Cathinone is a naturally occurring monoamine alkaloid found in the leaves of the Catha edulis tree. The ingestion of cathinone causes stimulation and euphoria. Use of Catha edulis, or “khat” by man can be traced back to ancient Egypt. Current use of khat is primarily in Africa and the Middle East. Cathinone exerts its effects by mimicking monoamine neurotransmitters. An entire class of substituted cathinones has been synthesized. The effect and reasons for use of these can be medicinal, recreational, or detrimental. This paper will address the biology of Catha edulis, its history and use by humans, and the biological activity cathinone exerts upon them. Next it will explain the biosynthesis of cathinone within Catha edulis followed by the chemical synthesis of cathinone and substituted cathinones in the lab. Finally it will discuss some of the chemical applications and consequences of the use of substituted cathinones in recent years.

1. Cathinone:
History, Synthesis, and Human
Applications
Kevin B. Hugins
Natural Products
Nevada State College
Spring 2014

2. Cathinone is a naturally occurring
monoamine alkaloid found in the
leaves of the Catha edulis tree.
Cathinone is chemically and
pharmacologically similiar to
amphetamine.
General effects include:
● Increased Alertness
● Increased Talkativeness
● Increased Heart Rate and Blood
Pressure
● Euphoria
● Decreased Appetite
● Pupil Dilation

3. Catha edulis or “khat”
(pronounced “cot”)
● An evergreen perennial shrub
● Grows 21 to 75 feet tall
● Oval, leathery leaves 2 to 4 inches
in length
● Small clusters of five petaled
flowers
● Fruit develops into reddish seeds
● Seeds do not germinate well

4. Historical Cultivation and Use
Ancient Egyptians used khat in religious ceremonies
to help achieve divinity.
Documentation of regular use
in the Horn of Africa begins to
appear around 1300 AD.
Most prevalent in Somalia,
Ethiopia, and Yemen where
chewing of khat leaves is akin
to coffee and tobacco use in
western countries.

5. World Health Organization Reports that in
Yemen:
Daily use:
● 90% of men
● 50% of women
● 15%-20% of children under 12
30%-50% household income spent on khat
Over 40% of the nation’s water supply is used in the cultivation of khat.
A “daily bag” of khat requires 130 gallons of water to produce.

6. As khat leaves dry out,
cathinone is reduced
into a less potent form
called cathine.
cathine
cathinone
To preserve freshness
khat is moistened with
water and wrapped in
banana leaves for
transportation.
Khat must be
consumed soon
after cultivation in
order to get the
desired effect.

7. ● In the Republic of South
Africa Catha edulis is a
protected species.
● In America, cathinone is a
schedule I controlled
substance, effectively
criminalizing khat.

8. BIOLOGICAL ACTIVITY
Cathinone acts on dopamine, serotonin, and epinephrine
transporters. The structure of cathinone is similiar to
these monoamines and thus can mimic their actions.
Cathinone
specifically causes
a significant
increase in
dopamine release
while inhibiting the
reuptake of
epinephrine,
norepinephrine
and seratonin.

9. Cathinone also acts specifically on the nerves of the
parasympathetic nervous system:
● Blocks adrenergic receptors
● Inhibits functions such as smooth muscle contraction

10. Acute effects include:
● Relief of fatigue, increased alertness, reduced sleepiness
● Mild euphoria and excitement
● Improved ability to communicate
● Tachycardia, hypertension
● Moderate hyperthermia
● Mydriasis, blurred vision
● Anorexia
● Psychotic reactions at high doses
● Irritability and depressive reactions at the end of a khat session
● Lethargy and sleepy state the next morning

11. Long Term Effects:
● Malnutrition
● Psychotic reactions after chronic use
● Depressive reactions
● Irritative disorders of the upper gastro-intestinal tract (gastritis, enteritis)
● Cardiovascular disorders
● Hemorrhoids
● Impaired male sexual function, spermatorrhoea, impotence
● Periodontal disease, mucosal lesions
And the teeth……..

12. Biosynthesis
There are two proposed pathways for the
biosynthesis of cathinone.
Both start with L-phenylalanine which is
converted to trans-cinnamic acid by
phenylalanine ammonia lyase (PAL)
One pathway is CoA-dependent
One pathway is CoA-independent
The pathways eventually reconverge
with the production of 1-phenylpropane-
1,2-dione which is converted to (S)-
cathinone with the help of a
transaminase enzyme.
This diagram ends with cathinone being
reduced to cathine.

13. Chemical Synthesis
Several procedures for the chemical synthesis of cathinone have been
developed. The drawback of most of these procedures is that the final
product is racemic, producing both S-(-)-cathinone, the natural form, and S-
(+)-cathinone which has limited bioactivity.
● The most effective procedure starts with S-alanine which is acetylated
using acetic anhydride in the first step.
● Next, phosphorous pentachloride is used to attack the carboxylic acid
and chlorinate it. In the same step a Friedel Crafts alkylation is
performed on the chlorinated ketone using aluminum chloride and
benzene.
● Finally, using
heat and HCl
the aldehyde
from step 1 is
removed and
replaced by
HCl.

14. Substituted Cathinones
Pure cathinone is seldom the goal of chemical
synthesis. A variety of substituted cathinones
have been synthesized in the lab (and in kitchens)
with effects that range from medically beneficial
to down right sinister.
A substituted cathinone begins with the basic
cathinone structure and a variety of R groups can
be added as shown in the diagram.

15. Bupropion
Bupropion, known by the
trade name Wellbutrin, is
one of the top prescribed
antidepressants.
Bupropion has also been
approved by the FDA for
smoking cessassion under
the trade name Chantix.

16. MDMA
MDMA was first synthesized in 1912 and was investigated for possible
medical uses. In the 1980’s MDMA, more widely known as ecstasy, began to
gain popularity as a club drug in the United States and Europe.
This marked the beginning of the era of “designer drugs”. When the
goverment outlawed MDMA, chemists began to produce MDEA which
produced similar effects. When the government outlawed MDEA, the
designer chemists began making MBDB. And so the game of isomerization
cat and mouse began.

17. Bath salts….
Substituted cathinones were brought to the forefront of American sensational
news stories beginning around 2010. Marketed, and sold legally, as “bath
salts” and “plant fertalizer” these products were labeled “not for human
consumption”. The active components in these products were a variety of
substituted cathinones.

18. These products were sold at truck stops and head shops so it was apparent
they were not intended to be used as labeled. Reports of extreme aggression,
suicide, and “zombie like behavior” began to surface.

19. The climax occured on May 26, 2012 in Miami Florida
when Rudy Eugene, naked and growling like a dog,
attacked Ronald Poppo and ate his face off. The attack
only ended when a police officer shot Eugene multiple
times.
Poppo survived the attack

20. Shortly after that incident, President
Barak Obama signed emergency
legislation that amended federal
drug policy and closed the loophole
that bath salts had slipped through.
Because of this incident and other similiar ones, public
hysteria began to rise to the point the Center for Disease
Control issued a public statement that, “The CDC does
not know of a virus or condition that would reanimate the
dead (or one that would present zombie-like symptoms)”

21. Future Research
The search for legitimate uses for
cathinone and substituted
cathinones continues.
● Post Traumatic Stress Disorder
● Appetite Supression
● Two studies at King’s College
in London have demonstrated
cathinone boosts sperm
production and health.

22. THE END

23. Figure 1. Digital image. Cathinone/Amphetamine. http://link.springer.com.ozone.nsc.edu:8080/static-
content/images/749/art%253A10.1007%252Fs00204-013-1163-9/MediaObjects/204_2013_1163_Fig13_HTML.gif
Figure 2. Digital image. Monoamines. http://www.bodybrainhealth.com/wp-content/uploads/2013/09/monoamines.png
Figure 3. Digital image. Adrenergic Receptors https://3fb29a17-a-62cb3a1a-s-
sites.googlegroups.com/site/khatcatinona/farmacologia/Nova%20imagem.bmp?attachauth=ANoY7cpLqu_NU35v_-
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_IWuAxzGJPvlqwDv_WCMCKJBOYRilzXCBHyXWFuaZW8D1iyoGzs%3D&attredirects=1
.Figure 4. Digital image. Cathinone Biosynthesis. 01 Oct. 2011. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229120/figure/f1-gmb-34-1-640/
Figure 5. Digital image. Cathinone Chemical Synthesis. http://etd.aau.edu.et/dspace/bitstream/123456789/2741/1/Yirga%20Adugna.pdf
Figure 6. Digital image. Substituted Cathinone Structure. http://link.springer.com.ozone.nsc.edu:8080/static-
content/images/749/art%253A10.1007%252Fs00204-013-1163-9/MediaObjects/204_2013_1163_Fig2_HTML.gif
Figure 7. Digital image. Various Substituted Cathinones. http://link.springer.com.ozone.nsc.edu:8080/static-
content/images/749/art%253A10.1007%252Fs00204-013-1163-9/MediaObjects/204_2013_1163_Fig3_HTML.gif
Figure 8. Digital image. Bupropion. http://link.springer.com.ozone.nsc.edu:8080/article/10.1007%2Fs00204-013-1163-9/fulltext.html
Figure 9. Digital image. MDMA. http://link.springer.com.ozone.nsc.edu:8080/static-content/images/749/art%253A10.1007%252Fs00204-013-1163-
9/MediaObjects/204_2013_1163_Fig4_HTML.gif
Title Page Photo. Digital image. Khat leaf. http://www.naturganznah.com/shop/out/oxbaseshop/html/0/dyn_images/1/kathstrauch05_p1.jpg

24. 1. Adeoya-Osiguwa, S.; Fraser, L. R. Cathine, an Amphetamine-related Compound, Acts on Mammalian Spermatozoa Via β1- and α2A-adrenergic
Receptors in a Capacitation State-dependent Manner. (2007, March 01) Hum. Reprod. 22(3), 756-765. http://humrep.oxfordjournals.org/content/22/3/756
(accessed February 5, 2014)
2. Adeoya-Osiguwa, S. A.; Fraser, L. R. Cathine and Norephedrine, Both Phenylpropanolamines, Accelerate Capacitation and then Inhibit Spontaneous
Acrosome Loss. (January 2005) Hum. Reprod. 20(1), 198-207. http://humrep.oxfordjournals.org/content/20/1/198.abstract (accessed Feb 5, 2014)
3. Adugna, Y. Phytochemical Studies on Khat (Catha edulis) Ph.D. Dissertation [Online]. Addis Ababa University, Addis Ababa, Ethiopia, 2009.
http://etd.aau.edu.et/dspace/bitstream/123456789/2741/1/Yirga%20Adugna.pdf (accessed Mar 2, 2014)
4. Al-Mugahed, L. Khat Chewing in Yemen: Turning Over a New Leaf. Oct 2008. Bull. W. H. O. 741-742. http://www.who.int/bulletin/volumes/86/10/08-
011008/en/index.html (accessed Feb 04, 2014)
5. Catha edulis. http://www.prota4u.org/protav8.asp?h=M4,edulis&p=Catha+edulis (accessed Feb 04, 2014)
6. DEA / Drug Scheduling, http://www.justice.gov/dea/druginfo/ds.shtml (accessed Apr 02, 2014)
7. Farmacologia - Khat- Catinona. https://sites.google.com/site/khatcatinona/farmacologia (accessed Mar 07, 2014)
8. Hagel, J. M., Krizevski, R.; Kilpatrick, K.; Sitrit, Y.; Marsolais, F.; Lewinsohn, E.; Facchini, P. J. Expressed Sequence Tag Analysis of Khat (Catha
edulis) Provides a Putative Molecular Biochemical Basis for the Biosynthesis of Phenylpropylamino Alkaloids. (2011) Genet. Mol. Biol. 34(4), 640-646.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229120/ (accessed Feb 05, 2014)
9. Heffez, A. How Yemen Chewed Itself Dry. (July 23, 2013) Foreign Affairs. http://www.foreignaffairs.com/articles/139596/adam-heffez/how-yemen-
chewed-itself-dry (accessed Feb 04, 2014)
10. Kirby, A. Yemen's Khat Habit Soaks Up Water. (July 4, 2007) BBC News.
http://news.bbc.co.uk/2/hi/programmes/from_our_own_correspondent/6530453.stm (accessed Jan 27, 2014)
11. Lemessa, D. Khat (Catha Edulis): Botany, Distribution, Cultivation, Usage and Economics in Ethiopia (June 2001). (Ethiopia, United Nations, UNDP-
EUE). http://www.coffeshop.comuv.com/dokumenty/khat_in_etiopia.pdf (accessed Mar 18, 2014)
12. López-Arnau, R.; Martínez-Clemente, J.; Pubill, D.; Escubedo, E.; Camarasa, J. Comparative Neuropharmacology of Three Psychostimulant Cathinone
Derivatives: Butylone, Mephedrone and Methylone. (2012). Br. J. Pharmacol. 167(2), 407-420. http://dx.doi.org/10.1111/j.1476-5381.2012.01998.x
(accessed Feb 5, 2014)
13. Prosser, J.; Nelson, L. The Toxicology of Bath Salts: A Review of Synthetic Cathinones. (2012) J. Med. Toxicol., 8(1), 33-42.
http://link.springer.com.ozone.nsc.edu:8080/article/10.1007%2Fs13181-011-0193-z/fulltext.html (accessed Feb 4, 2014)
14. Republic Of South Africa, Water Affairs and Forestry. (Sept 8, 2006). http://www.dwaf.gov.za/Documents/notices/29062b.pdf (accessed Jan 28, 2014)
15. Simmler, L.; Buser, T.; Donzelli, M.; Schramm, Y.; Dieu, L.; Huwyler, J. ... Liechti, M. Pharmacological Characterization of Designer Cathinones In
Vitro. (2013) Br. J. Pharmacol. 168(2), 458-470. http://dx.doi.org/10.1111/j.1476-5381.2012.02145.x (accessed Feb 5, 2014)
16. Synthetic Cathinones. (Feb 8, 2012). http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones (accessed Feb 05, 2014)
17. Valente, M.; Guedes dePinho, P.; Lourdes Bastos, M.; Carvalho, F.; Carvalho, M. Khat and synthetic cathinones: A review. (2014) Arch. Toxicol. 88(1),
15-45. http://link.springer.com.ozone.nsc.edu:8080/article/10.1007%2Fs00204-013-1163-9/fulltext.html (accessed Feb 4, 2014)