Archive File

History of Cannabis The word “Cannabis” has its origin in the mexican-spanish language and is often named “Marihuana”. The German law makes no difference between the source and the drug Cannabis. The arrangement in German law is written down at the Attachment 1 in the Narcotics Law.

The history of Cannabis is a long one. The following table gives an overview about the history.

Date Place Part from cannabis Source application 2737 B.C. China Resin Shennong ben cao jing -beriberi -occlusion -female disorder -gout -ague -rheumatism -absence of mind Before Egypt Plant Papyrus Ebers -cure for toenails ca.3500 years Before India Plant Indian literature -epilepsy ca.2400 -pain years 1st crusade European Plant -rheumatic disease (1096-1839) monastery -bronchial disease medicine 1839 European „Indian cannabis“ Report of the Irish doctor -rheumatism school William Brooke -cholera medicine O´Shaughnessy (1809-1890), -tetanus during he visited Kolkata 19th century USA Cannabis extract „Bromidia“ -hypnotic with henbane extract and potassium bromide and chloral hydrate First part of substitution of the cannabis products on the market, because other products were better and the 20th the veto on cannabis as a drug century Modern cannabis research Date Who? What? 1964 Raphael Mechoulam Isolation from THC At the End Discovery of the endocannabinoid system with its of 1980ies receptors and ligands

21.04.1999 Ministry for healthcare and social Ministry for healthcare and social services from the UN services from the UN gets an patent for „cannabinoids as antioxidants and neuroprotectants“

Since 1999 International consortium cannabis International consortium cannabis as medicine as medicine campaigns for medical use of cannabis Up to the first third of the twenties century cannabis was commonly used in ethanoic extracts. It was easy to get in form of medicine. For example ethanoic extracts were the most sold medicine in the 19th century.

On the 19/02/1925 was the second opium conference at Genève. There, the first agreement about dealing with drugs was revised. The second agreement came into effect on 25/09/1928.

As a result cannabis, heroin and cocaine became part of the list of drugs and equated with opium. First Germany was against this agreement because of the import of heroine (Bayer AG) and cocaine (Merck KGaA). But Egypt would break up the relationship with Germany, if they do not sign the agreement and so the German government has signed. With a new law for opium in 1929, cannabis became illegalized. In the Narcotics Law from 1971 this version became a directly part.

In the USA was at the beginning of 1936 a racism propaganda against cannabis. The opponents from cannabis represented Cannabis as a drug for perverts, “Nigger”, Mexican immigrants and poor people. Also it was represented as an “alien threat”.

The following chart presents the critical values for the consume of THC-COOH in Germany quantity meaning [ng/ml] Promptly measured after the consume

<5 5-10 Suspicion on occasional consume 10-150 Occasional consume >150 Regular consume Screening up to 8 days after the consume

<5 Possibility of consume onetime suspicion on occasional consume 5-75 Occasional consume >75 Regular consume

Due to all this points cannabis was prohibited in most countries. What leads you to the next topic “legalization of cannabis”.

Structure

The structure of the THC molecule consists of a hydrated form of a substance called chromen or benzopyran. This hydrated form is further called Chromane.

A hydroxyl group substitutes a Hydrogen atom at the aromatic ring of the Chromane part. Moreover there is a pentyl substituent at the same ring, meta to the hydroxyl group. At the c side of the chromane a hydrated derivate of toluol is attached with a double bond between the 9th and the 10th carbon atom. For the numbering the Tetrahydrocannabinol is seen as a dibenzopyran like system, and the chemical abstracts norms of numbering are used.

The following groups play an important role in the binding to the cannabinoid receptor type 1. The methyl group at the 9 position affects the binding to the receptor. The position of the double bound influences the potency. For example if the position is changed to the carbons 6a and 10a the molecule will lose two third of its potency. Another very important substituent regarding the potency is the alkyl functional group. If the chain of carbons is shortened to four or two carbons, the molecule shows almost no effect on the receptor. But if the length is extended to seven or more carbons the potency is increased by a lot. If the mentioned hydroxyl group is changed to a methoxy group the molecule does bind more to the cannabinoid receptor type 2 instead of the type 1 and the molecule shows more physical effects then psychological.

Biosynthesis

In the following the biosynthesis of the psychoactive substance Tetrahydrocannabinol (Δ9-THC) will be described. As educts, there are Geranylpyrophosphate and Olivetolic acid which are synthesized inside the plant, too.

OH O H3C O CH3 O OH O P - P O O O - - GOT (Enzyme) OH O O OH

HO CH3 HO CH3 H3C CH3 H C 3 CH3 Geranyl-Pyrophosphate Olivetolic Acid Cannabigerolic Acid

The aromatic system of Olivetolic acid is attacked by Geranylpyrophosphate through elimination of the diphosphate-groupe. This reaction is catalyzed by Geranyl-pyrophosphate-olivetolic acid geranyltransferase (GOT) and leads to Cannabigerolic acid, a substance that is not psychoactive.

CH3 OH O CH3 OH H O OH THCA Synthase (Enzyme)

OH

HO CH3 H H3C H3C CH O 3 CH3 CH3 Cannabigerolic Acid Tetrahydrocannabinolic Acid ( THCA)

Cannabigerolic acid can be transformed into different cannabinoids by variable enzymes. Tetrahydrocannabinolic acid (THCA) is built by the reaction catalyzed by Tetrahydrocannabinolic acid synthase. THCA is contained in the cannabis plant and can be extracted. Due to the effect of heat and ultraviolet radiation the decarboxylation, which leads to Tetrahydrocannabinol (Δ9-THC), is enabled.

Usually, THC, which is a lipophilic substance, is extracted out of the plant with nonpolar or slight polar solvents. Though, there are, especially for medical purposes, partial syntheses leading to THC. The most common example is Dronabinol (or Marinol). Therefore, Cannabidiol is extracted out of plants with a small percentage of THC. The extract gets transformed into THC. This procedure is very expensive and complex. In the US an Canada, Dronabinol gets prescribed, in Germany, it is not allowed to prescribe this medicine. In the course of new studies, bacteria are modified by some German scientists and are now able to produce THC, too.

The most famous fully synthetic analogues are Nabilon and Nabitan. Nabilon, a sort of ataractics, has anxiolytic and relaxing effects, furthermore, it oppresses nausea and sickness. There is no medical usage for Nabitan, because pure THC (or Dronabinol) or Nabilon are more effective.

Nabilon Nabitan

Effect

A part of the human nervous system is called endogenous cannabinoid system. It was discovered through the effects of cannabinoids out of the cannabis plant. This part of the nervous system contains the receptors called CB1 and CB2. The function and meaning is not clarified until now, though it is supposed that the CB1 receptors are involved in processes concerning learning and moving. Besides that, new studies indicate that the CB1 receptors affect the elimination of negative awkward memories. Furthermore, the CB2 receptors are supposed to have an important role concerning the immune system.

THC and other cannabinoids take effect on the receptors of the endogenous cannabinoid system. The effect is mostly induced through binding on the CB1 receptors, which are mainly found in the brain. Through this binding the central nervous system as well as the peripheral nervous system is affected. Symptoms of the consumption are an appearing feeling of happiness, relaxation, a slowed perception, pain relief and an appearing hungry feeling.

Medical application of Tetrahydrocannabinol

There are a lot of possible medical applications of THC with different knowledge of their medical efficiency. For the use of Cannabis to combat anorexia and cachexia in HIV/AIDS, nausea associated with cancer chemotherapy, chronic, neuropathic pain, spasticity in multiple sclerosis and spinal cord injury, there has been a particularly good medical research.

Positive experiences out of illegal usage of cannabis often lead to clinical studies with single content substances of cannabis, such as THC or with whole plant preparations. Particular highlights are the anti-emetic, the appetite increasing and the muscle relaxant effects, as well as the therapeutic use for tourette syndrom.

Nausea and vomiting with more than 40 clinical studies, the side effects of cancer chemotherapy are the best investigated indication. To treat nausea, THC has to be taken in high dosage, which causes a high amount of side effects. In lower dosages, THC can improve the efficiency of other medicaments for nausea and vomiting, when given together.

Tourette syndrome

There are first controlled studies of cannabis as treatment for tourette syndrome. The range of efficiency of the treatments is big. In some cases there are just little improvements, while the symptoms of others nearly vanish or can be totally controlled.

Drug

As a drug, THC is consumed while smoking marihuana or hashish with tobacco, or eaten as a contend of food, such as brownies or cookies. While smoking, the effect of THC starts showing after a few minutes and holds on up to two or three hours. In the event of oral consumption, the effects need at least half an hour to show up and they hold on much longer.

Proof of THC inside the body

The degradation of THC inside the human body takes place in the intestine, the kidney and via oxidation in the liver. THC and its metabolites 11-hydroxy-Δ9-Tetrahydrocannabinole (THC-OH) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinole (THC-COOH) are easily soluble in fat and they store themselves in fat tissue. Because of this, they can be indicated inside the body for a long time. After single use, THC and its metabolites can be indicated up to twelve days later. After regular or oral use it can be indicated up to four weeks later. Inside the human hair, the metabolites of THC can be indicated up to six month, depending on the length of the hair. One possible way to indicate THC and its metabolites is via GC/MS of urine.

Sources: http://de.wikipedia.org/wiki/Cannabis_als_Rauschmittel http://www.gesetze-im-internet.de/bundesrecht/btmg_1981/gesamt.pdf http://de.wikipedia.org/wiki/Cannabis_als_Arzneimittel http://www.cannabis-med.org/german/patients-use.htm#index http://www.cannabis-med.org/german/studies.htm http://www.drug-infopool.de/rauschmittel/cannabis.html http://www.drug-infopool.de/rauschmittel/cannabis.html

GERSTEL Aktuell Nr. 46, 13-15 https://de.wikipedia.org/wiki/Tetrahydrocannabinol https://de.wikipedia.org/wiki/Endocannabinoid-System https://en.wikipedia.org/wiki/Geranyl-pyrophosphate%E2%80%94olivetolic_acid_geranyltransferase https://en.wikipedia.org/wiki/Tetrahydrocannabinolic_acid_synthase http://www.spiegel.de/wissenschaft/mensch/biosynthese-bakterien-produzieren-cannabis-wirkstoff-a- 712513.html http://catbull.com/alamut/Lexikon/Mittel/thc3.htm http://catbull.com/alamut/Lexikon/Mittel/thc1.htm