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Cathinone: History, Synthesis, and Human Applications
Kevin B. Hugins
Natural Products
Nevada State College
Spring 2014
1
ABSTRACT
Cathinone is a naturally occurring monoamine alkaloid found in the leaves of the Catha edulis
tree. The ingesti...
2
History
Cathinone is a naturally occurring monoamine alkaloid found in the leaves of the Catha edulis
tree. The ingestio...
3
Biological Activity
Cathinone is chemically and pharmacologically similar to amphetamine. Like other similar
derivatives...
4
• Moderate hyperthermia
• Mydriasis, blurred vision
• Anorexia, dry mouth
• Constipation
• Psychotic reactions at high d...
5
it is converted into benzoyl-CoA using a thiolase enzyme. At this point the CoA-dependent pathway
converges with the CoA...
6
basic structure of cathinone and any R groups may be added as shown in the diagram. [17] The
pharmacological effect of t...
7
Shortly after this incident, President Barack Obama signed emergency legislation that amended federal
drug policy that p...
8
References
1. Adeoya-Osiguwa, S.; Fraser, L. R. Cathine, an Amphetamine-related Compound, Acts on Mammalian Spermatozoa ...
9
14. Republic Of South Africa, Water Affairs and Forestry. (Sept 8, 2006).
http://www.dwaf.gov.za/Documents/notices/29062...
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Cathinone history, synthesis, and human applications

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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.

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Cathinone history, synthesis, and human applications

  1. 1. Cathinone: History, Synthesis, and Human Applications Kevin B. Hugins Natural Products Nevada State College Spring 2014
  2. 2. 1 ABSTRACT 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. This information presented has been derived from a variety of peer reviewed journals, PhD dissertations, scholarly articles, government publications, and news articles. No original experiments or studies were conducted as a part of this paper.
  3. 3. 2 History Cathinone is a naturally occurring monoamine alkaloid found in the leaves of the Catha edulis tree. The ingestion of cathinone causes stimulation and euphoria. Documentation of the use of Catha edulis leaves dates back to ancient Egypt when it was used in religious ceremonies and was believed to help achieve divinity. Until the 20th century, the chewing of the leaves of the Catha edulis, commonly referred to as “khat”, was limited to the Horn of Africa. Particularly in Somalia, Ethiopia, and Yemen, the chewing of khat has been a common pastime comparable to drinking coffee or smoking tobacco in the west. [3] Traditionally, khat had to be consumed quickly after harvest to get maximal effects from the leaves. As the leaves dry out, cathinone is reduced to a less potent form called cathine. However, with the advent of better transportation, the geographic reach of khat has increased. Additionally, as more Africans immigrate to other continents, the global demand for khat has grown. The most common form of packaging for transport is to wrap the Catha edulis leaves in banana leaves to help keep them moist and fresh during transport. [5, 17] Catha edulis is an evergreen perennial shrub. It generally grows to a height of 21 feet but can grow as tall as 45 to 75 feet. Its leaves are oval and leathery and measure 2 to 4 inches in length. Khat has small clusters of white flowers, each having five petals. The flowers produce fruit that matures into small reddish seeds. The seeds however do not germinate particularly well. When cultivated, growers use cuttings or suckers from mature trees as stock to propagate new plants. Catha edulis is considered an ornamental plant and can be found on display in botanical gardens worldwide. [8] Use of Catha edulis By Humans According to the World Health Organization, globally, 10 million people use khat on a daily basis. Yemen is where use is most prevalent. The WHO estimates 90% of men and 50% of women in Yemen chew khat on a daily basis. 15%-20% of children under the age of 12 are daily users. The WHO estimates that 30% to 50% of Yemeni household income is spent on khat. Over 40% of the nation’s water supply goes toward the cultivation of khat and a single “daily bag” of khat requires 130 gallons of water to produce. Although khat is not considered to be a seriously addicting drug by the WHO, particularly in Yemen, its use is having serious social, economic, and environmental effects. [4, 9, 10] Not only is khat use legal and normal in most African and Middle-Eastern countries, the South African Department of Water Affairs and Forestry lists Catha edulis as a protected species. [14] However, the west feels differently about khat. Although most countries have not specifically criminalized Catha edulis, they have listed cathinone and cathine as controlled substances, effectively making possession or use of khat illegal. In America, cathinone is listed as a schedule I controlled substance. A schedule I controlled substance is defined as having a high potential for abuse and dependency and having no acceptable medical use. Cathine is listed as schedule IV. Schedule IV controlled substances have a low potential for abuse and dependence and can be dispensed with a prescription. [6]
  4. 4. 3 Biological Activity Cathinone is chemically and pharmacologically similar to amphetamine. Like other similar derivatives, general effects of cathinone ingestion include increased alertness, euphoria, increased talkativeness, decreased appetite, increased heart rate and blood pressure, and pupil dilation. [15, 16] Cathinone acts on dopamine, serotonin, and epinephrine transporters. These neurotransmitters are collectively referred to as monoamines due to their structure, which includes an aromatic ring which has an amine group attached to it by a two carbon chain. Cathinone likewise has an aromatic ring with an amine attached on a carbon chain, two carbons away from the ring. [12] Being very hydrophobic, cathinone can easily cross cell membranes and other barriers and interact with monoamine transporters in the synaptic cleft, either blocking the reuptake of neurotransmitters or increasing their secretion. Cathinone specifically causes a significant increase of dopamine release while inhibiting the reuptake of epinephrine, norepinephrine, and serotonin. In addition to effects in the brain, cathinone affects the peripheral nervous system. It specifically acts on nerves of the parasympathetic nervous system, blocking adrenergic receptors and inhibiting function such as smooth muscle contraction. [7] In a critical review of the assessment of khat, published by the United Nations Development Program Emergencies Unit for Ethiopia (UNDP-EUE), the author, Dechassa Lemessa published an exhaustive list of the physiological effects of khat on humans. This is the list as published in his report: [11] Acute effects include: • Relief of fatigue, increased alertness, reduced sleepiness • Mild euphoria and excitement; improved ability to communicate, loquacity • Tachycardia, hypertension Figure 1 Figure 2 Figure 3
  5. 5. 4 • Moderate hyperthermia • Mydriasis, blurred vision • Anorexia, dry mouth • Constipation • Psychotic reactions at high doses • Irritability and depressive reactions at the end of a khat session • Lethargy and sleepy state (next morning) Long-term effects include: • 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 (keratosis) Biosynthesis There are two proposed pathways for the biosynthesis of cathinone in the Catha edulis Tree. Both start with L-phenylalanine being converted to trans-cinnamic acid by phenylalanine ammonia lyase. At this point the two pathways diverge. One is dependent on CoA and the other is not. The first step in the CoA-independent pathway involves hydration of the trans-cinnamic acid producing 3-hydroxy-3-phenylpropionic acid. This is then converted to benzaldehyde by a retro- aldol cleavage that removes an acetic acid molecule. Using a dehydrogenase enzyme, NAD, and H2O, benzaldehyde is converted to benzoic acid. Using a Thiamine diphosphate-dependent enzyme, pyruvate and CO2, benzoic acid is converted to 1-phenylpropane-1,2-dione. Finally, using a transaminase enzyme, (S)-cathinone is produced. The first step in the CoA-dependent pathway converts trans-cinnamic acid into trans- cinnamoyl-CoA using CoA ligase and CoASH. Enol- CoAhydrase then catalyzes a hydration reaction forming 3-hydroxy-3-phenylpropionyl-CoA. Finally Figure 4
  6. 6. 5 it is converted into benzoyl-CoA using a thiolase enzyme. At this point the CoA-dependent pathway converges with the CoA-independent pathway using a thiamine diphosphate-dependent enzyme, pyruvate, and CO2. [8] I was unable to locate any information regarding the specific purpose of cathinone in the Catha edulis tree. However, the UNDP-EUE assessment of khat indicated that the wood is often used in construction of buildings and fences because it is resistant to termites and khat crops are resistant to many pests. [11] It is possible that cathinone has a role in pest resistance. This has not yet been specifically studied however. Chemical Synthesis Several procedures for the chemical synthesis of cathinone have been developed. One frequently published method begins with propiophenone and requires 7 steps. Another method frequently referred to begins with norephedrine and requires 4 steps. The drawback of both methods is that the final product is a racemic mixture of both S-(-)-cathinone and S-(+)-cathinone. S-(+)-cathinone has limited bioactivity. [3] What appears to be the most effective method for producing racemically pure S-(-)-cathinone involves a Friedel Crafts alkylation of S-alanine which leads to a final product of pure S-(-)-cathinone HCl. The first step is an acetylation of S-alanine using acetic anhydride. Next, phosphorus 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 hydrochloric acid, the aldehyde from the first step is removed and replaced by HCl. Pure cathinone is seldom the goal of chemical synthesis however. A variety of so called substituted cathinones are produced by a variety of chemists for human consumption. In order for a substance to be considered a substituted cathinone it must contain the Figure 5 Figure 6
  7. 7. 6 basic structure of cathinone and any R groups may be added as shown in the diagram. [17] The pharmacological effect of these cathinone derivatives is varied and can range from useful medical effects, to popular recreational highs, to psychosis. The best known cathinone used for medical purposes is bupropion, or Wellbutrin. [13] Bupropion is one of the top prescribed antidepressants and has also been approved by the FDA for use in smoking cessation. As can be seen in the diagram, bupropion is simply a cathinone with a tertiary butyl attached to the nitrogen and chlorine attached to the benzene ring. Although the exact mechanism of bupropion’s pharmacological effects is not known, it is believed to function as a dopamine and norepinephrine reuptake inhibitor. The structural similarity between cathinone and neurotransmitters has been harnessed for useful medical purposes. MDMA is a widely used substituted cathinone. [17] It was first synthesized in 1912 and was investigated for possible medical uses. In the 1980’s MDMA, more widely known as ecstasy, began to become a popular club drug. Recreational use of MDMA is now wide spread in Europe and the United States. As chemists began to recognize the potential desirable recreational effects of substituted cathinones they began to play a game of isomerization cat and mouse with the governmental agencies responsible for regulating and criminalizing illicit drugs. When synthesis, sales, and possession of methylone were criminalized, these chemists went on to make ethylone. As soon as legal restrictions were placed on ethylone, they simply moved on to butylone. This process continues to this day. Substituted cathinones have most recently masqueraded as “bath salts” which were marketed and sold legally in the United States. Also packaged as “plant fertilizer”, these cathinone analogs were labeled “not for human consumption.” [13] However, considering they were primarily offered for sale at truck stops and head shops, the intended purpose for these seem apparent. Snorted, smoked, or injected by users, these substituted cathinones led to a news media frenzy regarding suicides and erratic “zombie like” behavior beginning around 2010. This came to a climax in 2012 when a naked Rudy Eugene attacked a homeless man in Miami, FL and ate his victim’s face off before being shot by police. Figure 9 Figure 7 Figure 8
  8. 8. 7 Shortly after this incident, President Barack Obama signed emergency legislation that amended federal drug policy that placed a blanket ban on substituted cathinones. However, the search for legitimate uses for cathinone and substituted cathinones continues. Current research is investigating the usefulness of MDMA and its analogs in the treatment of Post- Traumatic Stress Disorder (PTSD). Likewise, in an effort to leave no stone unturned, researchers at King’s College in London have published the results of two different studies that have shown that cathinone boosts sperm production and health by making it develop faster, be more robust, and last longer, contrary to previous belief that it damaged sperm. [1, 2] The use of the natural product cathinone has a long history in African and Middle-Eastern countries. But as with all good things created by nature, man has sought new ways to make it stronger and better. As demonstrated with substituted cathinones this quest has brought about some great successes as well as unimaginable consequences. Based on the structural and functional similarities between cathinone and our bodies’ important neurotransmitters, research in this area will continue.
  9. 9. 8 References 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)
  10. 10. 9 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) Figures 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_- 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.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

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