Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 12B) pdf

10
NONMEDICAL
USE OF
DRUGS
Chronic
consumption
For
benefits
of
chronic alcohol consumption,
see
page
187.
Central
nervous system.
The
development
of
dependence
on
alcohol appears
to
involve alterations
in
central nervous system neurotransmission.
The
acute
effect
of
alcohol
is to

block NMDA receptors
for
which
the
normal agonist
is
glutamate,
the
main
excitatory
transmitter
in the
brain.
Chronic
exposure
increases
the
number
of
NMDA receptors
and
also
'L
type'
calcium channels, while
the
action
of the
(inhibitory)
GABA

neurotransmitter
is
reduced.
The
resulting excitatory
effects
may
explain
the
anxiety,
insomnia
and
craving that accompanies
sudden withdrawal
of
alcohol
(and
may
explain
why
resumption
of
drinking brings about
relief,
perpetuating dependence).
Malnutrition.
With heavy continuous drinking,
subjects
take
all the

calories they need
from
alcohol,
cease
to eat
adequately
and
develop
deficiency
of
B
group vitamins particularly.
The
malnutrition
complicates
the
long-term
effects
of
alcohol
itself.
Organ
damage. Chronic heavy alcohol
use is
associated with: hepatic cirrhosis, deteriorating
brain function (psychotic states, dementia, seizures,
Wernicke's
encephalopathy, episodes
of
loss

of
memory); peripheral neuropathy
and,
separately,
myopathy (including cardiomyopathy); cancer
of
the
upper alimentary
and
respiratory tracts (many
alcoholics
also smoke heavily,
and
this contributes),
hepatic carcinoma
and
breast cancer
in
women;
chronic
pancreatitis; cardiomyopathy; bone marrow
depression, including megaloblastosis
(due
to the
alcohol
and to
alcohol-induced
folate
deficiency);
deficiency

of
vitamin K-dependent blood clotting
factors
(due
to
liver
injury);
psoriasis; multiple
effects
on
the
hypothalamic/pituitary/endocrine system
(endocrine
investigations should
be
interpreted
cautiously);
Dupuytren's contracture.
Hypertension.
Heavy chronic
use of
alcohol
is an
important cause
of
hypertension
and
this
should
always

be
considered
in
both diagnosis
and
management. Cessation
of use may be
sufficient
to
eliminate
or
reduce
the
need
for
drug therapy.
But
even social drinking
can
raise blood pressure,
and
hypertensives should
be
told this.
In
general,
reversal
of all or
most
of the

above
effects
is
usual
in
early cases
if
alcohol
is
abandoned.
In
more advanced cases,
the
disease
may be
halted
(except
cancer)
but in
severe cases
it may
continue
to
progress. When
wine
rationing
was
introduced
in
Paris, France,

in the
1939-45
war,
deaths
from
hepatic
cirrhosis
dropped
to
about
one-sixth
the
previous level;
5
years
after
the war
they
had
regained
their
former
level.
Blood
lipoproteins. Moderate intake
of
alcoholic
drinks
may
increase

high
density lipoprotein
and
diminish
low
density lipoprotein, which
may
account
for the
observed protective
effect
against
ischaemic
heart disease (see below).
Alcohol dependence syndrome
32
General
aspects
of
dependence
are
discussed earlier
in
this chapter. Dependence (chronic alcoholism)
varies
from
social drinkers
for
whom companionship
is

the
principal
factor,
through individuals
who
take
a
drink
at the end of a
working
(or
indeed
any) day,
who
feel
a
need
and who
would
be
reluctant
to
give
it
up, to the
person
who is
overcome
by
need,

who
cannot
resist
and
whose whole
life
is
dominated
by
the
quest
for
alcohol.
The
major
factors
determining
physical
dependence
are
dose,
frequency
of
dosing,
and
duration
of
abuse.
WITHDRAWAL
OF

ALCOHOL
Abrupt
withdrawal
of
alcohol
from
a
person
who
has
developed physical
dependence,
such
as may
occur
when
an ill or
injured
alcoholic
is
admitted
to
hospital,
can
precipitate
withdrawal
syndrome
(agitation,
anxiety
and

excess sympathetic autonomic
activity)
in 6 h and an
acute psychotic
attack
(del-
irium
tremens)
and
seizures
(at 72 h).
Withdrawal
should
be
supervised
in
hospital
with
the
patient receiving
chlordiazepoxide
by
mouth
32
A
World
Health Organization report
prefers
this term
to

'alcoholism'.
184
CHRONIC
CONSUMPTION
10
Fig. 10.4
Features
of
alcohol
dependence.
10-50
mg
qid,
gradually reducing over
7-10
d.
Longer
exposure
to
chlordiazepoxide should
be
avoided
as it has the
potential
to
induce depend-
ence.
A
B-adrenoceptor blocker
may be

given
to
attenuate symptoms
of
sympathetic overactivity.
General
aspects
of
care,
e.g.
attention
to
fluid
and
electrolyte
balance,
are
important.
It is
usual
to
administer vitamins, especially thiamine,
in
which
alcoholics
are
commonly
deficient,
and
i.v.

glucose
unaccompanied
by
thiamine
may
precipitate
Wernicke's
encephalopathy.
Treatment
of
alcohol
dependence
Psychosocial support
is
more important than drugs,
which
nevertheless
may
help.
Acamprosate
bears
a
structural resemblance
to
both
glutamate
and
GABA
and
appears

to
reduce
the
effect
of
excitatory amino acids such
as
glutamate,
and
modifies
GABA
neurotransmission.
Taken
for
1
year (accompanied
by
counselling
and
psycho-
social
support), acamprosate increases
the
number
185
10
NONMEDICAL
USE OF
DRUGS
of

alcohol-free
days
and
also
the
chance
of
sub-
sequent complete abstinence.
The
benefit
may
last
for
1
year
after
stopping treatment. Acamprosate
may
cause gastrointestinal adverse
effects,
and
cutaneous eruptions.
Disulfiram
(Antabuse).
In
alcoholics
who are
well
and

motivated,
an
attempt
may be
made
to
dis-
courage drinking
by
inducing immediate unpleas-
antness.
Disulfiram
inhibits
the
enzyme aldehyde
dehydrogenase
so
that acetaldehyde
(toxic
meta-
bolite
of
alcohol)
accumulates.
The
objective
of
administering
disulfiram
is

that
patients
will
find
the
experience
so
unpleasant that they will avoid
alcohol.
It
should
be
administered only under
specialist supervision.
A
typical reaction
of
medium severity comes
on
about
5 min
after
taking alcohol
and
consists
of
generalised vasodilatation
and
fall
in

blood pressure,
sweating, dyspnoea, headache, chest
pain,
nausea
and
vomiting.
It may
result
from
even small amounts
of
alcohol (such
as may be
present
in
some oral
medicines
or
mouthwashes). Severe reactions include
convulsions
and
circulatory collapse; they
may
last
several hours. Some advocate
the use of a
test dose
of
alcohol under supervision
(after

the
fifth
day),
so
that patients
can be
taught what
to
expect
and
also
to
induce
an
aversion
from
alcohol.
SAFE
LIMITS
FOR
CHRONIC
CONSUMPTION
These cannot
be
accurately defined.
But
both patients
and
nonpatients
justifiably

expect some guidance,
and
doctors
and
government departments will wish
to be
helpful.
They
may
reasonably advise
as a
'safe'
or
prudent maximum (there being
no
particular
individual contraindication):
men,
not
more than
21
units
per
week (and
not
more than
4
units
in any one
day),

and
women,
14
units
per
week (and
not
more
than
3
units
in any one
day).
33
Consistent drinking
more
than
these amounts carries
a
progressive risk
to
health
(see
also Alcoholic drinks
and
mortality,
below).
In
other societies recommended maxima
are

higher
or
lower.
Alcoholics with established cirrhosis have usually
consumed about
23
units (230
ml; 184 g)
daily
for 10
years.
It has
long been thought that total
con-
sumption accumulated over
time was the
crucial
factor
for
cirrhosis. Heavy drinkers
may
develop
hepatic cirrhosis
at a
rate
of
about
2% per
annum.
The

type
of
drink
(beer,
wine, spirits)
is not
particularly
relevant
to the
adverse health consequences.
A
standard bottle
of
spirits (750
ml)
contains
300
ml
(240
g) of
alcohol
(i.e.
40% by
volume).
A
standard human cannot metabolise more
than
about
170 g per
day.

People whose intake
is
con-
centrated
at the
weekend allow
their
livers
time for
repair
and
have
a
lower risk
of
liver
injury
than
do
those
who
consume
the
same total
on an
even daily
basis.
Pregnancy,
the
fetus

and
lactation
Pregnancy
is
unlikely
to
occur
in
severely alcoholic
women (who
have
amenorrhoea
secondary
to
liver
injury).
The
spontaneous miscarriage rate
in the
second trimester
is
doubled
by
consumption
of
1-2
units/day.
Fetal
injury
can

occur
in
early pregnancy
(fetal
alcohol
syndrome).
It may be due to the
metabolite,
acetaldehyde,
and so
acute (binge) consumption
is
more hazardous
than
similar total intake
on a
daily
basis.
The
vulnerable period
of
pregnancy
is at
4-10 weeks.
Because
of
this, prevention cannot
be
reliably
achieved

after
diagnosis
of
pregnancy
(usually
3-8
weeks).
There
is no
level
of
maternal consumption that
can be
guaranteed
safe
for the
fetus.
But it is
plainly
unrealistic
to
leave
the
matter there,
and it has
been
suggested that
if the
ideal
of

total abstinence
is
unachievable
then women
who are
pregnant
or are
thinking
of
becoming pregnant should
not
drink
more
than
1-2
units
of
alcohol
per
week
and
should
avoid periods
of
intoxication.
34
In
addition
to the
fetal

alcohol syndrome there
is
general fetal/embryonic growth retardation
(1% for
33
Report
of an
Inter-Departmental Working Group, 1995
Sensible Drinking. Department
of
Health.
34
Report
of an
Inter-Departmental Working Group, 1995
Sensible
Drinking. Department
of
Health.
186
10
every
10 g
alcohol
per
day)
and
this
is not
'caught

up'
later.
Fetal
alcohol syndrome includes
the
following
characteristics:
microcephaly, mental retardation
with irritability
in
infancy
low
body weight
and
length, poor coordination, hypotonia, small
eyeballs
and
short
palpebral
fissures, lack
of
nasal
bridge.
35
Children
of
about
10% of
alcohol abusers
may

show
the
syndrome.
In
women consuming
12
units
of
alcohol
per day the
incidence
may be as
much
as
30%.
Lactation.
Even small amounts
of
alcohol taken
by
the
mother delay motor development
in the
child;
an
effect
on
mental development
is
uncertain.

Alcoholic
drinks
and
mortality
The
curve that relates mortality (vertical axis)
to
alcoholic
drink consumption (horizontal
axis)
is J-
shaped; i.e.
as
consumption rises above zero
the
all-
cause
mortality declines, then levels
off,
and
finally
rises.
The
benefit
is
largely
a
reduction
of
deaths

due
to
cardio-
and
cerebrovascular disease
for
regular
drinkers
of 1-2
units/d
for men
over
40
years
and
postmenopausal women. Consumption over
2
units/d
does
not
provide
any
major
additional
health
benefit.
The
mechanism
may be an
improve-

ment
in
lipoprotein (HDL/LDL)
profiles
and
perhaps
a
reduction
in
platelet aggregation.
The
effect
appears
to be due
mainly
to
ethanol
itself
but
nonethanol ingredients (antioxidants,
phenols,
flavinoids)
may
contribute (see below).
The
rising (adverse)
arm of the
curve
is
associated

with known
harmful
effects
of
alcohol (already
described),
but
also,
for
example,
with
pneumonia
(which
may be
secondary
to
direct alcohol
effects,
or
with
the
increased smoking
of
alcohol users).
Whether
the
cardioprotective
effect differs
between classes
of

alcoholic drink remains
an
open
issue. Suggestion that wine
confers
greater advan-
35
For
pictures
see
Streissguth
A P et al
1985 Lancet
2:
85-91.
ALCOHOL
AND
OTHER
DRUGS
tage than spirits
was not
supported
by a
review
of
12
ecological,
3
case-control
and 10

prospective
cohort
studies.
36
The
social importance
of
alcohol
combined with
the
very substantial
scientific
problems
posed
by
these studies (including
the
problem
of
unreliably reported intakes) render
the
whole
matter controversial.
Alcohol
and
other
drugs
All
cerebral
depressants

(hypnotics, tranquillisers,
antiepileptics, antihistamines)
can
either potentiate
or
synergise with alcohol,
and
this
can be
important
at
ordinary
doses
in
relation
to car
driving.
But,
when supplies
of
hypnotics
or
tranquillisers
are
given
to
patients known
to
drink heavily, they
should

be
warned
to
omit
the
drugs when they
have been drinking. Deaths have occurred
from
these
combinations.
Alcohol-dependent people with
a
physical toler-
ance
are
relatively tolerant
of
some other cerebral
depressant drugs (hydrocarbon anaesthetics),
but of
course
the
synergism with these drugs still occurs.
There
is no
significant
acquired cross-tolerance with
opioids.
A
disulfiram-like reaction

occurs with metro-
nidazole, griseofulvin, cefamandole, chlorpropamide,
procarbazine
and
(possibly) tinidazine.
Oral
anticoagulants.
Control
may be
disturbed
by
alcohol
inhibiting hepatic metabolism acutely,
or
enhancing
it by
enzyme induction; moderate
drinking
is
unlikely
to
cause trouble.
Antiepilepsy drugs
can be
metabolised
faster
due
to
enzyme induction
and

this contributes
to its
well-known adverse
effect
on
epilepsy.
Monoamine oxidase inhibitors
(MAOIs).
Some
alco-
holic
(and de-alcoholised) drinks contain tyramine,
sufficient
to
cause
a
hypertensive crisis
in a
patient
taking
a
MAOI.
Miscellaneous
uses
of
alcohol. Alcohol precipitates
protein
and is
used
to

harden
the
skin
in
bedridden
36
Rimm
E B et al.
1996 Review
of
moderate alcohol
consumption
and
reduced risk
of
coronary heart disease:
is
the
effect
due to
beer, wine
or
spirits? British Medical Journal
312:
731-741.
187
10
NONMEDICAL
USE OF
DRUGS

patients.
Local
application also reduces sweating
and may
allay itching.
As a
skin antiseptic
70% by
weight (76%
by
volume)
is
most
effective.
Stronger
solutions
are
less
effective.
Alcohol injections
are
sometimes
used
to
destroy nervous
tissue
in
cases
of
intractable pain (trigeminal neuralgia, carcinoma

involving nerves).
Psychodysleptics
or
hallucinogens
These substances produce mental changes that
resemble those
of
some psychotic states. They
are
used
by
people
seeking
a new
experience
or
escape.
Experiences
with these drugs vary greatly with
the
subject's expectations, existing
frame
of
mind
and
personality
and
environment.
Subjects
can be

prepared
so
that they
are
more likely
to
have
a
good
'trip'
than
a bad
one.
The
experience lasts
a few
hours,
depending
on
the
dose;
intervals
of
normality
then
occur
and
become progressively longer.
Somatic
symptoms include nausea, dizziness,

paraesthesiae, weakness, drowsiness, tremors, dilated
pupils,
ataxia.
Effects
on the
cardiovascular system
and
respiration vary
and
probably
reflect
fluc-
tuating anxiety.
There
is no
shortage
of
sensational accounts
of
experience with psychodysleptics, because there
has
been
a
vogue amongst intellectuals, begun
by Mr
Aldous Huxley,
37
for
publishing
their experiences.

Subsequent accounts
are
tedious
to
most except their
authors
and to
those
who
would
do the
same; they
have little pharmacological importance
and
reveal
more about
the
author's
egocentricity than about
pharmacology.
The
same applies
to
published
accounts
of
what
it is
like
to be a

drug addict.
Individual
substances
Experiences
with
psychodysleptics
The
following
brief
account
of
experiences with
LSD
(lysergic acid diethylamide, lysergide)
in
normal
subjects
will serve
as a
model. Experiences with
mescaline
and
psilocybin
are
similar:
•
Vision
may
become blurred
and

there
may be
hallucinations; these generally
do not
occur
in
the
blind
and are
less
if the
subject
is
blind-
folded.
Objects appear distorted,
and
trivial
things,
e.g.
a
mark
on a
wall,
may
change shape
and
acquire special significance.
•
Auditory acuity increases,

but
hallucinations
are
uncommon.
Subjects
who do not
ordinarily
appreciate music
may
suddenly come
to do so.
•
Foods
may
feel
coarse
and
gritty
in the
mouth.
•
Limbs
may be
left
in
uncomfortable positions.
•
Time
may
seem

to
stop
or to
pass slowly,
but
usually
it
gets
faster
and
thousands
of
years
may
seem suddenly
to go by.
• The
subject
may
feel
relaxed
and
supremely happy,
or may
become
fearful
or
depressed. Feelings
of
depersonalisation

and
dreamy states occur.
LYSERGIDE
(LSD)
Lysergic
acid provides
the
nucleus
of the
ergot
alkaloids
and it was
during
a
study
of
derivatives
of
this
in a
search
for an
analeptic that
in
1943
a
Swiss
worker
investigating
LSD

(which structurally resem-
bles nikethamide)
felt
peculiar
and had
visual
hallucinations. This
led him to
take
a
dose
of the
substance
and so to
discover
its
remarkable potency,
an
effective
oral dose being about
30
microgams.
The
t
l
/
2
is 3 h.
(See
description

of
experience, above.)
Mechanisms
of
action
are
complex
and
include
agonist
effect
at
presynaptic
5-HT
receptors
in
the
CNS.
Tachyphylaxis
(acute tolerance) occurs
to
LSD.
Psychological
dependence
may
occur; physical
dependence does
not.
Serious adverse
effects

include psychotic reactions
(which
can be
delayed
in
onset) with suicide.
LSD
has
curious
effects
in
animals: green
sunfish
become
aggressive, Siamese fighting
fish
float
nose
up,
tail
down
and
goats walk
in
unaccustomed
stereotyped patterns.
The
elephant exhibits episod-
37
Huxley A1964

The
doors
of
preception. Chatto
and
Windus, London.
188
INDIVIDUAL
SUBSTANCES
10
ically
a
form
of
sexual
or
delinquent behaviour
known
as
'musth'.
Mescaline
is an
alkaloid
from
the
Mexican peyote
cactus
(derived
from
the

Indian word peyotl,
meaning
'divine
messenger'),
the top of
which
is
cut off and
dried
and
used
as
'mescal
buttons'
in
religious ceremonies. Mescaline
does
not
induce
serious dependence
and the
drug
has
little
importance except
to
members
of
some North
and

Central
American societies
and to
psychiatrists
and
biochemists
who are
interested
in the
mechanism
of
induced psychotic states.
Tenamfetamine
('ecstasy', MDMA: methylenedioxy-
methamphetamine)
is
structurally related
to
mesca-
line
as
well
as to
amphetamine.
It was
originally
patented
in
1914
as an

appetite
suppressant
and has
recently
achieved widespread popularity
as a
dance
drug
at
'rave'
parties (where
it is
deemed necessary
to
keep pace with
the
beat
and
duration
of the
music; popular names
reflect
the
appearance
of the
tablets
and
capsules
and
include White Dove,

White
Burger,
Red and
Black,
Denis
the
Menace).
Tenamfetamine
stimulates central
and
peripheral
a-
and
(3-adrenoceptors; thus
the
pharmacological
effects
are
compounded
by
those
of
physical exertion,
dehydration
and
heat.
In
susceptible individuals
(poor
metabolisers

who
exhibit
the
CYP450
2D6
polymorphism)
a
severe
and
fatal
idiosyncratic
reaction
may
occur with fulminant hyperthermia,
convulsions, disseminated intravascular coagulation,
rhabdomyolysis,
and
acute renal
and
hepatic
failure.
Treatment
includes: activated charcoal, diazepam
for
convulsions,
(3-blockade
(atenolol)
for
tachycardia,
a-

blockade (phentolamine)
for
hypertension,
and
dantrolene
if the
rectal temperature exceeds 39°C.
In
chronic
users,
positive emission tomographic
(PET)
brain scans
show
selective dysfunction
of
serotonergic
neurones, raising concerns that neuro-
degenerative changes accompany long-term
use
of
MDMA.
Phencyclidine ('angel dust')
was
made
in a
search
for
a
better intravenous anaesthetic.

It is
structurally
related
to
pethidine. Phencyclidine
was
found
to
induce analgesia without unconsciousness,
but
with
amnesia,
in man
(dissociative anaesthesia).
The
postoperative course, however,
was
complicated
by
psychiatric disturbance.
As the
interest
of
anaesthetists waned,
so
that
of
psychiatrists grew
and
the

drug
has
been used
in
experimental
therapy.
Ketamine originated
from
this
work.
Overdose
can
cause agitation, abreactions, hallu-
cinations
and
psychosis,
and if
severe
can
result
in
seizures, coma, hyperthermia, muscular rigidity,
and
rhabdomyolysis.
Psilocybin
is
derived
from
varieties
of the

fungus
Psilocybe
('magic mushrooms') that grow
in
many
countries.
It is
related
to
LSD.
CANNABIS
Cannabis
is
obtained
from
the
annual plant
Cannabis
saliva
(hemp)
and its
varieties
Cannabis
indica
and
Cannabis
americana.
The
preparations that
are

smoked
are
called marijuana (grass,
pot,
weed, etc.)
and
consist
of
crushed leaves
and
flowers.
There
is
a
wide variety
of
regional names,
e.g.
ganja
(India,
Caribbean),
kif
(Morocco),
dagga
(Africa).
The
resin
scraped
off the
plant

is
known
as
hashish
(hash).
The
term cannabis
is
used
to
include
all the
above
preparations. Since most preparations
are
illegally
prepared
it is not
surprising that they
are
impure
and of
variable potency.
The
plant grows wild
in the
Americas,
38
Africa
and

Asia.
It can
also
be
grown
successfully
in the
open
in the
warmer southern
areas
of
Britain.
Pharmacokinetics
Of
the
scores
of
chemical compounds that
the
resin
contains,
the
most important
are the
oily
cannabinoids,
including tetrahydrocannabinol
(THC),
which

is the
chief
cause
of the
psychic action. Samples
of
resin
vary
greatly
in the
amounts
and
proportions
of
these cannabinoids according
to
their country
of
origin;
as the
sample ages,
its THC
content declines.
As a
result,
the THC
content
of
samples
can

vary
from
almost zero
to 8%.
Smoke
from
a
cannabis cigarette (the usual mode
of
use is to
inhale
and
hold
the
breath
to
allow
maximum
absorption) delivers 25-50%
of the THC
content
to the
respiratory tract.
38
The
commonest pollen
in the air of San
Francisco,
California
is

said
to be
that
of the
cannabis plant, illegally
cultivated.
189
10
NONMEDICAL
USE OF
DRUGS
THC
(t
1
/,
4 d) and
other cannabinoids undergo
extensive biotransformation
in the
body, yielding
scores
of
metabolites, several
of
which
are
them-
selves psychoactive. They
are
extremely lipid-

soluble
and are
stored
in
body
fat
from
which they
are
slowly released.
39
Hepatic drug metabolising
enzymes
are
inhibited acutely
but may
also
be
induced
by
chronic
use of
crude preparations.
Pharmacodynamics
The
discovery
of
cannabinoid CBj-receptors
(expressed
by

central
and
peripheral neurones)
and
CB
2
-receptors
(expressed
by
immune cells)
and the
presence
of
endogenous agonists will point
the way
to
identifying
its
mechanisms
of
action, although
these
are as yet not
well understood.
Psychological
reactions
are
very varied, being
much influenced
by the

behaviour
of the
group.
They
commence within minutes
of
starting
to
smoke
and
last
2-3 h.
Euphoria
is
common, though
not
invariable, with giggling
or
laughter which
can
seem pointless
to an
observer. Sensations become
more
vivid, especially visual,
and
contrast
and
intensity
of

colour
can
increase, although
no
change
in
acuity occurs. Size
of
objects
and
distance
are
distorted. Sense
of
time
can
disappear altogether,
leaving
a
sometimes distressing sense
of
time-
lessness. Recent memory
and
selective attention
are
impaired;
the
beginning
of a

sentence
may be
forgotten
before
it is
finished,
and the
subject
is
very
suggestible
and
easily distracted. Psychological tests
such
as
mental arithmetic, digit-symbol substitution
and
pursuit meter tests show impairment. These
effects
may be
accompanied
by
feelings
of
deep
insight
and
truth. Memory
defect
may

persist
for
weeks
after
abstinence.
Once memory
is
impaired, concentration becomes
less
effective,
since
the
object
of
attention
is
less
well remembered. With this
may go an
insensitivity
to
danger
or the
consequences
of
actions.
A
striking phenomenon
is the
intermittent wave-

like
nature
of
these
effects
which
affects
mood,
visual impressions, time sense, spatial sense,
and
other
functions.
The
desired
effects
of
cannabinoids,
as of
other
psychodysleptics, depend
not
only
on the
expec-
tation
of the
user
and the
dose,
but

also
on the
environmental situation
and
personality. Genial
or
revelatory
experiences
may
indeed occur, e.g.
'Haschich Fudge'.
40
(which
anyone
can
whip
up on a
rainy
day).
This
is
the
food
of
Paradise

euphoria
and
brilliant
storms

of
laughter,
ecstatic
reveries
and
extension
of
one's
personality
on
several
simultaneous
planes
are to be
complacently
expected.
Almost
anything
St
Teresa
41
did,
you can do
better
But
this cannot
be
relied
on.
The

effects
can be
unpleasant, especially
in
inexperienced subjects, particularly timelessness
and
the
feeling
of
loss
of
control
of
mental processes.
Feelings
of
unease, sometimes amounting
to
anguish
and
acute panic occur
as
well
as
'flashbacks'
of
previously
experienced hallucinations, e.g.
on
LSD.

There
is
also, especially
in the
habitual user,
a
tendency
to
paranoid thinking.
High
or
habitual
use can be
followed
by a
psychotic state; this
is
usually reversible, quickly with
brief
periods
of
cannabis use,
but
more slowly
after
sustained
exposures. Evidence suggests that chronic
use
may
precipitate schizophrenia

in
vulnerable
individuals.
The
effect
of an
acute dose usually ends
in
drowsiness
and
sleep.
It is
claimed that death
has
not
occurred.
Tolerance, with continued heavy use,
and a
with-
drawal
syndrome occur (depression, anxiety, sleep
disturbance, tremor
and
other symptoms). Many
users
find
it
very
difficult
to

abandon cannabis.
In
studies
of
self-administration
by
monkeys, sponta-
neous
use did not
occur but, once
use was
initiated,
drug-seeking behaviour developed. Subjects
who
have
become tolerant
to LSD or
opioids
as a
result
of
repeated dosage respond normally
to
cannabis
but
39
When
a
chronic
user

discontinues,
cannabinoids
remain
detectable
in the
urine
for an
average
of 4
weeks
and it can
be as
long
as 11
weeks
before
10
consecutive
daily
tests
are
negative
(Ellis
G M et al
1986 Clinical
Pharmacology
and
Therapeutics
38:
572).

40
From
The
Alice
B
Toklas cook
book
1954 Michael
Joseph,
London.
The
author
was
companion
to
Gertrude
('rose
is a
rose
is a
rose')
Stein
(1874-1946).
41
St
Teresa
of
Avila
(1515-82)
was

noted
for her
power
of
levitation.
190
INDIVIDUAL
SUBSTANCES
_10
there appears
to be
cross-tolerance between
cannabinoids
and
alcohol.
'Amotivational
syndrome'. This term dignifies
an
imprecisely
characterised state, ranging
from
a
feeling
of
unease
and
sense
of not
being
fully

effective,
up to a
gross lethargy, with social passivity
and
deterioration.
It is
difficult
to
assess,
when
personal traits
and
intellectual rejection
of
techno-
logical
civilisation
are
also taken into account.
Yet
the
reversibility
of the
state,
its
association with
cannabinoid use,
and its
recognition
by

cannabis
users make
it
impossible
to
ignore. (Escalation
theory,
see p.
171.)
Cannabinoids
and
skilled tasks, e.g.
car
driving.
General
performance
in
both motor
and
psycho-
logical
tests deteriorates, more
in
naive than
in
experienced subjects.
Effects
may be
similar
to

alcohol,
but
experiments
in
which
the
subjects
are
unaware that they
are
being tested (and
so do not
compensate voluntarily)
are
difficult
to do, as
with
alcohol.
Some scientists claim
the
effects
are
negligible
but
this view
has
been 'put
in
proper
perspective'

by a
commentator
42
who
asked
how
these scientists 'would
feel
if
told that
the
pilot
of
their
international
jet
taking them
to a
psychologists'
conference,
was
just having
a
reefer
or two
before
opening
up the
controls'.
Other

effects.
Cannabis smoked
or
taken
by
mouth
produces reddening
of the
eyeballs (probably
the
forerunner
of the
general dilatation
of
blood vessels
and
fall
of
blood pressure with higher doses),
unsteadiness (particularly
for
precise movements),
and
tachycardia.
The
smoke produces
the
usual
smoker's cough
and

delivers much more
tar
than
tobacco
cigarettes;
the tar
from
reefer
cigarettes
is as
carcinogenic
in
animal experiments
as
cigarette
tobacco
tar. Increase
in
appetite
is
commonly
experienced.
Cannabinoids
are
teratogenic
in
animals,
but
effect
in

humans
is
unproved, although there
is
impaired
fetal
growth with repeated use.
A
therapeutic
role
has
been suggested
for
cannabi-
noids
in a
variety
of
conditions including chronic
42
Dr G
Milner.
pain, migraine headaches, muscle spasticity
in
multiple sclerosis
or
spinal cord
injury,
movement
disorders, appetite stimulation

in
AIDS patients
and
nausea
and
vomiting.
One
systematic review
concluded that cannabinoids were
no
more
effective
that
codeine
for
acute
or
chronic pain although most
of
the
trials were conducted
in the
1970s.
43
A
further
review concluded that cannabinoids protected
against nausea
and
vomiting induced

by
chemo-
therapy
but the
studies were conducted mainly
in the
1980s, i.e.
before
the
introduction
of the
(highly
effective)
serotonin receptor antagonists.
44
Clinical
trials
now in
progress will
clarify
the
value
of
individual cannabinoids
in
such conditions, their
profile
of
adverse
effects

and
comparison with
other drug
and
non-drug therapies.
MANAGEMENT
OF
ADVERSE
REACTIONS
Mild
and
sometimes even severe episodes ('bad
trips')
can be
managed
by
reassurance including
talk,
'talking
the
patient down',
and
physical
contact,
e.g. hand holding (LSD
and
mescaline).
The
objective
is to

help patients relate their experience
to
reality
and to
appreciate that
the
mental experiences
are
drug-induced
and
will abate. Because short-term
memory
is
disrupted
the
treatment
can be
very
time-
consuming since therapists cannot absent themselves
without risking relapse.
But
with phencyclidine such
intervention
may
have
the
opposite
effect,
i.e.

overstimulation.
It is
therefore
appropriate
to
sedate
all
anxious
or
excited subjects with diazepam
(or
haloperidol). With sedation
the
'premorbid ego'
may
be
rapidly re-established.
If
the
user's
'bad
trip'
is due to
overdose
of an
antimuscarinic drug, natural
or
synthetic, then
diazepam
is

specially preferred,
or a
neuroleptic
with
no or
minimal antimuscarinic
effects,
e.g.
haloperidol.
A
dose
of an
anticholinesterase that
penetrates
the
central nervous system (physostig-
43
Campbell
FA et al
2001
Are
cannabinoids
an
effective
and
safe
treatment
option
in the
management

of
pain?
A
quantitative systematic review. British Medical Journal 323:
13-16.
44
Tramer
MR et al
2001
Cannabinoids
for
control
of
chemotherapy induced nausea
and
vomiting: quantitative
systematic review. British Medical Journal
323:16-20.
191
10
NONMEDICAL
USE OF
DRUGS
mine, tacrine)
is
effective
in
severe reaction
to an
antimuscarinic.

Stimulants
COCAINE
Cocaine (see also
Local
anaesthetics,
p.
422)
use is a
widespread
and
ancient practice amongst
South
American
peasants
who
chew
coca
leaves with
lime
to
release
the
alkaloid.
It is
claimed
to
give
relief
from
fatigue

and
hunger;
from
altitude
sickness
in the
Andes, experienced even
by
natives
when
journeying
by car or
other 'fast' trans-
portation;
and
also
to
induce
a
pleasant introverted
mental state.
Remarkable
feats
of
endurance attributed
to
chewing coca leaves have been reported,
but
there
is no

sound
scientific
confirmation
of
them.
A
United Nations enquiry into
coca-leaf
chewing
reported that there
was
psychological
but no
physical
dependence.
It
also reported that
its use
caused physical exhaustion rather than
the
reverse,
and
advocated gradual suppression
in the
interest
of
the
populations concerned.
But
what

may
have
been
(or
even still
may be) an
acceptable
feature
of
these ancient stable societies
has now
developed
into
a
massive, criminal business,
not for
leaf
chewing,
but for the
manufacture
and
export
of
purified
cocaine
to
supply
an
eager
and

lucrative
demand
from
unhappy
but
economically richer
societies where
its use
constitutes
an
intractable social
problem. These economically developed societies,
which cannot control social demand
and
importation,
seek
to
eliminate
the
drug
at its
source
in
peasant
societies that have come
to
rely
on it for
economic
subsistence. When

coca
plantations
are
destroyed
great
distress
to
local populations ensues
by a
combination
of
economic deprivation
and
removal
of
the
coca
leaf,
which, when used
in the
traditional way,
helps
to
make tolerable lives
of
deprivation.
Cocaine
(snow)
is
used

as
snuff
(snorting),
swallowed, smoked (below)
or
injected
i.v.
It is
taken
to
obtain
the
immediate characteristic intense
euphoria which
is
often
followed
in a few
minutes
by
dysphoria. This leads
to
repeated
use
(10-45
min)
during
'runs'
of
usually about

12 h.
After
the
'run'
there
follows
the
'crash'
(dysphoria, irritability,
hypersomnia) lasting hours
to
days.
After
the
'crash'
there
may be
depression ('cocaine blues')
and
decreased capacity
to
experience pleasure
(anhedonia)
for
days
to
weeks.
Psychological dependence with intense compul-
sive
drug-seeking behaviour

is
characteristic
of
even
short-term use,
but
physical dependence
is
arguably
slight
or
absent. Tachyphylaxis, acute tolerance,
occurs.
The
psychotropic
effects
of
cocaine
are
similar
to
those
of
amfetamine (euphoria
and
excitement)
but
briefer
and are due to
blockade

of the
reuptake
of
dopamine
at
central nervous system synapses,
which increases
its
concentration
at
receptors
and
produces
the
characteristic
'high'.
Intranasal
use
causes mucosal vasoconstriction,
anosmia
and
eventually necrosis
and
perforation
of
the
nasal septum.
Smoking involves converting
the
nonvolatile

HC1
into
the
volatile
'free
base'
or
'crack'
(by
extracting
the HC1
with alkali);
for use it is
vaporised
by
heat
(it
pops
or
cracks)
in a
special glass
'pipe';
or
mixed
with tobacco
in a
cigarette. Inhalation with
breath-holding allows pulmonary absorption that
is

about
as
rapid
as an
i.v.
injection.
It
induces
an
intense euphoric state.
The
mouth
and
pharynx
become anaesthetised.
Intravenous
use
gives
the
expected rapid
effect
(kick,
flash, rush). Cocaine
may be
mixed with
heroin
(as
'speedball').
Cocaine
is

metabolised
by
plasma esterases;
the
i
l
/
2
is 50
min.
Overdose
is
common amongst users
(up to 22% of
heavy users report losing consciousness).
The
desired
euphoria
and
excitement turns
to
acute
fear,
with
psychotic symptoms, convulsions, hypertension,
haemorrhagic storke, tachycardia, arrhythmias,
hyperthermia; coronary vasospasm
(sufficient
to
present

as the
acute coronary syndrome with chest
pain
and
myocardial
infarction)
may
occur,
and
acute
left
ventricular dysfunction. Treatment
is
chosen
according
to the
clinical picture (and
the
known
mode
of
action),
from
amongst, e.g. haloperidol
(rather
than chlorpromazine)
for
mental disturbance;
diazepam
for

convulsions;
a
vasodilator, e.g.
a
calcium
channel blocker,
for
hypertension; glyceryl
trinirrate
for
myocardial ischaemia (but
not a P-
192
STIMULANTS
10
blocker
which aggravates cocaine-induced coronary
vasospasm).
Fetal
growth
is
retarded
by
maternal use,
but
teratogenicity
is
uncertain.
AMFETAMINES
Amfetamine

has had
multifarious uses.
It is now
obsolete
for
depression
and as an
appetite suppres-
sant,
and its use in
sport
is
abuse (see
before).
There
is
concern
that
its
illicit
use as a
psychostimulant
is
widespread. Amfetamine
is a
racemic compound:
the
laevo-form
is
relatively inactive

but
dexamphet-
amine (the dextro- isomer)
finds
use in
medicine.
Amfetamine
will
be
described,
and
structurally-
related drugs only
in the
ways
in
which they
differ.
Mode
of
action. Amfetamine acts
by
releasing
noradrenaline (norepinephrine) stored
in
nerve
endings
in
both
the CNS and the

periphery.
As
with
all
drugs acting
on the
central nervous system,
the
psychological
effects
vary with mood, personality
and
environment,
as
well
as
with dose.
Subjects
become euphoric
and
fatigue
is
post-
poned.
Although physical
and
mental performance
may
improve, this cannot
be

relied
on;
subjects
may
be
more
confident
and
show more initiative,
and be
better
satisfied
with
a
more speedy performance
that
has
deteriorated
in
accuracy.
On the
other
hand
there
may be
anxiety
and a
feeling
of
nervous

and
physical tension, especially with large
doses,
and
subjects develop tremors
and
confusion,
and
feel
dizzy. Time seems
to
pass with greater rapidity.
The
sympathomimetic
effect
on the
heart, causing
palpitations,
may
intensify
discomfort
or
alarm.
Amfetamine
increases
the
peripheral oxygen con-
sumption
and
this, together with vasoconstriction

and
restlessness, leads
to
hyperthermia
in
overdose,
especially
if the
subject
exercises.
Dependence
on
amfetamine
and
similar sympa-
thomimetics occurs;
it is
chiefly
psychological,
but
there
is a
withdrawal syndrome, suggesting physical
dependence; tolerance occurs.
Mild
dependence
on
prescribed amfetamines
became common, particularly amongst people with
unstable personalities, depressives

and
tired, lonely
housewives.
In the
1960s, adolescents began
to
turn
to
amfetamines
for
occasional
use to
keep awake
to
have 'fun'
and
then
as an aid to the
challenges
normal
to
that stage
of
life.
Unfortunately, drugs
provide only
the
temporary solution
of
avoidance

and
postponement
of
such challenges, retarding
rather than assisting progress
to
maturity.
As
well
as
oral use, i.v. administration (with
the
pleasurable 'flash'
as
with
opioids)
is
employed.
Severe dependence induces behaviour disorders,
hallucinations
and
even
florid
psychosis,
which
can
be
controlled
by
haloperidol. Withdrawal

is
accompanied
by
lethargy,
sleep,
desire
for
food
and
sometimes severe depression, which leads
to an
urge
to
resume
the
drug.
Pharmacokinetics. Amfetamine
(i
l
/
2
12 h) is
readily
absorbed
by any
usual route
and is
largely
eliminated unchanged
in the

urine. Urinary
excretion
is pH
dependent; being
a
basic substance,
elimination will
be
greater
in an
acid urine.
Interactions
are as
expected
from
mode
of
action,
e.g. antagonism
of
antihypertensives; severe hyper-
tension
with
MAOIs
and
(3-adrenoceptor
blocking
drugs.
Acute
poisoning

is
manifested
by
excitement
and
peripheral sympathomimetic
effects;
convulsions
may
occur; also,
in
acute
or
chronic overuse,
a
state
resembling hyperactive paranoid schizophrenia
with hallucinations
develops.
Hyperthermia occurs
with cardiac arrhythmias, vascular collapse
and
death. Treatment
is
chlorpromazine with added
antihypertensive, e.g. labetalol,
if
necessary; these
provide sedation
and a- and

(3-adrenoceptor
blockade
(not
a
p-blocker alone), rendering unnecessary
the
enhancement
of
elimination
by
urinary
acidification.
Chronic overdose
can
cause
a
psychotic state
mimicking
schizophrenia.
A
vasculitis
of the
cerebral
and/or
renal vessels
can
occur, possibly
due to
release
of

vasoconstrictor amines
from
both platelets
and
nerve
endings.
Severe hypertension
can
result
from
the
renal vasculitis.
Structurally-related
drugs include
dexamfet-
amine (used
for
narcolepsy
and in
attention
defi-
cit
hyperactivity disorder
(ADHD)
see p.
387),
methylphenidate (used
for
ADHD), tenamfetamine
(Ecstasy,

see p.
189), phentermine, diethylpropion,
and
pemoline.
193
_10
NONMEDICAL
USE OF
DRUGS
METHYLXANTHINES (XANTHINES)
The
three xanthines,
caffeine,
theophylline
and
theobromine, occur
in
plants. They
are
qualitatively
similar
but
differ
markedly
in
potency.
•
Tea
contains
caffeine

and
theophylline.
•
Coffee
contains
caffeine.
•
Cocoa
and
chocolate contain
caffeine
and
theobromine.
• The
cola
nut
('cola' drinks) contains
caffeine.
Theobromine
is
weak
and is of no
clinical
importance.
Mode
of
action.
Caffeine
and
theophylline have

complex
and
incompletely elucidated actions,
which include
inhibition
of
phosphodiesterase
(the
enzyme that breaks down
cyclic
AMP,
see p.
191),
effects
on
intracellular calcium distribution,
and
noradrenergic
function.
When theophylline
(as
aminophylline)
is
used alongside salbutamol
in
asthma
its
action adds
up to
increased benefit

to the
bronchi,
but
increased risk
to the
heart.
Pharmacokinetics. Absorption
of
xanthines
after
oral
or
rectal administration varies with
the
preparation used.
It is
generally extensive
(>
95%).
Caffeine
metabolism varies much between individ-
uals
(i
l
/
2
2-12
h).
Xanthines
are

metabolised (more
than 90%)
by
numerous mixed
function
oxidase
enzymes,
and
xanthine oxidase. (For
further
details
on
theophylline,
see
Asthma.)
Actions
on
mental performance.
Caffeine
is
more
potent than theophylline,
but
both drugs stimulate
mental activity where
it is
below normal. They
do not
raise
it

above normal; thought
is
more rapid
and
fatigue
is
removed
or its
onset delayed.
The
effects
on
mental
and
physical performance vary according
to
the
mental state
and
personality
of the
subject.
Reaction-time
is
decreased. Performance that
is
inferior
because
of
excessive anxiety

may
become
worse.
Caffeine
can
also improve physical
perfor-
mance
both
in
tasks requiring more physical
effort
than
skill (athletics)
and in
tasks requiring more
skill
than physical
effort
(monitoring instruments
and
taking corrective action
in an
aircraft
flight
simulator).
It is
uncertain whether
the
improvement

consists only
of
restoring
to
normal performance
that
is
impaired
by
fatigue
or
boredom,
or
whether
caffeine
can
also enable
subjects
to
improve their
normal
maximum performance.
The
drugs
may
produce their
effects
by
altering both physical
capacity

and
mental attitude.
There
is
insufficient
information
on the
effects
on
learning
to be
able
to
give
any
useful
advice
to
students preparing
for
examination other than that
intellectual
performance
may be
assisted when
it
has
been reduced
by
fatigue

or
boredom.
Effects
on
mood vary greatly amongst individuals
and
according
to the
environment
and the
task
in
hand.
In
general,
caffeine
induces feelings
of
alertness
and
wellbeing, euphoria
or
exhilaration. Onset
of
boredom,
fatigue,
inattentiveness
and
sleepiness
is

postponed.
Overdose will certainly reduce performance
(see
chronic
overdose, below).
Acute
overdose,
e.g.
aminophylline
(see
p.
559) i.v.,
can
cause convul-
sions, hypotension, cardiac arrhythmia
and
sudden
death.
Other
effects
Respiratory stimulation occurs with substantial
doses.
Sleep.
Caffeine
affects
sleep
of
older more than
it
does

of
younger people
and
this
may be
related
to the
fact
that older people show greater catecholamine
turnover
in the
central nervous system than
do the
young. Onset
of
sleep (sleep latency)
is
delayed,
bodily
movements
are
increased, total
sleep
time
is
reduced, there
are
increased awakenings. Tolerance
to
this

effect
does
not
occur,
as is
shown
by the
provision
of
decaffeinated
coffee.
45
Skeletal muscle. Metabolism
is
increased,
and
this
may
play
a
part
in the
enhanced
athletic performance
mentioned above. There
is
significant
improvement
of
diaphragmatic

function
in
chronic obstructive
pulmonary disease.
45
The
European Union regulations
define
'decaffeinated'
as
coffee
(bean)
containing 0.3%
or
less
of
caffeine
(normal
content
1-3%).
194
STI
MU
LANTS
10
Cardiovascular
system. Both
caffeine
and
theo-

phylline directly stimulate
the
myocardium
and
cause
increased cardiac output, tachycardia
and
sometimes ectopic beats
and
palpitations. This
effect
occurs
almost
at
once
after
i.v.
injection
and
lasts
half
an
hour. Theophylline contributes
usefully
to the
relief
of
acute
left
ventricular

failure.
There
is
peripheral (but
not
cerebral) vasodilatation
due to a
direct
action
of the
drugs
on the
blood vessels,
but
stimulation
of the
vasomotor centre tends
to
counter
this.
Changes
in the
blood pressure
are
therefore
somewhat unpredictable,
but
caffeine
250
mg

(single dose) usually causes
a
transient rise
of
blood pressure
of
about
14/10
mmHg
in
occasional
coffee
drinkers
(but
has no
additional
effect
in
habitual
drinkers); this
effect
can be
used
advan-
tageously
in
patients
with
autonomic nervous
system

failure
who
experience postprandial hypoten-
sion
(2
cups
of
coffee
with
breakfast
may
suffice
for
the
day).
In
occasional
coffee
drinkers
2
cups
of
coffee
(about
160 mg
caffeine)
per day
raise blood pressure
by
5/4

mmHg. Increased coronary artery blood
flow
may
occur
but
increased cardiac work coun-
terbalances
this
in
angina pectoris.
When theophylline (aminophylline)
is
given
i.v.,
slow
injection
is
essential
in
order
to
avoid transient
peak
concentrations which
are
equivalent
to
administering
an
overdose (below).

Smooth
muscle (other than vascular muscle, which
is
discussed
above)
is
relaxed.
The
only important
clinical
use for
this action
is in
reversible airways
obstruction (asthma), when
the
action
of
theo-
phylline
can be a
very valuable addition
to
therapy.
Kidney.
Diuresis occurs
in
normal people
chiefly
due to

reduced tubular reabsorption
of Na,
similar
to
thiazide action,
but
weaker.
Miscellaneous
effects.
Gastric secretion
is
increased
by
caffeine
given
as
coffee
(by
decaffeinated
coffee
too)
more than
by
caffeine
alone,
and the
basal
metabolic
rate
may

increase slightly
(see
Skeletal
muscle, above).
Preparations
and
uses
of
caffeine
and
theophylline
Aminophylline.
The
most generally
useful
prepara-
tion
is
aminophylline which
is a
soluble, irritant salt
of
theophylline with ethylenediamine (see Asthma).
Attempts
to
make nonirritant orally reliable
preparations
of
theophylline have resulted
in

choline
theophyllinate
and
numerous variants. Sustained-
release
formulations
are
convenient
for
asthmatics,
but
they cannot
be
assumed
to be
bioequivalent
and
repeat
prescriptions should adhere
to the
formulation
of
a
particular manufacturer. Suppositories
are
available.
Aminophylline
is
used
in:

•
Asthma.
In
severe asthma (given i.v.) when
(3-
adrenoceptor agonists
fail
to
give adequate
response;
and for
chronic asthma
(orally)
to
provide
a
background bronchodilator
effect.
•
Acute
left
ventricular
failure
(see
p.
518).
•
Neonatal
apnoea;
caffeine

is
also
effective.
Caffeine
is
used
as an
additional ingredient
in
analgesic tablets; about
60 mg
potentiates NSAIDs;
also
as an aid in
hypotension
of
autonomic
failure
and
to
enhance oral ergotamine absorption
in
migraine
XANTHINE-CONTAINING
DRINKS
(see
also above)
Coffee,
tea and
cola drinks

in
excess
can
make
people tense
and
anxious. Small children
are not
usually given
tea and
coffee
because they
are
thought
to be
less tolerant
of the
central nervous
system stimulant
effect,
but
cola
drinks irrationally
escape this prohibition.
It is
possible
to
make
an
imposing list

of
diseases which
may be
caused
or
made worse
by
caffeine-containing
drinks,
but
there
is no
conclusive evidence
to
warrant
any
general
constraints. High
doses
of
caffeine
in
animals damage
chromosomes
and
cause
fetal
abnormalities;
but
studies

in man
suggest that normal consumption
poses
no
risk. Epidemiological studies
are not
conclusive
but
indicate either
no, or
only slight,
increased risk
(x
2-3)
of
coronary heart disease
in
heavy (including
decaffeinated)
coffee
consumers
(>
4
cups/day)
(see Lipids, below).
Tolerance
and
dependence.
The
regular,

frequent
use of
caffeine-containing drinks
is
part
of
normal
social
life
and
mild overdose
is
common. Slight
tolerance
to the
effects
of
caffeine
(on all
systems)
occurs.
Withdrawal symptoms, attributable
to
psy-
chological
and
perhaps mild physical dependence
195
10
NONMEDICAL

USE OF
DRUGS
occur
in
habitual
coffee
drinkers
(5 or
more
cups/day) 12-16
h
after
the
last cup; they include
headache (lasting
up to 6
days), irritability, jitteriness;
they
may
occur with transient changes
in
intake, e.g.
high
at
work, lower
at the
weekend. Habitual
tea and
coffee
drinkers

are
seldom willing
to
recognise that
they have
a
mild drug dependence.
Chronic overdose. Excessive prolonged consump-
tion
of
caffeine
causes anxiety,
restlessness,
tremors,
insomnia; headache, cardiac extrasystoles
and
con-
fusion;
diarrhoea
may
occur
with
coffee
and
con-
stipation with tea.
The
cause
can
easily

be
overlooked
if
specific
enquiry into habits
is not
made; including
children regarding
cola
drinks.
Of
coffee
drinkers,
up
to 25% who
complain
of
anxiety
may
benefit
from
reduction
of
caffeine
intake.
An
adult heavy user
may
be
defined

as one who
takes more than
300 mg
caffeine/day
i.e.
4
cups
of 150 ml of
brewed
coffee,
each
containing
80 + 20 mg
caffeine
per cup or 5
cups
(60
± 20) of
instant
coffee.
The
equivalent
for tea
would
be 10
cups
at
approximately
30 mg
caffeine

per
cup;
and of
cola drinks about 2.01. Plainly,
caffeine
drinks brewed
to
personal taste
of
consumer
or
vendor must have
an
extremely variable con-
centration
according
to
source
of
coffee
or
tea, amount
used, method
and
duration
of
brewing. There
is
also
great

individual variation
in the
effect
of
coffee
both
between individuals
and
sometimes
in the
same
individual
at
different
times
of
life
(see Sleep, above).
Decaffeinated
coffee
contains about
3 mg per
cup;
cola
drinks contain 8-13
mg
caffeine/100
ml;
cocoa
as a

drink,
4 mg per
cup; chocolate (solid)
6-20
mg per 30 g.
In
young
people
high
caffeine
intake
has
been
linked
to
behaviour disorders
and a
limit
of 125
mg/I
has
been proposed
for
cola drinks.
Blood
lipids.
Drinking
5
cups
of

boiled
coffee/day
increases
serum total cholesterol
by up to
10%;
this
does
not
occur
with
coffee
made
by
simple
filtration.
Cessation
of
coffee
drinking
can
reduce
serum cholesterol concentration
in
hypercholest-
erolaemic
men.
Breast-fed
infants
may

become sleepless
and
irritable
if
there
is
high maternal intake. Fetal
cardiac
arrhythmias have been reported with
exceptionally
high maternal
caffeine
intake, e.g.
1.5
1
cola
drinks/day.
Ginseng
is the
root
of 2
plants
of the
same
family
(oriental,
Panax
ginseng;
Siberian,
Eleutherococcus

senticosis)
and
contains
a
range
of
biologically active
substances (ginsenosides).
It
has
been used
as a
tonic
or
stimulant
for
thou-
sands
of
years.
In
animal studies
ginseng
doubles
the
time
that mice placed
in
water
can

swim
before
becoming
exhausted;
it
appears
to
have antifatigue
effects
in
various other tests
in
mice (climbing
up a
rope
that
is
moving downwards)
and it
increases
sexual
activity.
In
man,
ginseng
has
been claimed
to
benefit
performance

of
athletes
and
astronauts
(fewer
fatigue-caused
errors),
and to
reduce absenteeism
due
to
respiratory illness
in
mining
and
steel workers
and
truck
drivers. Oriental soldiers
at war
have used
ginseng. Despite accumulating evidence
and
wide
use by the
public,
the
medical profession
in
Western

countries remains sceptical
of the
value
of
this tonic.
A
range
of
adverse
effects
is
reported, including
oedema, hypertension, rashes, diarrhoea, sleepless-
ness
and
oestrogen-like
effects
Khat.
The
leaves
of the
khat shrub
(Catha
edulis)
contain
alkaloids (cathinine, cathine, cathidine) which
are
structurally like amphetamine
and
produce

similar
effects.
They
are
chewed
fresh
(for
maximum
alkaloid
content)
so
that
the
habit
was
confined
to
geographical
areas
favourable
to the
shrub (Arabia,
E.
Africa)
until modern transportation allowed wider
distribution.
Khat
chewers (mostly male) became
euphoric, loquacious, excited, hyperactive
and

even
manic.
As
with some other drug dependencies
subjects
may
give priority
to
their drug needs above
personal,
family
and
other social
and
economic
responsibilities. Cultivation takes
up
serious amounts
of
scarce
arable land
and
irrigation water.
Drugs
as
adjuvants
to
crime
Since
time immemorial drugs have been used

to
facilitate
sexual excess
and
robbery, e.g. opium
and
plants containing antimuscarinics, e.g. hyoscine.
All
such
acts constitute
a
criminal
offence.
The
advent
of
synthetic drugs widened
the
scope
and
ease
of
administration.
In
19th century Chicago (USA)
the
proprietor
of
196
DRUGS

AS
ADJUVANTS
TO
CRIME
10
the
Lone
Palm
Saloon, Michael
J
Finn,
employed
girls
to
ensure
his
customers
consumed
drinks
to
which
he had
added
chloral hydrate—the 'Mickey
Finn'—they
were
robbed
when
unconscious.
Recently there

has
been
a
vogue
for
using
clonidine
for the
same
purpose
(a
doctor
or
pharmacist
must
surely
have
been
responsible
for
this
curious
but,
it
seems,
effective
choice). Victims
become confused
and
unresisting

from
sedation,
bradycardia,
other
cardiac
arrhythmias,
ataxia,
hypothermia,
hypo-
or
hypertension.
GUIDETO
FURTHER
READING
Criqui
M H,
Ringel
B
L1994 Does diet explain
the
French
paradox? Lancet
344:1719-1723
(A
study
of
diet, alcohol
and
mortality
from

21
affluent
contries.)
Doll
R et al
1994 Mortality
in
relation
to
smoking:
40
years' observations
on
male British doctors. British
Medical Journal 309:
901-911
Doll
R1997
One for the
heart. British Medical Journal
315:1664-1668
Gawin
F H,
Ellinwood
E H
1988 Cocaine
and
other
stimulants: actions, abuse,
and

treatment.
New
England
Journal
of
Medicine
318:1173-1182
Green
A R,
Goodwin
G M
1996 Ecstasy
and
neurodegeneration. British Medical Journal 312:
1493-1494
Hall
W,
Solowij
N
1998 Adverse
effects
of
cannabis.
Lancet
352:1611-1616
Hollander
J E
1995
The
management

of
cocaine-
associated myocardial ischaemia.
New
England
Journal
of
Medicine
333:1267-1272
Lange
R A,
Hillis
L D
2001 Cardiovascular
complications
of
cocaine use.
New
England Journal
of
Medicine 345:
351-358
MacAuley
D
1996 Drugs
in
sport. British Medical
Journal
313:
211-215

Mendelson
J H,
Mello
N K
Management
of
cocaine
abuse
and
dependence.
New
England Journal
of
Medicine 334: 965-972
Ness
R B et al
Cocaine
and
tobacco
use and the
risk
of
spontaneous abortion.
New
England Journal
of
Medicine 340:
333-339
Nutt
D J

1996 Addiction: brain mechanisms
and
their
treatment implications. Lancet 457:
31
(see also
other articles
in
this series
on
pages 97,162, 237,
301, 373)
Raw
M,
McNeill
A,
West
R
1999 Smoking cessation:
evidence based recommendations
for the
healthcare system. British Medical Journal 318:
182-185
Strang
J,
Witton
J,
Hall
W
2000

Improving
the
quality
of
the
cannabis debate: defining
the
different
domains. British Medical Journal
320:108-110
Swift
R M
1999 Drug therapy
for
alcohol dependence.
New
England Journal
of
Medicine 340:1482-1490
197