From Wikipedia, the free encyclopedia
Jump to: navigation, search
Trihexyphenidyl ball-and-stick.png
Systematic (IUPAC) name
Clinical data
AHFS/ monograph
MedlinePlus a682160
Pregnancy cat.
Legal status
  • Rx-Only (US)
Routes Oral, as tablet or elixir
Pharmacokinetic data
Half-life 3.3-4.1 hours
CAS number 144-11-6 YesY
ATC code N04AA01
PubChem CID 5572
DrugBank DB00376
ChemSpider 5371 YesY
KEGG D08638 YesY
Chemical data
Formula C20H31NO 
Mol. mass 301.466 g/mol
 YesY (what is this?)  (verify)

Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol and trihex, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades. The drug is available as the hydrochloride salt.


The exact mechanism of action in parkinsonian syndromes is not precisely understood, but it is known that trihexyphenidyl blocks efferent impulses in parasympathetically innervated structures like smooth muscles (spasmolytic activity), salivary glands, and eyes (mydriasis). In higher doses direct central inhibition of cerebral motor centers may contribute. In very high doses central toxicity as seen in atropine overdose is noted.

It binds to the M1 muscarinic receptor[1] and possibly the dopamine receptor.[2]


Trihexyphenidyl is rapidly absorbed from the gastrointestinal tract. The onset of action is within 1 hour after oral dosing. The peak activity is noted after 2 to 3 hours. The duration of action of one single dose is 6 to 12 hours in a dose dependent manner. It is excreted in the urine, probably as unchanged drug. More precise data in animals and humans have so far not been determined.


Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono- and combination therapy. It is active in postencephalitic, arteriosclerotic, and idiopathic forms. The drug is also commonly used to treat extrapyramidal side effects occurring during antipsychotic treatment. It reduces the frequency and duration of oculogyric crises as well as of dyskinetic movements and spastic contractions. Excessive salivation may also respond. Trihexyphenidyl may improve psychotic depression and mental inertia frequently associated with Parkinson's disease and symptomatic problems caused by antipsychotic treatment.

The drug cannot cure Parkinson's disease, but may provide substantial alleviation of symptoms. An estimated 50 to 75% of patients with Parkinson's disease will react positively and experience a 20 to 30% symptomatic improvement. To increase therapeutic activity trihexyphenidyl is often given concomitantly with levodopa, other antimuscarinic or antihistaminic (e.g. diphenhydramine) agents. Combination treatment with dopaminergic agonists such as cabergoline is also possible. This is often termed a 'multidimensional approach'.

It has also been prescribed for essential tremor and akathisia.


Equivocal preliminary results from small studies exist for:

Trihexyphenidyl does not improve cerebral palsy and hemiplegia.

Contraindications and cautions[edit]

  • Hypersensitivity to trihexyphenidyl
  • Narrow angle glaucoma
  • Ileus
  • Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia
  • Patients under 18 yrs. of age should not be treated due to a lack of clinical experience.
  • Patients should allow a period to adjust to the dose when first starting trihexyphenidyl and when the dose has been increased or added to a regimen with other drugs because acute somnolence and accumulated fatigue can make it particularly dangerous to operate an automobile, heavy machinery etc.

Pregnancy and lactation[edit]

The safe use of Trihexyphenidyl during pregnancy and lactation has not been established.

Side effects[edit]

Dose-dependent side effects are frequent. Particularly geriatric patients may react with confusional states or develop delirium.

  • CNS : Drowsiness, vertigo, headache, and dizziness are frequent. With high doses nervousness, agitation, anxiety, delirium, and confusion are noted. Trihexyphenidyl may be abused due to a short acting mood-elevating and euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Trihexyphenidyl may lower the seizure-threshold.
  • Peripheral side effects : Blurred vision, dry mouth, impaired sweating, abdominal discomfort, and constipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension.
  • Eyes : Trihexyphenidyl causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma.
  • Tolerance may develop during therapy which requires dose adjustments.


  • Other anticholinergic drugs (e.g. spasmolytics, antihistamines, TCAs) : Side effects of trihexyphenidyl may be increased.
  • Quinidine : Increased anticholinergic action (particular on AV conduction).
  • Antipsychotics : Long term use of trihexyphenidyl may mask or increase the risk of tardive dyskinesia.
  • Pethidine (meperidine) : Central effects and side effects of pethidine may be increased.
  • Metoclopramide : Action of metoclopramide is decreased.
  • Alcohol : Risk of serious intoxication.


  • Parkinson's disease : One mg is given on the first day. Increments are usually 2 mg every 3 days until 6 to 10 mg are reached. In postencephalitic cases up to 15 mg might be necessary, but then excessive dryness of mouth or nausea could be a problem. To increase tolerability Trihexyphenidyl may be given in 3 divided doses.
  • Extrapyramidal side effects : Usually, 5 to 15 mg daily are needed in 2 or 3 divided doses. Some patients, however, are successfully treated with as little as 1 mg daily.


Trihexyphenidyl mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particularly in children. Premortal signs are respiratory depression and cardiac arrest. A specific antagonist is physostigmine which combines a peripheral and a central action. Carbachol can be used to treat atonic bowel and bladder. The vital functions should be monitored and stabilized. It may be necessary to treat hyperthermia with cooling blankets.

Recreational use[edit]

In a 2008 news report, trihexyphenidyl has been used recreationally among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress.[4]

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s.[5]

Trihexyphenidyl can be used via virtually all routes of administration, and smoking it mixed into opium and chasing the dragon with morphine, heroin etc. have also been reported (see below).

As is the case with structurally-similar agents such as dicycloverine/dicyclomine (q.v.), scopolamine (q.v.), benztropine and others, there are several different groups of recreational users who use the drug for very different reasons. They could be divided into eight groups, the first of which has virtually no overlap with next six, and the last on the list is somewhat mysterious and may combine parts of the other seven, which do share the same much lower dose range and probably overlap to a high degree. Some of the uses grade off into off-label therapeutic uses, e.g. to combat excessive sweating, hasten sleep, and others. Of course, using any medication in a manner other than that intended can pose problems. In rough order of descending doses usually used, trihexyphenidyl abusers/misuers/unsupervised users can be said to be:

  • I. Hallucinogen (Anticholinergic & Deliriant Categories): There are those who use dangerously high doses to induce delirium and hallucinations, much as is done with Datura stramonium and Atropa belladonna preparations. As this article and its sources state elsewhere, this is an exceedingly dangerous pastime which can cause death by several different mechanisms ranging from dehydration to hyperthermia to accidents. An example of the latter cited in the book Chocolate To Morphine[6] and elsewhere is when people who have taken huge doses of anticholinergics for delirium go looking for water to slake the great thirst that arises from using the drug and stumble into bodies of water and drown. Some in this group seek it out specifically for the very real-seeming hallucinations and/or feeling for flying, much like Witches' Ointments through the ages.
  • II. Stimulant or Set-Up: At much lower doses, ranging from sub-therapeutic to still quite elevated, trihexyphenidyl can have a marked stimulating effect. As is the case with many anticholinergics such as ethanolamine and alkylamine first-generation antihistamines, there are some people, the elderly in particular, who experience the dopaminergic and atropine-like excitant effect without much CNS depression. Euphoria is one result of drugs like these being administered. Use in Iraq and elsewhere of use of trihexyphenidyl in conjunction with caffeine, other natural stimulants, or centrally-acting stimulants is described in recent literature on the topic. Pure amphetamine-type stimulation from an anticholinergic on its own is very unlikely but the observed effects of the elevated doses and an altered means of administration can lead to a characteristic anticholinergic-based euphoria which can even under some conditions, usually parenteral administration but not always, manifest as a "bang" and "rush" as well as being functionally similar to a "set-up", meaning a combination of a stimulant (most often centrally-acting like amphetamines) and depressants or related drugs of many descriptions ranging from barbiturates to opioids to beta-blockers and antihistamines in some cases. Many of the effects of trihexyphenidyl are boosted with centrally-acting stimulants as well.
  • III. Non-Benzodiazepine Tranquilliser/Daytime Sedative: The aforementioned anxiolysis users achieve the desired effect with a dose much closer to the therapeutic dose, with the changes wrought by changing the route of administration from oral to injection or smoking having some effect. There are those who also take it, usually by mouth, as a specific against insomnia although for many people it has the opposite effect. The tranquillising effect appears to be a very commonly-sought result in Iraq amongst police and armed forces.
  • IV. Euphoriant (Dopaminergic): Therapeutic or somewhat elevated doses can also have a marked anti-depressant effect in many people in addition to anxiolysis with promotion of sociability being a noted.[7] It is from a combination of altering the acetylcholine/dopamine ration in the CNS to favour the latter and some structural similarities to tricyclics. A similar anti-depressant effect to that seen with scopolamine (q.v.) in clinical trials in the past few years (q.q.v.) is the reason for research into medical use in cases of refractory depression, and the anticholinergic-antidepressant connexion can also be seen in cases such as orphenadrine (q.v.), cyclobenzaprine,[8] and dicycloverine/dicyclomine, which are structurally related to tricyclic antidepressants, although the tricyclics are stronger and have dirtier side effect profiles. The use of trihexyphenidyl as self-medication for depression and use by non-depressed people for euphoria is mentioned en passant in the DSM IV and research on anticholinergic abuse in general has appeared in recent decades.
  • V. Opioid Potentiator: Trihexyphenidyl is also used in a manner similar to some first-generation antihistamines like diphenhydramine, tripelennamine, brompheniramine, hydroxyzine, cyproheptadine and members of each of those antihistamine families, some anticholinergic eye drops, and similar drugs to enhance the effectiveness of narcotic analgesics[9] by non-clinical users and others seeking better analgesia and euphoria from a given quantity of drug. One of the dangers of this kind of combination is severe constipation proceeding to paralytic ileus.[10] Trihexyphenidyl is quite similar to dicyclomine and both are used in clinical research as active placebos for morphine, levorphanol, and other sedative-hypnotic and opioid (narcotic) drugs. Intensification of "The Nod" after simultaneous use of narcotics like morphine, nicomorphine, and hydromorphone with trihexyphenidyl is noted by some users as is the tendency to simply fall asleep.[11]
  • VI. Aphrodisiac: This group of recreational users claim that trihexyphenidyl has a marked aphrodisiac effect intermediate which at least some users have described as being intermediate between that of dicycloverine/dicyclomine and methaqualone and sharing many parts of both;[12] scientific disagreement about whether there is even such a thing as an aphrodisiac is a reason why there is controversy about this. This would appear to be the smallest group because of the percentage of people who do not like the other side effects of anticholinergics. There is considerable lore about the tendency of dicycloverine/dicyclomine "to make people horny" and trihexyphenidyl reportedly is stronger and like dicycloverine/dicyclomine also has a remarkably fast onset of action when taken orally, buccal and sublingual administration even more so. This is an excitant effect, but trihexyphenidyl also appears to be more of an anxiolytic than dicycloverine/dicyclomine, and to last longer; this is also the case with the euphoriant effect.
  • VII. Labelled Uses: Of course, trihexyphenidyl can be used to combat the effects other drugs being taken for whatever reason.
  • VIII. Berserker Pre-Medication: In the Middle East and other regions reports occasionally surface of an uncommon military and civilian use for high doses of trihexyphenidyl (often along with stimulants and/or alcohol), specifically that of soldiers, police, or others use it to prepare for engagement in conflict, essentially working themselves into an uncontrollable frenzy like the berserkers of past centuries, some of whom were known to use plant-based anticholinergics like henbane and belladonna for this reason.

The street names for trihexyphenidyl include its trade name Artane® and the following, in alphabetical order: courage, octane, Sexy Trihexy, T Rex, Tri-Sexual. Except as noted elsewhere in the article, trihexyphenidyl is not as common on the street many places.

Dosage forms and availability[edit]

  • Elixir, as hydrochloride: 2 mg/5 mL (480 mL)
  • Tablet, as hydrochloride: 2 mg, 5 mg


Trihexyphenidyl, 1-cyclohexyl-1-phenyl-3-piperidineopropan-1-ol, is synthesized in two ways (linear and convergent synthesis):

In the first way, the initial 2-(1-piperidino)propiophenone is synthesized in turn by the aminomethylation of acetophenone using paraformaldehyde and piperidine in a so-called Mannich reaction. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesiumbromide in a Grignard reaction. [13][14][15][16]

Trihexyphenidyl Syntheses.png

Linear vs Convergent syntheses. Although the convergent synthesis is used on an industrial scale, it is uses hazardous reagents and is not as desirable as the linear procedure for small-scale preparations.


  1. ^ Giachetti, A.; Giraldo, E.; Ladinsky, H.; Montagna, E. (1986). "Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine". British Journal of Pharmacology 89 (1): 83–90. doi:10.1111/j.1476-5381.1986.tb11123.x. PMC 1917044. PMID 2432979.  edit
  2. ^ Berke, J. D.; Hyman, S. E. (2000). "Addiction, dopamine, and the molecular mechanisms of memory". Neuron 25 (3): 515–532. doi:10.1016/S0896-6273(00)81056-9. PMID 10774721.  edit
  3. ^ Sanger, T. D.; Bastian, A.; Brunstrom, J.; Damiano, D.; Delgado, M.; Dure, L.; Gaebler-Spira, D.; Hoon, A.; Mink, J. W.; Sherman-Levine, S.; Welty, L. J.; Child Motor Study, G. (2007). "Prospective Open-Label Clinical Trial of Trihexyphenidyl in Children with Secondary Dystonia due to Cerebral Palsy". Journal of Child Neurology 22 (5): 530–537. doi:10.1177/0883073807302601. PMID 17690057.  edit
  4. ^ Mudhafer Al-Husaini; Erica Goode (2008-12-20), Abuse of Prescription Drugs Rises Among Stressed Iraqi Soldiers, New York Times 
  5. ^ Oliver Sacks shares his hallucinations, Guardian, 2012-10-30 
  6. ^ Chocolate To Morphine
  7. ^ Inside Narcotics, 5th Edition (2010), Ch VII
  8. ^ Inside Narcotics, 5th Edition (2010), Ch VII
  9. ^
  10. ^ Morphine
  11. ^ Inside Narcotics
  12. ^ Inside Narcotics, Ch XI
  13. ^ US patent 2680115, Wayne, R. A., "Substituted tertiary-aminoalkyl carbinols", issued 1954-06-01 
  14. ^ US patent 2716121, Denton, J. J., "Basic tertiary piperidino alcohols", issued 1955-08-23 
  15. ^ US patent 2682543, Wilkinson, S. & Adamson, D. W., "Catalytic reduction of diphenyl-alkanolamines", issued 1954-06-29 
  16. ^ GB patent 750156, Adamson, D. W. & Duffin, W., "Improvements in cyclohexyl-phenyl-amino-propanols", issued 1956-06-13 

External links[edit]