Phenmetrazine (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
,
USAN
280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk(于山國)was Ulleungdo(鬱陵島)
Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...
,
BAN) (brand name Preludin, and many others) is a
stimulant drug first synthesized in 1952 and originally used as an
appetite suppressant
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" ...
, but withdrawn from the market in the 1980s due to widespread
abuse. It was initially replaced by its
analogue phendimetrazine
Phendimetrazine (Bontril, Adipost, Anorex-SR, Appecon, Melfiat, Obezine, Phendiet, Plegine, Prelu-2, Statobex) is a stimulant drug of the morpholine chemical class used as an appetite suppressant.
Pharmacology
Phendimetrazine functions as a p ...
(under the brand name Prelu-2) which functions as a
prodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of abuse and
addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
. Chemically, phenmetrazine is a
substituted amphetamine containing a
morpholine ring.
History
Phenmetrazine was first patented in
Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
in 1952 by
Boehringer-Ingelheim
C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's largest pharmaceutical ...
, with some pharmacological data published in 1954.
It was the result of a search by Thomä and Wick for an
anorectic
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" a ...
drug without the side-effects of
amphetamine.
Phenmetrazine was introduced into
clinical use in 1954 in
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...
.
Medical use
In clinical use, phenmetrazine produces less
nervousness
Nervous may refer to:
* nervousness
* Nervous system, a network of cells in an animal's body that coordinates movement and the senses
** Nervous tissue, the cells of the nervous system that work in aggregate to transmit signals
Music
* "Nervous" ...
, hyperexcitability,
euphoria and
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
than drugs of the amphetamine family.
It tends not to increase
heart rate
Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...
as much as other stimulants. Due to the relative lack of
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s, one study found it well tolerated in children.
In a study of the effectiveness on
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
between phenmetrazine and
dextroamphetamine
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance an ...
, phenmetrazine was found to be slightly more effective.
Pharmacology
Phenmetrazine acts as a
releasing agent
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the synapse, release of a monoamine neurotransmitter from the synapse, presynaptic neuron into the synapse, leading to an increase in the extracellular conc ...
of
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
and
dopamine with
EC50 values of 50.4 ± 5.4 nM and 131 ± 11 nM, respectively.
It has negligible efficacy as a releaser of
serotonin, with an EC
50 value of only 7,765 ± 610 nM.
After an oral dose, about 70% of the drug is
excreted
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
from the body within 24 hours. About 19% of that is excreted as the unmetabolised drug and the rest as various
metabolites.
In trials performed on rats, it has been found that after
subcutaneous administration of phenmetrazine, both
optical isomer
In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...
s are equally effective in reducing food intake, but in
oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or or ...
administration the
levo isomer is more effective. In terms of central stimulation however, the dextro isomer is about 4 times as effective in both methods of administration.
The salt which has been used for immediate-release formulations is phenmetrazine hydrochloride (Preludin). Sustained-release formulations were available as resin-bound, rather than soluble, salts. Both of these dosage forms share a similar
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
as well as time to peak onset, however, sustained-release formulations offer improved
pharmacokinetics with a steady release of
active ingredient
An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. The ...
which results in a lower peak concentration in blood plasma.
Synthesis
![Phenmetrazine Synthesis](https://upload.wikimedia.org/wikipedia/commons/d/d6/Phenmetrazine_Synthesis.svg)
Phenmetrazine can be synthesized in three steps from 2-bromopropiophenone and
ethanolamine
Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid w ...
. The intermediate alcohol 3-methyl-2-phenylmorpholin-2-ol (1) is converted to a fumarate salt (2) with
fumaric acid
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as fu ...
, then reduced with
sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applica ...
to give phenmetrazine free base (3). The free base can be converted to the fumarate salt (4) by reaction with fumaric acid.
Chemistry
Its structure incorporates the backbone of
amphetamine, the prototypical CNS stimulant which, like phenmetrazine, is a releasing agent of dopamine and norepinephrine. The molecule also loosely resembles
ethcathinone
Ethcathinone, also known as ethylpropion or ETH-CAT, is a stimulant drug of the phenethylamine, amphetamine, and cathinone chemical classes. It is an active metabolite of the prodrug diethylcathinone and is fully responsible for its effects. ...
, the active metabolite of popular anorectic
amfepramone (diethylpropion). Unlike phenmetrazine, ethcathinone (and therefore amfepramone as well) are mostly selective as noradrenaline releasing agents.
Recreational use
Phenmetrazine has been used recreationally in many countries, including
Sweden. When stimulant use first became prevalent in Sweden in the 1950s, phenmetrazine was preferred to
amphetamine and
methamphetamine by users. In the autobiographical novel ''Rush'' by
Kim Wozencraft, intravenous phenmetrazine is described as the most euphoric and pro-sexual of the stimulants the author used.
Phenmetrazine was classified as a
narcotic in Sweden in 1959, and was taken completely off the market in 1965. At first the illegal demand was satisfied by smuggling from
Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
, and later
Spain
, image_flag = Bandera de España.svg
, image_coat = Escudo de España (mazonado).svg
, national_motto = ''Plus ultra'' (Latin)(English: "Further Beyond")
, national_anthem = (English: "Royal March")
, i ...
and
Italy
Italy ( it, Italia ), officially the Italian Republic, ) or the Republic of Italy, is a country in Southern Europe. It is located in the middle of the Mediterranean Sea, and its territory largely coincides with the homonymous geographical ...
. At first, Preludin tablets were smuggled, but soon the smugglers started bringing in raw phenmetrazine powder. Eventually amphetamine became the dominant stimulant of abuse because of its greater availability.
Phenmetrazine was taken by
the Beatles
The Beatles were an English rock band, formed in Liverpool in 1960, that comprised John Lennon, Paul McCartney, George Harrison and Ringo Starr. They are regarded as the most influential band of all time and were integral to the developmen ...
early in their career.
Paul McCartney
Sir James Paul McCartney (born 18 June 1942) is an English singer, songwriter and musician who gained worldwide fame with the Beatles, for whom he played bass guitar and shared primary songwriting and lead vocal duties with John Lennon. One ...
was one known user. McCartney's introduction to drugs started in
Hamburg
(male), (female) en, Hamburger(s),
Hamburgian(s)
, timezone1 = Central (CET)
, utc_offset1 = +1
, timezone1_DST = Central (CEST)
, utc_offset1_DST = +2
, postal ...
,
Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
. The Beatles had to play for hours, and they were often given the drug (referred to as ''Prellies'') by the maid who cleaned their housing arrangements, German customers, or by
Astrid Kirchherr
Astrid Kirchherr (; 20 May 1938 – 12 May 2020) was a German photographer and artist known for her association with the Beatles (along with her friends Klaus Voormann and Jürgen Vollmer) and her photographs of the band's original member ...
(whose mother bought them). McCartney would usually take one, but
John Lennon
John Winston Ono Lennon (born John Winston Lennon; 9 October 19408 December 1980) was an English singer, songwriter, musician and peace activist who achieved worldwide fame as founder, co-songwriter, co-lead vocalist and rhythm guitarist of ...
would often take four or five.
Hunter Davies
Edward Hunter Davies (born 7 January 1936) is a British author, journalist and broadcaster. His books include the only authorised biography of the Beatles.
Early life
Davies was born in Johnstone, Renfrewshire, to Scottish parents. For four y ...
asserted, in his 1968 biography of the band,
that their use of such stimulants then was in response to their need to stay awake and keep working, rather than a simple desire for kicks.
Jack Ruby said he was on phenmetrazine at the time he killed
Lee Harvey Oswald
Lee Harvey Oswald (October 18, 1939 – November 24, 1963) was a U.S. Marine veteran who assassinated John F. Kennedy, the 35th president of the United States, on November 22, 1963.
Oswald was placed in juvenile detention at the age of 12 fo ...
.
Preludin was also used recreationally in the US throughout the 1960s and 1970s. It could be crushed up in water, heated and injected. The street name for the drug in Washington, DC was "Bam". Phenmetrazine continues to be used and abused around the world, in countries including
South Korea
South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korean Peninsula and sharing a land border with North Korea. Its western border is formed by the Yellow Sea, while its eas ...
.
See also
*
Substituted phenylmorpholine
*
3-Benzhydrylmorpholine
3-Benzhydrylmorpholine is a drug that was developed by American Home Products in the 1950s. It has stimulant and anorectic effects and is related to both pipradrol and phenmetrazine.
See also
* Desoxypipradrol
* β-Phenylmethamphetamine
β-P ...
*
Fenbutrazate
*
Edivoxetine
*
Phendimetrazine
Phendimetrazine (Bontril, Adipost, Anorex-SR, Appecon, Melfiat, Obezine, Phendiet, Plegine, Prelu-2, Statobex) is a stimulant drug of the morpholine chemical class used as an appetite suppressant.
Pharmacology
Phendimetrazine functions as a p ...
*
Morazone
Morazone (Novartrina, Orsimon, Rosimon-Neu, Tarcuzate) is a nonsteroidal anti-inflammatory drug (NSAID), originally developed by the German pharmaceutical company Ravensberg in the 1950s, which is used as an analgesic.
It produces phenmetrazine a ...
*
Reboxetine
Reboxetine, sold under the brand name Edronax among others, is a drug of the norepinephrine reuptake inhibitor (NRI) class, marketed as an antidepressant by Pfizer for use in the treatment of major depression, although it has also been used of ...
*
The Beatles drug use in Hamburg
*
3-Fluorophenmetrazine
3-Fluorophenmetrazine (also known as 3-FPM, 3-FPH and PAL-593) is a phenylmorpholine-based stimulant and fluorinated analogue of phenmetrazine that has been sold online as a designer drug.
Chemistry
3-Fluorophenmetrazine is a fluorinated anal ...
References
{{Phenethylamines
Stimulants
Anorectics
Withdrawn drugs
Phenylmorpholines
Euphoriants
Norepinephrine-dopamine releasing agents
Substituted amphetamines