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Alfaxalone (also spelled alphaxalone) is a synthetic neuroactive steroid of the pregnane class that produces general anesthesia by acting as a positive allosteric modulator (a molecule that amplifies a receptor's response to its own neurotransmitter) at the GABA-A receptor, the principal inhibitory ion channel of the central nervous system. First introduced in 1971 as the main active component of the intravenous anesthetics Althesin (human) and Saffan (veterinary), it was withdrawn from human use in the 1980s because the solubilizing vehicle Cremophor EL provoked anaphylactoid reactions, then reintroduced in a cyclodextrin formulation marketed for veterinary anesthesia as Alfaxan. Because it lacks classical hormonal activity yet retains rapid, non-cumulative central depressant effects, alfaxalone occupies a distinct pharmacological niche among intravenous anesthetics and now serves as a template for a new generation of water-soluble neurosteroid sedatives such as Phaxan.
- Fast, smooth anaesthetic induction
- Rapid recovery
- Wide safety margin in cyclodextrin form
- Gold-standard research probe for the neurosteroid GABA-A site
- Produces rapid, smooth induction of general anesthesia
- Fast, non-cumulative recovery even after repeated doses or continuous infusion
- Wide margin of safety and relative cardiovascular stability compared with older induction agents
- Effective across an exceptionally broad range of species, including exotics such as reptiles and fish
- Cyclodextrin formulation avoids the histamine-releasing Cremophor vehicle, reducing anaphylactoid risk
- Preclinical evidence suggests less neuronal apoptosis than some conventional anesthetics
- Activates pregnane X receptor signaling linked to raised BDNF and preserved postoperative cognition in early studies
- Respiratory depression and apnea on rapid injection
- Hypotension
- Dose-dependent cardiovascular depression
- Dose-dependent respiratory depression and apnea after rapid intravenous injection
- Transient muscle twitching, tremor, or paddling movements
Overview
A synthetic pregnane neurosteroid anesthetic that potentiates GABA-A receptors; the active core of the historic Althesin and Saffan mixtures, now a cyclodextrin-solubilized veterinary induction agent and a scaffold for water-soluble neurosteroid sedatives.
- it was once a mainstream human anaesthetic (Althesin) but was pulled because of its castor-oil solvent, not the drug.
- it is now mostly a veterinary anaesthetic (Alfaxan) for cats and dogs.
- at anaesthetic doses it can open the GABA-A chloride channel directly, not just amplify GABA.
- the modern fix was caging it inside a cyclodextrin sugar ring to make it water-soluble.
- The hypnotic power of steroids was discovered in 1941 by Hans Selye, who found that injecting progesterone rapidly put rats to sleep; alfaxalone was later engineered to keep this GABAergic anesthetic action while shedding classical hormonal activity.
- Most of the pain relief from the original Saffan and Althesin preparations came from the second steroid in the mixture, alfadolone, acting on spinal GABA-A receptors, and not from alfaxalone itself.
- Alfaxalone anesthesia cannot be reversed with flumazenil, the standard benzodiazepine antidote, because neurosteroids occupy a distinct binding site on the GABA-A receptor.
- Alfaxalone works across vertebrate classes, so fish such as koi carp and rainbow trout can be anesthetized simply by immersion in a drug bath.
Mechanism
Alfaxalone is 3-alpha-hydroxy-5-alpha-pregnane-11,20-dione, a synthetic analogue of endogenous ring-A-reduced pregnane neurosteroids such as allopregnanolone. Its defining action is positive modulation of the -A receptor, the main inhibitory chloride channel of the brain: at nanomolar to low micromolar concentrations it binds a transmembrane site distinct from the neurotransmitter pocket and prolongs channel open time, increasing chloride influx, hyperpolarizing neurons, and deepening inhibitory tone.
Voltage-clamp studies in bovine chromaffin cells and rat cuneate nucleus slices established that this potentiation is strictly stereoselective, requiring a 3-alpha-hydroxyl group on a ring-A-reduced steroid backbone, whereas the 3-beta epimer is largely inactive. At higher concentrations alfaxalone also directly gates the channel as an , opening -A receptors even without GABA present, which contributes to the steep concentration-response relationship underlying surgical anesthesia.
Photoaffinity-labeling experiments localized the modulatory neurosteroid site to an intersubunit interface between the third transmembrane helix of a beta subunit and the first transmembrane helix of the neighboring alpha subunit, a pocket separate from the site that mediates direct activation. The drug potentiates both -A receptors, which mediate fast phasic inhibition, and extrasynaptic delta-subunit-containing receptors, which generate a persistent tonic current important for deep sedation and reduced arousal.
Its action is insensitive to the benzodiazepine flumazenil, confirming that the neurosteroid site is pharmacologically separate from the benzodiazepine site. Beyond the ion channel, alfaxalone activates the pregnane X receptor, a nuclear transcription factor, a genomic action associated with increased brain-derived neurotrophic factor and preservation of postoperative cognition. It is cleared rapidly by hepatic phase I oxidation and phase II conjugation, giving a short and non-cumulative recovery; notably, the historically co-formulated steroid alfadolone, rather than alfaxalone itself, carried most of the spinal -A-mediated antinociceptive activity of the original mixtures.
receptor fingerprint
-A receptor ( and extrasynaptic)positive allosteric modulator; at anaesthetic concentrations also directly activates (gates) the chloride channel
-A receptor (delta-subunit extrasynaptic)positive allosteric modulator of tonic inhibition, like other neurosteroids
-A receptor (, gamma-subunit-containing)Positive allosteric modulation that prolongs chloride channel opening
-A receptor (extrasynaptic, delta-subunit-containing)Positive allosteric modulation of the persistent tonic current
-A receptor (direct channel gating)Agonist at higher concentrations, opening the channel without GABA
Pregnane X receptor (PXR)Nuclear receptor agonist
Spinal -A antinociceptive circuitsPositive modulation contributing to antinociception
Safetyrisks and cautions, not medical advice
In its modern cyclodextrin formulation alfaxalone has a wide therapeutic index and a favorable cardiovascular profile relative to older induction agents; controlled comparisons in dogs show that it tends to preserve mean arterial pressure and cardiac output by raising heart rate, whereas propofol more often produces hypotension. The dominant adverse effects are dose-dependent respiratory depression and apnea after rapid injection, transient muscle twitching or tremor, and occasionally rough or excitable recoveries when the drug is used without sedative premedication.
The anaphylactoid reactions that ended human use of Althesin are attributed to the polyethoxylated castor oil vehicle Cremophor EL rather than to alfaxalone itself; reformulation in 2-hydroxypropyl-beta-cyclodextrin or sulfobutylether-beta-cyclodextrin removed that hazard, and human phase 1 studies of the aqueous preparation reported no pain on injection and cardiovascular stability.
Pharmacodynamic sensitivity varies with sex and hormonal status, an effect first reported in rats in which females remained anesthetized longer than males in an apparently oestrogen-dependent manner. Because its effects are not reversed by flumazenil, management of overdose is supportive. Alfaxalone is a controlled substance in several jurisdictions owing to a recognized potential for misuse.
History
Alfaxalone emerged from a Glaxo research program in the late 1960s that screened steroids for the rapid anesthetic property first noted for progesterone by Hans Selye in 1941. Combined with a second solubilizing steroid, alfadolone acetate, and dissolved in about 20 percent Cremophor EL, it was marketed from 1971 as the code compound CT-1341, sold for human anesthesia as Althesin and for veterinary anesthesia as Saffan.
The mixture was prized for smooth, quickly reversible anesthesia, but a low yet persistent rate of anaphylactoid reactions attributed to the Cremophor vehicle led to withdrawal of Althesin from human practice in 1984; Saffan remained in veterinary use, though it was contraindicated in dogs, which were particularly prone to histamine release.
Throughout the 1970s and 1980s Althesin was studied extensively as a research tool, including cerebral metabolic mapping with 2-deoxyglucose autoradiography and interaction experiments with the newly discovered benzodiazepine antagonist Ro 15-1788, now called flumazenil. The compound was revived commercially around 2000, when substituting Cremophor with 2-hydroxypropyl-beta-cyclodextrin yielded Alfaxan, now a widely used small-animal and exotic-species induction agent. Concurrent work by Colin Goodchild and colleagues produced Phaxan, a water-soluble alphaxalone preparation in sulfobutylether-beta-cyclodextrin, which returned the molecule to human phase 1 trials as a potential propofol alternative.
Reputation
Within veterinary medicine alfaxalone enjoys a strong reputation as a versatile induction agent, valued for hemodynamic stability, a wide safety margin, and utility across an unusually broad range of species, from cats and dogs to horses, reptiles, amphibians, and fish, in which it can even be delivered by immersion. Among neuropharmacologists it is regarded as a cleaner experimental probe of GABA-A receptor modulation than the endogenous neurosteroids, and it has become a reference hypnotic in studies arguing that neurosteroid anesthetics may spare developing neurons from the apoptosis linked to older agents.
In human anesthesia its reputation is bifurcated: the original Althesin is remembered both as an elegant steroid anesthetic and as a cautionary tale about formulation vehicles, while the cyclodextrin-solubilized successor is viewed as a promising, cardiovascularly stable candidate that has yet to reach broad clinical adoption. Recreationally the compound carries a minor reputation for misuse, reflected in its scheduling in some jurisdictions.
Subjective profileweighing the evidence above
A genuinely good anaesthetic in its modern cyclodextrin form, with a wide margin and better blood-pressure behaviour than propofol, and still the reference probe for the neurosteroid GABA-A site. It is also an injectable that causes apnea if pushed in too fast, so it belongs entirely in trained hands.
Resources
This entry is here for reference.
Research
- 1982first citedSex difference in response to alphaxalone anaesthesia may be oestrogen dependent.
- 2015controlled trialA Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone…
- 2020most active year4 papers
- 2025most recentFailure of intravenous flumazenil to antagonize alfaxalone anesthesia in cats.
- 1.Alfaxalone is an effective anesthetic for the electrophysiological study of anoxia-tolerance mechanisms in western painted turtle pyramidal neurons.
- 2.Modulation of GABAA receptor activity by alphaxalone.
- 3.Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids.
- 4.Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.
- 5.Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes.
- 6.Neurosteroid modulation of native and recombinant GABAA receptors.
- 7.Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABA(A)) receptors.
- 8.Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA(A) currents, but are not neurotoxic to the developing rat brain.
- 9.Binding site location on GABA(A) receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo.
- 10.Sex difference in response to alphaxalone anaesthesia may be oestrogen dependent.
- 11.Local changes in cerebral 2-deoxyglucose uptake during alphaxalone anaesthesia with special reference to the habenulo-interpeduncular system.
- 12.In vivo interactions between the benzodiazepine antagonist Ro 15-1788 and the steroid anaesthetic althesin in rats.
27 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is alfaxalone used for?
as a fast-acting general anaesthetic. it was once used in humans (Althesin) and today is mainly a veterinary induction agent (Alfaxan) for cats and dogs.
Why was it removed from human medicine?
not because of the steroid itself but because the original formulation dissolved it in Cremophor EL (polyethoxylated castor oil), which caused histamine release and anaphylaxis. the drug was later reformulated in cyclodextrin.
How does it work?
it is a neurosteroid that strongly potentiates GABA-A receptors, and at anaesthetic doses can open the chloride channel directly, producing rapid loss of consciousness.
Is it related to allopregnanolone?
yes; it is a synthetic pregnane steroid acting at the same neurosteroid site on the GABA-A receptor as the body's own allopregnanolone, which is why it is grouped with the neurosteroid anaesthetics.
Can I use it as a sleep or calm aid?
no; it is an injectable general anaesthetic with a short step to apnea, given only under professional monitoring. any non-clinical use is dangerous.
Is it a controlled substance?
it is a prescription veterinary anaesthetic; in several jurisdictions it is scheduled due to misuse potential. it is not an over-the-counter product anywhere.
Is alfaxalone the same as allopregnanolone or ganaxolone?
No. All three are pregnane neurosteroids that positively modulate GABA-A receptors, but alfaxalone is a distinct synthetic molecule (3-alpha-hydroxy-5-alpha-pregnane-11,20-dione) developed as an anesthetic, whereas allopregnanolone is an endogenous hormone metabolite and ganaxolone is a separate synthetic analogue approved as an anticonvulsant.
Why was Althesin taken off the human market?
The alfaxalone molecule was not the main problem; the injectable had to be dissolved in Cremophor EL, a castor oil surfactant that triggered histamine release and occasional severe anaphylactoid reactions, which led to withdrawal from human use in 1984.
Is alfaxalone used in people today?
Not in routine practice. It is mainly a veterinary anesthetic marketed as Alfaxan, but a water-soluble cyclodextrin version called Phaxan has been tested in human phase 1 trials as a possible propofol alternative.
Does alfaxalone act like a benzodiazepine?
It enhances the same inhibitory GABA-A receptor, but through a different, neurosteroid-specific binding site; consequently its anesthesia is not reversed by the benzodiazepine antagonist flumazenil.
Is alfaxalone a nootropic or cognitive enhancer?
No. It is a general anesthetic and central depressant, not a cognitive enhancer, although some research links its activation of pregnane X receptors to increased BDNF and better preservation of cognition after surgery compared with certain other anesthetics.
Adverse effects
- Respiratory depression and apnea on rapid injection
- Hypotension
- Dose-dependent cardiovascular depression
- Dose-dependent respiratory depression and apnea after rapid intravenous injection
- Transient muscle twitching, tremor, or paddling movements
Notes and cautions
- Not for home or recreational use
- Rough or excitable recoveries when used without sedative premedication
- Anaphylactoid reactions with the historical Cremophor EL vehicle (Althesin and Saffan)
- Not reversible with flumazenil, so overdose management is supportive
- Potential for misuse; scheduled as a controlled substance in some regions