Transcript Marijuana

Psychoactive Plants
Psychoactive plants produce their effects by acting on the
nervous system. In general they mimic, block, or affect the
normal metabolism of neurotransmitters.
They can be classified as stimulants, depressants, or
hallucinogens.
Stimulants excite portions of the nervous system, promote
alertness and activity, reduce fatigue, and suppress appetite.
Depressants reduce physical activity and alertness. Typically,
the reduced awareness is seen as a near-sleep, dreamlike state.
Hallucinogens alter perception, mood and thought patterns.
Most are alkaloids (but not the active ingredient in marijuana).
Some have legitimate medical uses (including marijuana), but
many are illegal, recreational drugs.
The use of these plants and drugs is not new – the use of
opium poppy goes back at least 6000 years in Sumerian
records.
We typically think of these drugs collectively as narcotics,
but by definition the name only applies to depressants.
Modern usage adds to depressants any other drugs that are
addictive. Addictive means that the drugs cause one or more
of: psychological dependence, physiological dependence, and
tolerance.
Psychological dependence means that the experience of the
drug is so pleasurable that the person has an irresistible need
to re-experience the sensations produced by taking the drug.
Physiological dependence means that the body needs the drug
to avoid painful withdrawal symptoms.
Tolerance means that it takes more and more of the drug to
obtain the same sensations or responses to the chemical.
Your text has a fine description of the common neurological
mode of addictive drugs…
The mesolimbic pathway links the ventral tegmentum to the
nucleus accumbens of the limbic system. This pathway uses
the neurotransmitter dopamine, and is involved in both
pleasure and psychosis.
Dopamine is released at the nucleus accumbens by axons of
neurons of the ventral tegmentum.
Normally, those neurotransmitters are recollected after a short
time and returned to VT neurons. Different drugs act in
different ways to prevent the normal cycle of controlled
release and recollection. The end result is accumulation of
dopamine at the nucleus accumbens neurons, producing a
euphoric sensation, whether in a state of heightened or
depressed activity.
Stimulant drugs like cocaine prevent the recollection.
Depressant drugs like heroin shut down the control pathway
that normally reduces or stops the production and release of
dopamine.
Above is a cartoon depiction of the normal state of the
mesolimbic pathway. A complex dendritic tree of a ventral
tegmentum neuron gathers stimulation. It connects to the
nucleus accumbens neuron at a synapse that releases
dopamine.
With addiction, there are physical, as well as control and
chemical changes to the pathway. The dendritic tree of the VT
neuron simplifies. Without a larger amount of drug, the NA
cell is ‘starved’ for dopamine.
What was at first an increase in dopamine becomes a reduced
amount with tolerance.
The basic molecular biology of tolerance is now understood.
Chronically elevated dopamine in the nucleus accumbens
causes its neurons to produce cyclic AMP. Cyclic AMP
triggers a transcription factor called CREB (cyclic AMP
response element-binding protein – sorry!) that, when
phosphorylated, triggers genes that inhibit dopamineproducing neurons in the VT. It takes more drug to overwhelm
this tolerance.
It is also important to recognize that neurons in our brains
have opiate receptors. They respond to endorphins –
endogenous opiate-like molecules that enhance pleasure and
reduce pain, but also to the various narcotics injected, inhaled,
smoked, drunk or consumed.
What are those narcotics, and what plants produce them?
• opium – from the opium poppy (Papaver somniferum),
from which morphine, codeine, and heroin are derived.
• marijuana – from Cannabis sativa, which is also the
source for hasish (under its various names) and hash oil
• cocaine – from Erythroxylum coca
• nicotine – from Nicotiana tabacum
• peyote – from Lophophora williamsii
• kava – from Piper mysticum
• caffeine – from many sources
• alcohol – from many sources
Starting through this long list, we have already seen a lot about
opium. There is more to add here…
Opium
In the dried resin of the poppy’s pod are ~20 alkaloids. Both
morphine and codeine are medically important. Both are
phenanthrenes. There is another whole class of alkaloids
present, in a group called benzylisoquinolines.
The leading producer of opium is Afganistan (>1000 metric
tons, 70% of the world’s supply). Other producers supplying
the illegal drug trade are Myanmar, Laos, Thailand, Pakistan,
Iran, and some countries of Central America and northern
South America. The leading producer of legal opium poppies
is India.
There have been many famous opium addicts: Elizabeth
Barrett-Browning, Samuel Coleridge, and Hector Berlioz.
Berlioz got the ideas for his Symphonie Fantastique ‘under
the influence’ in a dream.
There have also been many famous heroin addicts. During the
1950s and 1960s heroin addiction was common among the
leading jazz musicians: Charlie ‘Yardbird’ Parker, Miles
Davis, and Billie Holiday among many others.
Heroin is 6 times more addictive than morphine. As well,
withdrawal from heroin addiction is much more severe than
from morphine. So much more severe that withdrawal from
heroin addiction is very difficult.
Instead of withdrawal ‘cold turkey’ (the descriptive term
comes from the tendency to feel cold and get ‘goose bumps’
during withdrawal), medicine has found that slow reduction in
the dose of methadone, a synthetic opiate that is less addictive,
can make withdrawal manageable.
Overdoses of either heroin or morphine can be fatal. The
opiates are central nervous system depressants, and can, in
overdose, completely suppress the respiratory center in the
brain.
Morphine as a prescription medicine is still used to treat
intense pain, for example following surgery or in the case of
severe burns, for those in the pain of terminal cancer, and for
kidney stones.
Both morphine and heroin were once in commonly available,
over-the-counter remedies, like cough syrups, but the dangers
were recognized early in the 20th century, and those products
were no longer available by 1920.
Marijuana – The species is a dioecious (separate sexes)
annual. The active ingredient is -9-tetrahydrocannabinol. It
is present at low concentrations even in the leaves of hemp
grown for rope, but is in much higher concentration in the
resin from unfertilized pistillate (female) flowers and
adjacent leaves. It takes about 5 mg of THC to have a
detectable psychological or physiological effect.
THC is a phenolic molecule, in its own class called
cannabinoids.
There are two receptor types for cannabinol, called CB1 and
CB2 types. CB1 receptors are in the brain, including the
limbic system, hippocampus (short term memory) and
amygdala (emotional memory), but are absent in the medulla
oblongata. CB2 receptors are in the immune system
(particularly the spleen), and are probably responsible for
anti-inflammatory response.
Much like endorphins, we produce endogenous cannabinols.
After discovering cannabinol receptors in animal brains in
1988, endogenous cannabinols were discovered in 1992. This
is the structure of the first one found:
It’s called anandamide, which comes from the Sanskrit word
for bliss, with the suffix for its structure as an amide. It is
approximately as potent as THC and binds to both receptor
types.
Cannabis has been used for at least 5,000 years for its ‘drug’
properties, beginning in China, then India and among the
Scythians of central Asia. Use spread from there into Asia
Minor (the Arabic and Persian countries) and northern Africa.
It was used as a hallucinogen and in religious ceremony.
It is still used in religious ceremony in India (it is one of the
five sacred plants), and is the preferred ‘relaxant’ in alcoholfree Muslim countries like Pakistan and Bangladesh, smoked
in hookahs.
Estimates suggest at least 20% of the populations of the U.S.
and Canada have used cannabis. Is that accurate? An
underestimate? An overestimate?
Symptoms and effects of marijuana:
• sporadic, uncontrollable laughter
• often the (mistaken) impression their
conversation is witty and brilliant
• limbs feel light....
• decreased sperm count; decreased Testosterone levels
• ‘the munchies’…hunger, usually for snack foods
• an altered (distorted) sense of time and space
• smoke may damage lungs as cigarette smoke
does
However, there are valuable medical uses for marijuana. It
is used to treat glaucoma – a high intraocular pressure that
can be caused by advancing age, diabetes, and other factors
– THC reduces intraocular pressure.
It is used to treat the nausea, vomiting, and loss of
appetite brought on by cancer chemotherapy.
It is used to reduce or eliminate spastic movements in
patients with multiple sclerosis and Parkinson’s disease.
It is used to counteract the wasting syndrome that is part
of terminal AIDS.
In Canada marijuana is a “schedule II” drug, meaning that it
can be prescribed for approved medical conditions when
necessary. The medical marijuana is all produced under
contract to the federal government by Prairie Plant Systems
in Manitoba and Saskatchewan.
In the U.S. there is no parallel federal approval system for
medical marijuana; it is a schedule I drug (with heroin). In a
(conflicted) situation, some states have a licensed mechanism
to distribute medical marijuana.
The AMA is significantly more ‘liberal’ than government,
and wants marijuana reclassified as a schedule II drug.
Though they are controversial, there are local regulations in
some jurisdictions (e.g. Ann Arbor, MI) that make possession
of personal use amounts of marijuana a civil offense like a
traffic ticket.
State laws concerning
Cannabis:
Blue-medical marijuana
Red-decrimilization
Purple-both
Even where marijuana is available for medical use, smoking
it, as noted with effects, can do much the same damage as
smoking tobacco (see below). An inhaler for THC would be
much better medically, but has not become available.
One last point: modern growth systems have increased the
THC content of marijuana in two ways: one is classical
selection, the other is the production of sinsemilla plants that
are seedless hybrids of C. sativa and C. indica. Artificial
growth systems clone pistillate plants of the hybrid that are
dwarfed in size, but have abundant flowers and resin.
One of the products of this new growth method is a larger
yield of hashish (hash, hash oil, etc.)
The origin of the term “Hashish” is from Hashishin, which
is the Arabic word for ”assassin” or, possibly more likely,
from the Arabic for grass.
The source for the term assassin, and the reason for its
association with marijuana is the Hashshashin, the
medieval Shia sect of militants founded by Hassan-i-Sabah.
They were said to have been inspired to commit murder
under the influence of hashish
Hashish normally means the compressed trichomes from
upper leaves which are the source of the resin that is the
most concentrated source for THC. The current ‘product’ is
a much stronger material today than in the 1960s and
1970s; the THC content has increased by about 10x.
Cannabis trichomes
hashish
Cocaine – coca leaves have been chewed by natives in Peru
and the pre-Columbian Andes for hundreds of years. Cocaine
has been used in western culture for more than a century.
Among famous users (neglecting the many models (Kate
Moss) and musicians) have been: Arthur Conan Doyle,
Sigmund Freud (where do you think those dreams for analysis
came from?), and Ulysses S. Grant.
You know that Coca-cola once contained cocaine, and still
contains a non-narcotic extractive of coca leaves grown under
government control in New Jersey.
Cocaine may be taken by injection, consumption, smoking, or
‘snorting’ (formally insufflation). Effects occur fairly rapidly
(seconds to less than one hour).
Cocaine is a powerful stimulant, producing a euphoria and a
burst of energy and alertness. However, after that short-term
‘high’ there is a period of depression and lethargy. All this
happens because cocaine blocks the transporter protein
involved in re-uptake of dopamine. Long term users may
suffer from a psychosis like schizophrenia.
Cocaine is extracted from the coca leaves by processing with
sulfuric acid. Leaves are macerated (stomped like grapes or
otherwise crushed), and mixed into the acidic solution. After
maceration, the water is evaporated, leaving a brown mush
that is dried into impure cocaine sulfate.
That product is sold in South America. What is transported to
North America is much more concentrated cocaine
hydrochloride. This is the white powder sometimes called
‘snow’.
From this ‘base’ cocaine, the many more dangerous forms are
made: crack cocaine, freebase cocaine, etc.
‘lines’ for insufflation
Cocaine hydrochloride
‘crack’
Tobacco – tobacco is a product of a New World genus, and
only two species are commonly used:
Nicotiana tabacum
and
N. rustica.
Both are tetraploid hybrids of closely related Nicotiana
species. As members of the nightshade family, they have
certain properties that are particularly interesting (and another
reason not to smoke) for Canadians.
Members of the nightshade family accumulate soil cadmium
in their leaves (but not fruits). Canadian soil (at least where
tobacco was mostly grown around Delhi, Ont.) is high in
cadmium, a toxin for kidneys (second only to Japan in Cd
concentration).
We eat the fruits of other Solanaceae: e.g. tomatoes, green
peppers, potatoes, eggplants, but what we use of tobacco is the
leaves, the parts with high cadmium.
The use of tobacco isn’t new; it was used by native Americans
long before Europeans arrived. It was smoked in large
quantities as a hallucinogen by shamans. It was also chewed,
eaten, and drunk. Missionaries saw the effects, and sent seeds
back to Europe, initially Spain.
From Spain use spread to France, then England. It is argued
that the desire for tobacco fueled the European colonization of
North America.
John Rolfe came to Jamestown in 1609, and became the first
person to successfully raise tobacco (N. tabacum) as a crop,
replacing the inferior N. rustica. He later married Pocahontas.
He became rich on tobacco export to England, and continued
to improve the crop quality by selection.
Tobacco also drove the initial slave trade, bringing the first
slaves to Jamestown in 1619.
King James I disliked tobacco intensely, wrote a polemic
about that, and imposed a high tariff on imported tobacco.
Here are those characters:
John Rolfe with an
imagined Pocahontas
Pocahontas as
painted in England
King James I
Tobacco is an annual plant. It is grown from seeds that are
started in special beds. In the U.S. these beds are fertilized
with apatite, a mineral that causes the plants to be partially
starved for nitrogen – the object is taste.
When the seedlings reach sufficient size, they are transplanted
into fields and grown.
To maximize leaf area of tobacco plants, they are generally
not allowed to flower or to branch laterally.
Harvesting occurs by pulling mature leaves off the plants,
beginning at the bottom and working upward over time as
leaves mature. The leaves are hand-picked. Alternatively,
harvest can wait until most leaves are mature, then the whole
plant is cut.
The cut leaves are then moved to barns to cure. Curing is
basically ‘fermentation’ and drying. This is the time when the
flavors develop; the leaves turn from green to brown as the
chlorophylls break down and carotenoids degrade.
Tobacco leaves can be air-cured, smoke-cured, or flue-cured
(heated without exposure to smoke).
The cured leaves are aged for weeks to years before
manufacturing the final product (cigarettes, cigars, pipe
tobacco, chewing tobacco). Each product involves a mixture
of leaves of different cures as well as additives.
Cigarettes are the most recent of these products, only having
been marketed after the Crimean War (1854-6) pitted Russia
against an alliance of France, England and the Ottoman
Empire. Mass marketing only followed the development of
machinery that could manufacture cigarettes cheaply,
beginning in 1881.
Cigarette consumption peaked in 1963 in the U.S., when 42%
of the population were at least occasional smokers. Today
numbers have declined, but there are still more than 1 billion
smokers worldwide.
Why are we concerned about smoking?
Because tobacco contains the most widely used addictive drug
– nicotine.
All means of consuming tobacco result in the absorption of
nicotine in varying amounts into the user's bloodstream, and
over time the development of tolerance and dependence, i.e.
addiction.
The addiction has significant health consequences. Among
the statistics:
• 85% of lung cancer in men and 75% of lung cancer in
women is caused by smoking
• 30% of all cancer deaths can be linked to smoking
• Male smokers die 13 years and women 14.5 years
earlier on average than otherwise similar non-smokers.
• Coronary heart disease and stroke, leading killers, are
caused by smoking. 120,000 deaths from coronary
artery disease are attributed to smoking annually.
Smokers having double the risk of dying.
• Chronic obstructive pulmonary disease (bronchitis,
asthma, emphysema) is next on the list of leading
causes of death. 90% of these deaths are due to
smoking.
•
Second-hand smoke is now recognized as dangerous.
Exposed babies have higher risk of SIDS. Asthma,
emphysema and cancer risk is increased in exposed
children.
Public recognition of the danger took a long time. In 1964 the
US Surgeon General’s Office reported links between smoking
and lung cancer, heart disease emphysema etc.
In 1998 California became the first state to ban smoking in
bars. In that same year settlements with the five major
cigarette manufacturers in the U.S. gave damages to the states
totaling $200 billion to recover costs of medical treatments for
smokers.
Today most states and Canada ban smoking in public
buildings. Bans are currently being extended more broadly.
States in red are members of one or more of the suits
against tobacco manufacturers.
Nicotine is the addictive component, but not necessarily the
most dangerous compound in tobacco. Table 20.1 in your text
lists some of the 2000 compounds in tobacco smoke. Check
them out. Many are carcinogens and/or toxic.
Nicotine comprises 0.3 – 5% of the dry weight of tobacco
leaves. It is a potent neurotoxin. You get about 1mg absorbed
nicotine/cigarette (non-filtered).
Nicotine acts on acetylcholine receptors. In small
concentrations it increases their activity, among other things
leading to an increased flow of adrenalin, a stimulating
hormone. The release of adrenaline causes an increase in heart
rate, blood pressure and respiration, as well as higher glucose
levels in the blood.
However, in higher doses, nicotine causes a blocking of
acetylcholine receptors, which is the reason for its toxicity
(higher than cocaine) and its effectiveness as an insecticide.
In addition, nicotine increases dopamine levels in the reward
circuits of the brain. Studies have shown that smoking tobacco
inhibits monoamine oxidase, an enzyme responsible for
breaking down dopamine.
In this way, it generates feelings of pleasure, similar to that
caused by cocaine and heroin, thus causing the addiction. The
same dependence and tolerance effects are observed.
Breaking the addiction, just as with the ‘hard’ drugs, is
difficult. Transdermal nicotine patches are being used
successfully. They wean the person off smoking by providing
a steady, but slowly decreasing supply of the alkaloid.
Peyote and Mescaline
Peyote is the cactus Lophophora wiliamsii that is native to
southwestern Texas and Mexico. It is a spineless cactus.
It is slow growing, taking 10 – 30 years in the wild to reach
adult, flowering size. What is harvested is the above ground
‘button’. It contains a number of phenethylamine alkaloids,
the most important of which is mescaline.
Overharvesting has made Lophophora an endangered species.
The effective dose is 300 – 500 mg mescaline, or about 5g of
dried peyote. It is a hallucinogen.
The hallucinogenic visions vary widely, from LSD-like light
shows to frightening visions of snakes, demons and feelings as
if trapped in a cave.
There are, additionally, many side effects, including nausea,
vomiting, and tremors. Those effects typically precede the
hallucinatory phase of effects.
In Canadian law, mescaline is a prohibited (illegal) substance,
but peyote is exempt. In the U.S., after a protracted series of
legal challenges, use of peyote by a religious group, the Native
American Church, was permitted, but the Supreme Court also
upheld the rights of individual states to outlaw peyote. The
situation might now be described as a morass, with conflicting
regulations in different states.
Kava - is a soporific derived from Piper mysticum. The plant
is native to the western Pacific and was transported from
island to island by Polynesians. The name kava refers both to
the plant and the beverage made from it.
The active ingredients are lactones. There are 15 – 20 lactones
in the leaves and roots, but only 6 are pharmacologically
active. Fresh roots contain about 15% lactones, while leaves
contain ~5%.
Exact proportions of different lactones differ among the many
sources across the South Pacific. The effects vary similarly.
Overharvesting of roots has meant population decline and the
harvesting of younger and younger plants.
The most potent kava is produced by grinding or pounding
fresh roots, adding cold water, and drinking the emulsion that
results. It can also be prepared by chewing, which is the
traditional Polynesian method.
The effects of consuming kava occur within an hour or two of
consumption. Initially blood vessels of the lips and tongue
constrict, some numbness occurs there. Then there is a
somewhat euphoric period, and finally there is an anxiolytic
effect (reduced anxiousness, calming, friendliness) and,
typically, sleep.
Stronger beverages produce somnolence, then deep, dreamless
(??, there are also reports of vivid dreams) sleep. Either mild
or stronger effects have the advantage that this ‘drug’ is not
addictive, has no aftereffects, and, unlike alcohol, does not
affect reaction time.
Use in Europe and North America has been directed towards
reduction of anxiety and as a sleep aid. However, there is
conflicted evidence of liver disease.
Kava has been the subject of an FDA alert, but has not been
banned.
The difference between a lack of liver disease in Polynesian
users and occurrence in Europe and North America is
suggested to be due to difference in extraction/preparation
methods.
Commercial preparation has used ethanol extraction of
lactones from roots versus the traditional method that uses
only water.
However, there is tentative evidence that methanol extracts of
kava roots may be useful in treating leukemia and ovarian
cancer.
A few last pharmacoactive plants –
Other plants from among the Solanaceae also produce
alkaloids that can be poisonous, but used are used medically in
small amounts.
The plants are: deadly nightshade (Atropa belladonna) and
jimsonweed (Datura strumonium)
Both species contain atropine and scopolamine. Both
chemicals are hallucinogens and are dangerously toxic, but
also have medical applications.
Symptoms of atropine poisoning are tachycardia,
hallucinations, loss of balance, confusion, and constipation.
Atropine completely blocks acetylcholine neurotransmission
(and function of the parasympathetic system).
Atropa belladonna
Datura strumonium
Atropine has valuable medical applications:
• when your optometrist or ophthalmologist puts drops
in your eyes to dilate your pupils, the active ingredient
was atropine, more recently replaced by synthetic agents
• it is the antidote to poisoning by cholinesterase
inhibitors used in pesticides (Malathion, Parathion)
• it acts much like pseudoephedrine, and is in some
over-the-counter cold and flu medicines
It takes only a few berries to reach a toxic dose. The atropine
is most concentrated in the seeds within the berries.
So why do people ‘fool around’ with jimsonweed? The
hallucinations, of course. The problem: before hallucinations a
consumer will suffer the anticholinergic effects, nausea,
vomiting, etc. The answer? Don’t
Salvia
Salvia divinorum is a hallucinogenic plant in the mint family.
It is native to the Sierra Mazateca mountains in the state of
Oaxaca, Mexico. It has long been used by shamans of the
Mazateca in rituals that are Christian in origin.
The active ingredient is a diterpenoid
called salvinorin. It seems not to be
toxic, unlike other hallucinogens that
bind to opiate and serotonin receptor sites.
Oaxaca
Salvinorin is also (by concentration) the most potent
naturally-occurring hallucinogen. Since it appears to be nontoxic, has high potency, and is readily available in the form of
plants or dried leaves, it is growing in ‘popularity’.
Methods of ‘consumption’ include smoking (apparently
higher temperature (>240C) releases a much greater
proportion of the salvinorin in the leaves), chewing (like using
chewing tobacco), and using a tincture. Intake method affects
how rapidly and how long-lasting effects are, but mostly they
last only a few minutes.
Because Salvia is a relatively recently adopted hallucingen,
there is still controversy about its safety, and there are a global
variety of laws and prohibitions.
Legality of Salvia divinorum
Banned by law
Imports/sales prohibited
Sale to minors prohibited
A list of the effects from a book about using Salvia includes:
•Uncontrollable laughter
•Past memories, such as revisiting places from childhood
memory
•Sensations of motion, or being pulled or twisted by forces
•Visions of membranes, films and various two-dimensional
surfaces
•Merging with or becoming objects
• Overlapping realities, such as the perception of being in
several locations at once
We won’t talk about it here, but alcohol could easily be classed
with the other psychoactive drugs. It is a CNS depressant, it is
addictive and shows tolerance development.