the craving lowered cortisol, stopped tissue destruction, and stopped free fatty acids from poisoning the pancreas.

Cannabis

Cannabis sativa botanical illustration

Cannabis contains THC, CBD, and other cannabinoid compounds. Effects include sedation, appetite change, anxiety in some users, and dependence risk.

Mechanism

Cannabis is antiandrogenic or estrogenic, but it can be protective in some situations. [CBD] It can probably be helpful for lowering nitric oxide in some situations, but there's some evidence that it increases prostaglandins, which could be harmful in a person whose tissues have a lot of PUFA. The acidic form, CBDA, seems likely to be more broadly protective.

— Ray Peat

The antiandrogenic mechanism is documented directly. Both THC and cannabidiol displaced dihydrotestosterone from the androgen receptor in early binding studies, and a 2022 computational docking study confirmed both cannabinoids bind and inhibit the human androgen receptor with affinities relevant to reproductive dysfunction. In organ-cultured human scalp hair follicles, both the endocannabinoid anandamide and THC dose-dependently inhibited hair shaft elongation and hair-matrix cell proliferation and triggered premature follicle regression, an effect blocked by a CB1-receptor antagonist, a direct mechanistic link between cannabinoid exposure and hair loss.

Pharmacologically, THC binds a receptor complex combining CB1 with the serotonin 5-HT2A receptor, while CBD acts at 5-HT1A, 5-HT2A, and 5-HT3A receptors; cannabis doesn't raise serotonin directly so much as modulate serotonergic signaling and receptor activity. Separately, both THC and CBD suppress mitogen-stimulated tryptophan degradation via indoleamine-2,3-dioxygenase (IDO), which would tend to preserve tryptophan for serotonin synthesis rather than deplete it. A randomized, double-blind, placebo-controlled human laboratory study in 20 participants, using cannabis with 6.9% (about 50.6 mg) THC, found oral, smoked, and vaporized cannabis all altered endocrine pathways tied to appetite and metabolism, chiefly blunting the insulin spike normally seen after eating.

Mental health

Chronic cannabis use is associated with hypodopaminergic anhedonia, cognitive decline, poor memory, inattention, and impaired learning in young adults, with concern rising alongside the higher THC content of modern vaped and edible products; a proposed "dopamine homeostasis" restoration approach is preliminary, not established treatment. A systematic review and meta-analysis found cannabis use associated with earlier onset and worse course of bipolar disorder. Epigenetic (DNA methylation) signatures distinguishing current cannabis users appeared in two independent first-episode psychosis cohorts, a molecular correlate of the clinical cannabis-psychosis link.

Contaminants

Cannabis is a metal hyperaccumulator. In NHANES data (2005-2018, n=7,254), exclusive marijuana users had significantly higher blood and urinary cadmium and higher blood lead than non-users of marijuana or tobacco, after adjusting for tobacco use.

Practice

Smoking adds combustion toxins on top of any cannabinoid effect; edible dosing is easy to overshoot since onset is delayed and variable. Cannabis is not a foundational metabolic therapy in the bioenergetic framework; it's a recreational/symptomatic tool with its own risk profile, antiandrogenic/estrogenic in Peat's assessment though CBDA may be more broadly protective. Local law and personal mental-health history (cannabis can worsen anxiety and, in vulnerable people, psychosis risk) matter before use.

Harm reduction

The harms Peat's framework emphasizes are estrogenic and antiandrogenic effects, smoke exposure, and psychosis risk in vulnerable users. The measures below lower some of that load; they do not make heavy use safe.

Problem	Mechanism	Mitigation
Estrogenic and antiandrogenic effects	Cannabis is antiandrogenic or estrogenic. Heavy marijuana smoking is definitely estrogenic, though some of that may come from any kind of smoke.	Protein, thyroid, sugars, and saturated fats are protective against both alcohol and cannabis.
Smoke	The main danger of smoke is polycyclic aromatic hydrocarbons, which are inflammatory, estrogenic, and carcinogenic. Carbon monoxide can accumulate and have chronic harmful effects.	Not burning it removes the combustion load. Edibles trade that for delayed, easily overshot dosing, see practice.
Prostaglandins	Some evidence that cannabis increases prostaglandins, which could be harmful in a person whose tissues hold a lot of PUFA.	The acidic form of CBD, CBDA, seems likely to be more broadly protective.
Psychosis risk	In mice, chronic THC exposure during adolescence increased pro-hallucinogenic signaling of the serotonin 5-HT2A receptor.	Avoidance is the only measure the sources support. See mental health.
Withdrawal and liver load	Coming off, adrenaline can rise to compensate for low thyroid function and dilate the pupils. Heavy use interferes with liver function.	A preparation containing both T4 and T3 (such as Armour thyroid) may work better than T4 alone, and thyroid medication needs a physician. While the liver recovers, eat enough protein daily: orange juice, eggs, milk, cheese, cooked mushrooms, occasional shellfish.

Acute intoxication is managed supportively. The most common emergency presentations are anxiety, tachycardia, dizziness, and transient psychotic reactions, and a calm environment, reassurance, and observation are generally sufficient; most cases resolve within a few hours. A clinician may give a benzodiazepine for agitation or panic. Rare complications include acute coronary events, mostly in young adults without prior cardiovascular disease. Synthetic cannabinoids are full agonists that can be several hundred times more potent than THC, with unpredictable toxicity including seizures and hyperthermia.

Withdrawal

Drug withdrawal (drug withdrawal syndrome) is a cluster of adverse effects that can follow dose reduction or stoppage of a drug that the body has adapted to. Reporting databases such as the U.S. FDA Adverse Event Reporting System (FAERS) capture spontaneous reports of withdrawal-coded events; disproportionality metrics such as the reporting odds ratio (ROR) flag drugs that appear more often than expected among those reports. ROR is a reporting signal, not a measure of how common withdrawal is among people who take the drug.

FAERS disproportionality (2004 Q1–2023 Q3)

A Frontiers in Pharmacology analysis of FAERS from the first quarter of 2004 through the third quarter of 2023 identified 94,370 reports coded to drug withdrawal syndrome and screened the 50 drugs with the highest report counts; 29 of those drugs showed a positive disproportionality signal (ROR and proportional reporting ratio). The strongest signal categories were opioids, antidepressant drugs, and antianxiety drugs; other classes with positive signals included an opioid antagonist, a muscle relaxant (baclofen), antiepileptics, analgesics, hypnotic-sedatives, and antipsychotics.

FAERS is a spontaneous reporting system. Disproportionality establishes a statistical association in reported events and does not prove that a drug causes withdrawal, does not estimate clinical incidence or prevalence among users, and can be skewed by reporting biases, exposure volume, and confounding.

Ranking by reporting odds ratio

Among drugs ranked by reporting signal intensity, the top three signals were for oxycodone, butorphanol, and hydromorphone hydrochloride.

Antidepressants with strong signals included:

• Paroxetine: ROR 29.36 (28.59–30.15), fourth overall by ROR and above several opioids in that ranking
• Duloxetine: ROR 17.41 (17.00–17.83)
• Venlafaxine: ROR 10.32 (9.98–10.67)

Among anxiolytics, alprazolam, lorazepam, and diazepam showed positive withdrawal signals; baclofen (muscle relaxant) had ROR 18.49 (17.64–19.38), and naloxegol (opioid antagonist) 13.23 (11.15–15.69). Treat every ROR above as a FAERS reporting disproportion, not as a clinical incidence rate.

Serotonergic antidepressant withdrawal as an acute stoppage or taper syndrome is distinct from Post-SSRI Sexual Dysfunction, which by definition persists after the drug is stopped. See SSRIs for SSRI-class context.

Opiates

Morphine is an opioid analgesic and the reference compound for the opioid drug class, acting on mu-opioid receptors for pain relief and, with chronic use, physical dependence.

Morphine withdrawal as a hot-flash model

Ray Peat discussed morphine less as a clinical drug than as a research tool: morphine withdrawal in animals is a standard experimental model for hot flashes, because it produces the same flushing and temperature changes seen in menopausal hot flashes, and because estrogen can suppress the flushing in both cases.

One of the animal 'models' used to study hot flashes is morphine withdrawal.

— Ray Peat

The model seems relevant to human hot flashes, because estrogen can stop the morphine withdrawal flushing... estrogen's acute and chronic effects on the brain-pituitary-ovary system involve the endorphins and the opioidergic nerves.

— Ray Peat

In young rats, precipitating morphine withdrawal with naloxone causes tail-skin flushing and a small drop in core temperature, the same withdrawal-flushing response very large doses of estrogen can suppress. The shared opioid and endorphin response offers a mechanism for hot flashes beyond a simple "estrogen deficiency."

Clinical use

As a drug, morphine is a standard-of-care opioid for severe acute and cancer pain. It carries the class risks common to opioids: tolerance, physical dependence, respiratory depression in overdose, and constipation.

See also

• Learned helplessness
• Loneliness