Introduction

• Psychoactive drugs affect the CNS in various ways by influencing the release of neurotransmitters or mimicking their actions.

• They can be stimulants, hallucinogens, and depressants

• Stimulants: enhance mental alertness, decrease fatigue, decrease hunger

  • Cocaine, Caffeine

• Hallucinogens: produce changes in mood, perception, and thought

  • Marijuana, Peyote, LSD

• Depressants: dull mental awareness, decrease physical performance, often induce sleep

  • Opium and its derivative (morphine, codiene, heroin, fentanyl)

Narcotics

• Narcotics: Strictly speaking, induces CNS depression and sleep

  • Vernacular definition: psychoactive addictive drugs

• Most psychoactive drugs are alkaloids

  • With the exception of THC (Cannabis)

The Opium Poppy (Papaver Somniferum)

• A “true” narcotic

• Unripe fruits are seed capsules, which exude milky latex when cut.

  • Latex is called opium.

  • The latex is dried and then can be eaten, smoked, or drunk.

    • The usual method of preparation was to dissolve it in wine

    • Laudanum: the preparation of opium by dissolving it in alcohol to make a tincture

• The dried latex contains morphine (an OH group) and codeine (an OCH3 group) but there is a big difference in their potency

  • Stereochemistry is important

• There are about 20 active components in opium

History

• The properties of opium poppies have been known for 4,000 years

• 1806: the major one was 1st shown to be an alkaloid by a German chemist

• 1817: It was named Morphine after “Morpheus - God of Dreams”

• 1839-1842: the Opium Wars occurred between the Chinese and the British

  • The Chinese traded silk, tea, and porcelain for British silver and opium.

  • In 1839 in order to stop the rising addiction rate, the Chinese government confiscated and destroyed opium in the Canton Harbor

  • The British retaliated by sending warships kicking off the war

  • Chinese opposition was defeated by the British who demanded the right to trade opium, payment for the destroyed opium, the opening of foreign ports for more trade, and the acquisition of Hong Kong as a British Colony

  • The Opium trade did not end in China till 1913 due to moral pressure

Nowadays Cultivation

• Nowadays Cultivation is controlled by the International Narcotic Control Board of the UN.

• India produces opium legally to meet world requirements

• China and North Korea grow it for domestic needs

• Other countries are allowed to legally grow poppies for poppy seed and poppy straw

  • Poppy straw: the raw material for morphine production by the pharmaceutical industry.

  • Poppy seeds are used in baking and the alkaloid content is negligible

• The illegal cultivation of opium poppies in the Golden Crescent and the Golden Triangle has a huge impact on global politics

  • Golden Crescent: Pakistan, Afghanistan, and Iran

    • Afghanistan is the largest illicit grower of opium, supplying 70% of the world’s opium

  • Golden Triangle: Myanmar, Laos, and Thailand

Clinical Uses Opium

• It is used for post-op pain and severe burns

• Its use is discontinued as soon as possible

• Longer-term use is allowed in patients who are terminally ill

Morphine

• Morphine is a powerful painkiller

• Morphine depresses parts of the brain involved in the perception of pain and reduces the anxiety that comes with the pain.

• Acts at several sites in the CNS producing analgesia

• Morphine is hypnotic and narcotic

• Morphine Side Effects: nausea, vomiting, and constipation

• Highly addictive

Codeine

• Codeine is known as methyl morphine and is the most commonly used opiate

• It can be isolated from opium but is normally produced from morphine by methylation

• Works very well in combination with other non-opiate analgesics such as aspirin and Tylenol

  • Tylenol 3 is codeine and acetaminophen.

• Codeine has 10% of the analgesia activity of morphine

  • It is converted to Morphine in the liver

• Less toxic and addictive than morphine

Naturally Occurring Agonist for the Opioid Receptors

• The body contains the three types of endogenous opioids

  • Beta-endorphins

  • Enkephalins

  • Dynorphin

• These are peptides occurring in the brain that allow us to tolerate pain.

• Morphine can mimic part of the structure of the endorphins and enkephalins

Heroin

• Heroin: the acetate derivative of morphine

• Introduced in 1898 by Bayer as a “Nonaddictive opiate with analgesic properties”

  • By 1917 it was no longer available

• 6 times more addictive than morphine

• Illegal in the US

  • Comes into the US illegally from Mexico and Columbia

Fentanyl

• Fentanyl is synthetic

• It was developed in 1960

• Used legally as an anesthetic for surgery and for pain management in cancer patients

• It is 100x more powerful than morphine

• Illegally produced fentanyl is responsible for many of the deaths associated with the opioid crisis

Opioid Crisis in the US

• Over 47,000 people died in the US in 2017 from an opioid overdose

• Legal drugs - morphine, oxycodone (Percocet), hydrocodone (Vicodin)

• Illegal drugs - heroin, illegally produced fentanyl

• In 2012 there were 282,000 prescriptions written for opioids

• In 2016 over 6 billion Vicodin tablets were distributed in the US

  • This is 99.7% of the world’s hydrocodone use

• In 2017 1.7 million people in the US had substance use disorders related to prescription opioids.

• Approximately 650,000 suffered from heroin use disorder.

Marijuana (Cannabis Sativa)

• The marijuana plant has separate male and female plants (Dioecious)

• Glandular hairs (trichomes) produce resins

  • Most resins are produced by the female inflorescences

  • The potency of the resin depends on genetic stains and growing conditions

• A part of the family Cannabaceae

• There are multiple species

  • Sativa

  • Indica

  • Ruderalis

• The parts of the plant used are the dried flowers, leaves, and stems

• Sativa and Indica: Native to Central and Western Asia, cultivated widely in India and many tropical and temperate regions

• Ruderalis: Native to Siberia

• Marijuana has multiple uses such as paper products, textiles, molded plastics, body care products, construction, livestock feed and bedding, nutritional supplements, essential oils, medicine, and food.

• Marijuana can be smoked or eaten to alter physical and mental states

  • In moderate doses, it produces a sense of detachment, feelings of euphoria, and increased alertness

History

• Marijuana was used as a medicine, fiber source (hemp), and intoxicant in India, China, and the American colonies

• It arrived in the US in the early 20th century from Mexico and the Caribbean

• 1937: the Federal Marijuana Tax Act was introduced to control the legal sale and virtually eliminated its legal use

  • Despite this, there is considerable recreational use

• 1964: THC was identified

• 1992: Specific receptors that bind THC were discovered in the brain

  • Known as Cannabinoid Receptors

• 1995: the first endogenous neurotransmitter that binds these receptors was discovered and named Anandamide

  • Other compounds have been identified and all of the chemicals that bind THC receptors are classified as endocannabinoids.

Recreational Use

• By 1979 68 million people in the US had tried marijuana

• In 2005 14.6 million were using marijuana on a monthly basis

  • It is used globally by 200-300 million people

• Smoking marijuana increases the risk of cancer, bronchitis, and emphysema

  • While also impairing learning as well as short-term memory and slowing reaction time

Active Components

• Tetrahydrocannabinol (THC) was identified as the primary psychoactive and medicinal components

• THC: A phenolic compound (known as cannabinoids)

  • There are ~60 related compounds present in the plant

Legality

• Medical marijuana is legal in 39 states

  • It is used as a mild pain killer for treating MS, a tranquilizer, an anti-emetic, and an appetite stimulant

  • Anti-emetic and appetite stimulant: treat nausea, vomiting which are side effects of cancer and AIDS treatments

  • May also be used to treat glaucoma and as an aid to chemotherapy

    • THC decreases ocular pressure

• 33 states have legalized the recreational use of marijuana, and more states get added at each election

  • However, these are state laws and there are still possibilities of federal prosecution

Cocaine (Erythroxylum Coca)

• The Coca tree is a part of the family Erythroxylacea

• The genus comprises small trees (6 feet in height)

  • Indigenous to South America

  • Trees are kept small by pruning, and the leaves are harvested several times a year

    • Kept short for easy harvest

  • The trees are grown at high altitudes (500-2000m)

• Peru and Bolivia are the only countries that can grow it legally for the pharmaceutical market

  • These counties are also a major source of illicit coca used for cocaine production

    • Columbia is a big one too

• 25% of the harvest is used by indigenous people who chew the leaves to enable them to withstand the harsh living and working conditions as well as malnourishment.

• The Coca leaves contain 0.7-2.5% alkaloid by weight

  • the ecgonine group of alkaloids is the only group of medicinal importance

    • this includes the ecgonine itself and the cocaine

• Cocaine was first isolated in 1860 and its local anesthetic properties were discovered shortly after.

• The Harrison Act of 1914 was the 1st anti-narcotic law that regulated the use of cocaine, heroin, opium, and morphine.

Production

• To obtain cocaine, leaves are steeped in acid to convert all of the different alkaloids in the plant to ecgonine by acid hydrolysis

• Then all the ecgonine is converted to cocaine by esterification with methanol and then benzoic acid

• This yields very high-purity cocaine in greater abundance when compared to cocaine directly isolated from the plant

• Illicit labs convert this to cocaine hydrochloride, which is transported to and sold in the US

Use

Illegal Use

• Illicit use involves snorting it into the nostrils where it is rapidly absorbed through the mucus membranes

• It can also be vaporized and inhaled (the free base or crack is more volatile) and is absorbed and reaches the brain in seconds

  • Free-base: purifies the powder by boiling it in an ether solution to produce pure cocaine

  • Crack: a form of freebase prepared by heating a cocaine hydrochloride solution with baking soda

• Highly dangerous and addictive

  • It blocks the reuptake of neurotransmitters in the synaptic space, causing the neurotransmitter levels to increase

  • The elevated neurotransmitter levels produce a “high” and also have physiological effects causing increased heart rate, respiratory rate, elevated body temperature

  • Cocaine use can be fatal as it is impossible to predict a “safe” dose

• 966,000 people in the US have a cocaine use disorder

Legal Use in the Clinic

• Cocaine is used as a local anesthetic with topical application in dentistry

• It is also used in ENT surgery and ophthalmology

• Safer, less toxic, local anesthetics based on the chemical structure of cocaine are procaine, benzocaine, lidocaine, etc.

Tobacco (Nicotiana tabacum)

• A part of the family Solanaceae

  • Same family as tomatoes and white potatoes

• Indigenous to North and South America

• Cultivation nowadays is of Tetraploid (4n) hybrids.

  • Leaves are bigger

History

• 600-1000 CE: the first picture of a smoker found on pottery

• It was grown extensively in Central and South America

• Associated with Mayan Culture

• Taken to Europe by Columbus

• 1560: Jean Nicot, France’s Ambassador to Portugal, writes of tobacco’s medicinal properties, describing it as a panacea (cure-all).

  • Nicot sends plants to the French court

  • Smoking became commonplace

  • Leaves are dried, cured, rolled, and smoked

    • Leaves are hung on drying racks, chopped up, and made into cigarettes

• 1881: Cigarette manufacturing was mechanized allowing for the mass production of cheap cigarettes

• 1965: Cigarettes are now labeled as hazardous to your health in the US

  • The tobacco industry lobbied heavily to reduce the impact of the wording and to delay the label in advertising

  • The tobacco industry concealed evidence for years of the harmful effects of smoking

    • They added more and more nicotine to maintain their addicted consumer base

Active Components

• Nicotine: is the principal alkaloid in tobacco occurring throughout the plant

• Pure Nicotine is one of the most toxic plant poisons

  • Can be used as an insecticide

• Nicotine is addictive and it and other compounds in the smoke causes cancers not only of the lungs but many other parts of the body

  • Nicotine has no clinical uses

    • other than weaning people off smoking

Other Uses

• Tobacco Farmers want alternate use of their tobacco crop

• Using recombinant DNA technology scientists can generate tobacco plants that can synthesize novel compounds that can be used in the pharmaceutical industry

• One of the advantages of tobacco is that it is a non-food crop

Atropine and Related Alkaloids

• These come from members of the Solanaceae family

  • Tobacco, tomatoes, pepper, and white potato family

• Mandrake, Henbane, Jimsonweed, Belladonna

  • Hallucinogenic

Tropane Alkaloids

• (-) Hyoscyamine in plant; enantiomer to - hyoscyamine

• (+) Hyoscyamine formed on extraction; enantiomer to + Hyoscyamine

  • a 1:1 mixture of the two is called atropine

• (-) Hyoscine (AKA scopolamine)

• These alkaloids relax smooth muscle, dilate the pupil of the eye, dilate blood vessels, stimulate the CNS

  • Their toxicity resides in the ability to induce coma and respiratory arrest

Clinical Uses

• Used in surgery to restrict saliva production for people under anesthesia

• Atropine is used in ophthalmology to dilate pupils

• Used to control digestive disorders including spastic colitis

• Hyoscine (scopolamine) is used to reduce motion sickness and post-op nausea

Atropa Belladonna (Deadly Nightshade)

• The roots and leaves are used.

• Nightshade is a perennial indigenous to Central and Southern Europe and Asia Minor

• Gets its name from the fact that ladies put the juice in their eyes to “look Beautiful”

  • Belladonna means beautiful lady

• VERY TOXIC

• Other plants that contain the tropane alkaloids are Datuara (Thorn apple/Jimsonweed), Hyoscyamus (Henbane), and Mandragora (Mandrake)

• Historically these plants have been associated with witchcraft and potions containing Belladonna or Henbane give people images of flight (witches on a broomstick)

Fungi

• There are important medical compounds that come from fungi (Penicillin)

Claviceps purpurea

• Claviceps purpurea infects cereal plants

• When growing on the plant the fungus makes what we call “ergot alkaloids” including ergotamine.

• Ergots are fungus-infected cereal grains

  • If these are ground into flour is contaminated by the alkaloids and people will have hallucinations

  • There is evidence of this from Europe in the Middle Ages, periods when people displayed madness and hallucinated.

    • Historians have traced these times to years when there was a lot of rainfall and fungus infecting cereal plants.

Clinical Uses

• These alkaloids restrict blood flow and can be used for treating migraine headaches

  • Migraines are pulsing headaches caused by increased blood flow in the temporal arteries

• They can also be used to prevent post-partum bleeding

Illicit Uses

• In the 1960s after the structures of ergot alkaloids were characterized, synthetic versions of the drugs were made

  • Such as LSD (Lysergic Aid Diethylamine)

Conclusion

• Psychoactive drugs from plants and fungi can have profoundly useful therapeutic effects.

• They can also be used recreationally

• Since they are so addictive, they can be abused leading to devastating costs to society