KHAT Latest Revision: June 11, 2005

Home , Cathine, Phenylpropanolamine

CH3

NH2

Cathinone

CH3

NH2

Cathine

N CH3

H3C N

3,6-dimethyl-2,5-diphenylpyrazine (dimer of Cathinone)

1. SYNONYMS

CFR: Cathinone Cathine

CAS #: Cathinone Hydrochloride: 71031-15-7 Cathine Hydrochloride: 2153-98-2 Cathine Base: 492-39-7

Other Names: Catha edulis Kat Mutsawhari Mutsawari Mdimamadzi Musitate Mirungi Miraa Ol meraa

Tumayot Liruti Ikwa Arabian Tea

2. CHEMICAL AND PHYSICAL DATA

Khat is used as a stimulant or as a medicine in parts of Africa and the Arabian Peninsula. The plant is thought to have been in cultivation before the coffee plant; historical references date the use of the plant to the fourteenth century. Peter Forsskal, a physician and botanist, collected khat specimens in an expedition organized by the King of Denmark in the eighteenth century. Forsskal assigned the name Catha edulis to the plant.

The effects produced by the drug include excitation, hypersensitivity, anorexia, insomnia, euphoria, increased respiration, and hyperthermia. These effects closely parallel the effects of d-amphetamine.

Khat is a bush or tree that grows naturally in the humid mountainous regions (elevations of 5000 to 6500 feet) of East and South Africa. The trees can grow naturally to over 60 ft; however, cultivated khat trees are pruned and their height to kept to approximately 16 feet. Khat also grows to a height of 3 feet as a small bush in arid regions. Like opium, the alkaloid content of khat will vary with the soil, climatic conditions, and cultivation. Khat belongs to the genus Catha edulis. It is recognized that the genus consists of only one species; however, the plant exhibits extreme polymorphism. The plant comprises several cultural varieties, which do not have the same properties. The leaves may be thin and narrow or very broad. The leaves may be arranged on a branch in opposite pairs, but are sometimes displaced resulting in an alternating orientation. New leaves are a reddish- brown color, becoming greenish-yellow when fully grown. The leaves are bifarious (arranged in two rows), elliptical, lanceolate with sharp edges and coriaceous (leather like). Some have reported the leaves to be almost tasteless, while others report the leaves are aromatic, sweet, and astringent. Dimensions of the leaves vary from 0.5 cm to 7 cm in length.

The khat plant will produce small, white, or light green flowers. The flowers will be arranged in auxiliary cymes (a flower cluster, in which the main axis and branch end in a flower will open before the flowers below or to the side of it). The flowers have five equal sepals and five oblong petals.

Khat can be used in a variety of ways. Fresh plant material is generally chewed for the stimulant effect of the cathinone. Large leaves or dried leaves are powdered in a mortar. The powdered material is then mixed with sugar and sometimes spices and water making a paste, which is chewed. Dried leaves can also be brewed into a tea, or alternatively, the leaves can be crushed and rolled into cigarettes.

Khat is quality rated by connoisseurs in a manner similar to tea and coffee. The criteria utilized depend upon the part of the plant that will be used – leaves, buds, or twigs. This is coupled with the degree of maturity, the size of the leaf and the area of plant origin. Larger and older leaves will be tough and not easily chewed. Additionally, these leaves will contain a lower amount of cathinone as compared to younger leaves from the same plant. In addition, the red leaf type known as “dimma” is known to have more cathinone than the white leaf type known as “dallota”.

Three to six alkaloids have been identified in khat. The principle active alkaloid in khat is S-(-)- - aminopropriophenone, or (-)-cathinone. In some khat samples this compound accounts for up to 70% of the phenylalkylamine fraction. The content of the (-)-cathinone is directly associated with the market price of khat. Cathinone exists in khat as the racemic mixture; the total cathinone content can vary with reported values

ranging from 0.9% up to 3.3% in a Kenyan khat sample. Other phenylalkylamines present in khat include (+)- norpseudoephedrine (cathine), norephedrine and 1-phenyl-1,2-propanedione.

The (-)-cathinone in the leaf material will begin to degrade to cathine and (-)-norephedrine once the leaf has been harvested. Traditionally, the conversion process is slowed by tightly wrapping the leaves in moist false banana leaves to retain moisture. The freshly harvested leaves can be air dried or frozen to preserve the (-)- cathinone. Air-dried leaf material had detectable levels of (-)-cathinone after ten days and frozen leaf material had detectable levels of (-)-cathinone after one year. Cathinone base will also dimerize in the presence of oxygen to form 3,6-dimethyl-2,5-diphenylpyrazine.

large and small Khat leaves

red Khat leaf

Left: top side of Khat leaf Right: bottom side of Khat leaf

2.1. CHEMICAL DATA Form Chemical Formula Molecular Weight Melting Point (°C)

Cathinone base C9H11NO 149.2 amu 77-78

Cathine Hydrochloride C9H13NO HCl 187.7 amu 180-181

3,6-dimethyl-2,5- C18H16N2 260.3 amu diphenylpyrazine

2.2. SOLUBILITY

Cathinone and cathine are soluble in ethyl ether, hexane, chloroform and alcohol.

3. SCREENING TECHNIQUES

3.1. MICROSCOPIC EXAM

A microscopic examination of the leafy material should be conducted to note the general leaf characteristics.

3.2. COLOR TESTS

Color tests performed directly on plant material will not yield results. Extracted and purified material may give the following results.

REAGENT COLOR PRODUCED Cathine Marquis No color development Sodium Nitroprusside Rose Cathinone Marquis No color development Sodium Nitroprusside Rose

3.3. THIN LAYER CHROMATOGRAPHY

Visualization

UV light Ninhydrin reagent

COMPOUND RELATIVE Rf and COLOR UV light Ninhydrin spray Cathine 0.26, brown 0.26, purple Cathinone 0.48, brown 0.48, orange Ephedrine 0.17, brown 0.17, purple Phenylpropanolamine 0.26, red 0.26, orange

Pseudoephedrine 0.23, brown 0.23, no color Developing Solvent: ethyl acetate – methanol – ammonia (85 : 10 : 5)

3.4. GAS CHROMATOGRAPHY

Method General Screen1

Instrument: Gas chromatograph operated in split mode with FID

Column: 5% diphenyl/95% dimethylsiloxane 15 m x 0.25 mm x 0.25 µm film thickness

Carrier gas: Helium at 1.6 mL/min

Temperatures: Injector: 275°C Detector: 280°C Oven program: 1) 100°C initial temperature for 2.0 min 2) Ramp to 300°C at 15 degrees/min

Injection Parameters: Split Ration = 35:1, 1 µL injected

Samples extracted with 1N NaOH into chloroform and filtered.

COMPOUND RRT amphetamine 0.694 methamphetamine 0.865 cathinone 1.000 cathine 1.003 1S,2R-(d)- 1.340 phenylpropanolamine 1S,2R-(d)-ephedrine 1.456 1S,2S-(d)- 1.470 pseudoephedrine

4. SEPARATION TECHNIQUES

The khat alkaloids are separated from the plant material by acid / base extractions into solvents. The khat alkaloids can then be separated by GC, HPLC or TLC and identified with GC-IRD or GC-MSD.

Extraction scheme A Five grams of leafy material is macerated in a plant mill or torn into very small pieces. Ten milligrams of oxalic acid and 50 mL of water are added to the leafy material and either mechanically blended for three, one- minute increments or sonicated for 15 minutes. The mixture is filtered through a Buchner funnel to separate the liquid from the solid plant material. The liquid material is made basic (pH 9) with saturated sodium bicarbonate and extracted into two 10 mL aliquots of chloroform. The chloroform aliquots are combined and evaporated to near dryness under a stream of air. This extract can then be analyzed by GC, HPLC, TLC, GC-IRD or GC-MS.

Extraction scheme B Five grams of leafy material is macerated in a plant mill or torn into very small pieces. Fifteen to 20 mL of methanol is added and sonicated for 15 minutes. The mixture is filtered through a Buchner funnel to separate the liquid from the solid plant material. The alcohol solution is evaporated to near dryness under a stream of air. The small volume is reconstituted in 0.02 N sulfuric acid, extracted into chloroform, and separated. The aqueous acidic layer is made basic with saturated sodium bicarbonate and extracted into dichloromethane. This extract can then be analyzed by GC, HPLC, TLC, GC-IRD or GC-MS.

5. Quantitative Procedures

N/A

6. Qualitative Data

6.1. Ultraviolet Spectroscopy

COMPOUND SOLVENT MAXIMUM ABSORBANCE (NM)

cathine 0.1 N H2SO4 249

cathinone 0.1 N H2SO4 256, 250, 262

See spectra on the following pages for FT-IR, Mass Spectrometry, FT-Raman, Nuclear Magnetic Resonance, and Vapor Phase IR..

7. REFERENCES

Brenneisen, R. and Geisshusler, S., “Psychotropic Drugs”, Pharmaceutica Acta Helvetiae, Vol. 60, No. 11, 1985, pp. 290-301.

Bulletin on Narcotics, “Khat”, Vol. 8, No. 4, Oct. – Dec. 1956, pp. 6-13.

Clarke, E.G.C., Isolation and Identification of Drugs, 2nd Edition, The Pharmaceutical Press, 1986.

Geisshusler, S. and Brenneisen, R., “The Content of Psychoactive Phenylpropyl and Phenylpentyl Khataminesw in Catha Edulis Forsk. Of Different Origin”, Journal of Ethnopharmacology, Vol 19, 1987, pp. 269-277.

Kalix, P., “Pharmacological Properties of the Stimulant Khat”, Pharmac. Ther, Vol 48, pp. 397-416, 1990.

Kalix, Peter and Khan, Inayat, “Khat: an amphetamine-like plant material”, Bulletin of the World Health Organization, 62, (5), pp. 681-686, 1984.

Lee, M. M., “The Identification of Cathinone in Khat (Catha edulis): A Time Study”, Journal of Forensic Sciences, Vol. 40, No. 1, January 1995, pp. 116-121.

Szendrei, K., “The Chemistry of Khat”, Bulletin on Narcotics, Vol. 32, No. 3, 1980, pp. 5-35.

Mathys, K. and Brenneisen, R., “HPLC and TLC Profiles of Phenylalkylamines of Khat (Catha edulis Forsk.) Confiscated in Switzerland”, Pharmaceutica Acts Helvetiae, Vol. 68, 1993, pp. 121-128.

Morselli, O., Bovolenta, A., Ripani, L.,and Garofano, L., “Gas – Chromatography / Mass Spectrometry Determination of the Active Principles of “Catha Edulis” African Vegetable”, Microgram, Vol. 35, No. 11, Nov., 1992, pp. 290-294.

Nordal, A., and Laane, M. M., “Identification of Khat”, Medd. Norsk Farm. Selsk., Vol. 40, 1978, pp. 1-18.

United Nations Narcotics Laboratory, “Studies on the Chemical Composition of Khat. III. Investigations on the phenylalkylamine fraction”, MNAR/11/1975.

United Nations Narcotics Laboratory, “Studies on the Chemical Composition of Khat. IX. The phenylalkylamines of Catha edulis Forsk. The absolute configuration of cathinone”, MNIR/7/1978.

8. ADDITIONAL RESOURCES

Forendex (cathinone, cathine)

Wikipedia

UV: Cathinone standard in 0.1 N H2SO4 1.20

1.1

1.0 249.30

0.9

0.8

0.7

0.6 A 0.5

0.4

0.3

0.2

0.1

-0.02 220.0 240 260 280 300 320 340 360 380 400.0 nm

UV: Cathine standard in 0.1 N H2SO4 1.71

1.6

1.4

1.2 256.76

250.94 1.0 262.80

A 0.8

0.6

0.4

0.2

-0.02 220.0 240 260 280 300 320 340 360 380 400.0 nm

MS: Cathine Abundance

Scan 598 (4.646 min): cathine.D 3400000 44

3200000

3000000

2800000

2600000

2400000

2200000

2000000

1800000

1600000

1400000

1200000

1000000

800000

600000 77

400000

200000 51 105 63 91 117 57 72 86 98 127 132 152 0 40 50 60 70 80 90 100 110 120 130 140 150 m/z-->

MS: Cathinone Abundance

Scan 578 (4.540 min): cathinone.D 3200000 44

3000000

2800000

2600000

2400000

2200000

2000000

1800000

1600000

1400000

1200000

1000000

800000 77 600000 51 400000 105 200000

57 63 70 89 98 116 128 134 150 0 40 50 60 70 80 90 100 110 120 130 140 150 m/z-->

MS: 3,6-dimethyl-2,5-diphenylpyrazine Cathinone dimer Abundanc e

32000 115 30000 259 28000 26000 24000 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 89 103 44 63 77 2000 130 148 173 207 218 235 281 0 40 60 80 100 120 140 160 180 200 220 240 260 280 m/z-->

RAMAN:: Cathine HCl standard 16 scans, 8 cm-1 resolution

20 Raman intensity

3000 20002000 1500 1000 500 Raman shift (cm-1)

RAMAN: Cathinone HCl 6 scans, 8 cm-1 resolution

Raman intensity 12

3000 20002000 1500 1000 500 Raman shift (cm-1)

FTIR: Cathine HCl standard, KBr pellet. 16 scans, 2 cm-1 resolution

25 %Transmittance

3000 2000 1500 10001000 800 600 Wavenumbers (cm-1)

FTIR: Cathinone HCl standard, KBr pellet. 16scans, 2 cm-1 resolution

35 %Transmittance 30

3000 2000 1500 10001000 800 600 Wavenumbers (cm-1)

IR (Vapor Phase): Cathine Optical resolution 1.58 cm/s

100.5

100

99.5

98.5

4000 3000 2000 1000 Wavenumber (cm-1)

IR (Vapor Phase): Cathinone Optical resolution 1.58 cm/s

100

4000 3000 2000 1000 Wavenumber (cm-1)

NMR (Proton): Cathinone

CD3Cl, 8 repetitions 4.85

1.0

0.9

0.8

0.7

0.6

0.5 NormalizedIntensity

0.4 4.84

0.3

3.30

3.31 1.57

0.2 1.55

4.86

8.03

7.59

8.06

1.54

7.61

8.04 7.57 0.1 7.72

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm)

NMR (Proton): Cathine hydrochloride

CD3Cl, 8 repetitions 4.84

1.0

0.9

0.8 7.38 0.7

0.6 1.08

0.5 NormalizedIntensity 0.4

0.3 3.28 4.47 0.2

0.1

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm)