Cathinone:

History, Synthesis, and Human Applications

Kevin B. HuginsNatural Products

Nevada State CollegeSpring 2014

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

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

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.

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.

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.

● In the Republic of South Africa Catha edulis is a protected species.

● In America, cathinone is a schedule I controlled substance, effectively criminalizing khat.

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.

Cathinone also acts specifically on the nerves of the parasympathetic nervous system:

● Blocks adrenergic receptors

● Inhibits functions such as smooth muscle contraction

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

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……..

BiosynthesisThere 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-dependentOne 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.

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.

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.

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.

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.

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.

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.

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

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)”

Future ResearchThe 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.

THE END

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.pngFigure 3. Digital image. Adrenergic Receptors https://3fb29a17-a-62cb3a1a-s-sites.googlegroups.com/site/khatcatinona/farmacologia/Nova%20imagem.bmp?attachauth=ANoY7cpLqu_NU35v_-AiPwGlQ1UwBkJi42uhFtHpih2KrE7RRXW2YPkFpQTHG2V-8eYDyCCydYX_CUyG7qEhgN2lRu4AGTsd1lH3H7Ab8gQcEoO6zmeIT7hdNv4vzqNP8wQnpmZQdPa-uL4Wcwbz8OzXosTavG3f9yIgRoKR9mboLdWIFr0yu9H5DS0bspOx-FW-_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.pdfFigure 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.gifFigure 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.gifFigure 8. Digital image. Bupropion. http://link.springer.com.ozone.nsc.edu:8080/article/10.1007%2Fs00204-013-1163-9/fulltext.htmlFigure 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.gifTitle Page Photo. Digital image. Khat leaf. http://www.naturganznah.com/shop/out/oxbaseshop/html/0/dyn_images/1/kathstrauch05_p1.jpg

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