Acute
alcohol withdrawal
Net inhibitory effect on central nervous system Net excitatory effect on central nervous system Ca2 Ca2 Cl Cl(following chronic abuse)
High intra-
cellular Cl cellular ClLow intra-
Low intra- cellular Ca2
High intra- cellular Ca2 NMDA
rec. GABAA NMDArec. GABAA
NMDA rec. N-Methyl-D-aspartate receptor
Treatment options
Drugs that treat acute intoxication
Benzodiazepine partial-inverse agonist (?)
Drugs that treat acute withdrawal
Bezodiazepines Carbamazepine Clonidine Propranolol
Drugs that minimize alcohol intake Acamprostate Bromocriptine Calcium carbamide/disulfiram* Naltrexone Ondansetron Up-/downregulated receptors, respectively Calcium carbamide/ disulfiram Acetic acid Alcohol Aldehyde
dehydrogenase dehydrogenaseAlcohol
Toxic when accumulated !!
Acetaldehyde
GABAA c-Aminobutyric acid
receptor, type A
* Induces typical 'disulfiram reaction':
Liver
Notes about the scheme
The brain maintains neurochemical balance through inhibitory and excitatory
neurotransmitters. The brain’s main inhibitory neurotransmitter is c-aminobutyric acid (GABA), which usually acts through GABAAreceptors,
while the major excitatory neurotransmitter is glutamate, which acts through the N-methyl-D-
aspartate (NMDA) receptor. Acute alcohol
(ethanol) intoxication enhances the effect of
GABA, resulting in decreased overall excitability. Acute alcohol intoxication also downregulates NMDA receptors, while chronic alcohol exposure results in upregulation of these receptors. Hence, abrupt cessation of alcohol exposure results in brain hyperexcitability, because receptors inhibited by alcohol are no longer inhibited and excitatory receptors (i.e. NMDA) are upregulated. Brain excitability manifests clinically as anxiety, irritability,
agitation, seizures, and delirium tremens. From a neurochemical perspective, alcohol also
interacts with several other brain neurotransmitter systems, including the
dopaminergic, serotonergic, and opioid systems. Treatment options for alcohol abuse have focused on all of the above-mentioned
neurotransmitter systems. The following are among the best studied treatments, which have shown at least some established efficacy.
Disulfiram is the first-line therapy for
alcohol abuse. Disulfiram (and calcium
carbamide) prevent the metabolism of alcohol
by inhibiting the enzyme aldehyde
dehydrogenase, leading to accumulation of acetaldehyde and subsequent unpleasant intoxication. The objective of disulfiram treatment is to create an aversion to alcohol, rather than modulating its neurochemical effects. However, controlled clinical trials have yielded inconsistent results.
Naltrexone is an opioid antagonist that is
thought to reduce the positive reinforcing pleasurable effects of alcohol and to reduce craving. However, the largest study performed to date produced negative findings.
Nalmefene is also an opioid antagonist,
and its use has demonstrated a reduction in frequency of heavy drinking. As with
naltrexone, the treatment effects seemed to
wane after discontinuation of treatment.
Acamprosate has effects on drinking
behavior that are related to modulation of glutamatergic transmission. In particular,
acamprosate depresses the elevated
glutamatergic transmission and NMDA receptor activation that occur in alcohol dependence and withdrawal. The effect of acamprosate appears to be most effective in decreasing alcohol consumption and prolonging abstinence. This drug remains the most widely validated treatment medication for the treatment of alcoholism.
Topiramate is an antiepileptic drug that
attenuates the rewarding effect of alcohol associated with abuse by inhibiting
mesocorticolimbic dopamine release via facilitation of GABA activity and inhibition of glutamate function. It has been demonstrated to reduce both alcohol consumption and craving.
Ondansetron, a 5-HT3serotonergic
receptor antagonist, has demonstrated some efficacy with regard to measures of drinking frequency and intake.
Carbamazepine has shown some efficacy
with regard to alcohol consumption, while
lithium has no effect on drinking behavior.
Pharmacological treatment of alcohol withdrawal involves the use of medication that is cross-tolerant with alcohol. Benzodiazepines have been shown to be safe and effective, particularly for preventing or treating seizures and delirium, and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. Carbamazepine is an effective alternative to benzodiazepines in the treatment of alcohol withdrawal syndrome in patients with mild to moderate symptoms. It is not sedating and has little potential for abuse; however, there is not sufficient evidence that
carbamazepine prevents seizure and delirium
due to alcohol withdrawal. Haloperidol or medium- to high-potency antipsychotics can be used to treat agitation and hallucinations. Treatment with b-blockers should be considered in patients with coronary artery disease. Dopamine antagonists (tiapride,
flupenthixol, and amisulpiride) have been
tried in alcohol-dependent patients, with negative results.31–45
6.7 Abused substances – cannabis
Supposed mechanism of dependence, withdrawal symptoms, and treatment options
11-OH-THC CB1 Gi Cation channel (mainly K, Ca2) Postsynaptic neurons in basal ganglia, cerebellum, hippocampus
(where CB1 receptors are abundant)
Inhibits
cholinergic and glutamatergic
neurotransmission
(possible mechanism for cannabis-induced adverse effects)
Enhances
dopaminergic
neurotransmission (possible mechanism for
'rewarding' effects) Via inhibiting central nervous system GABAergic (e.g. inhibitory) neurons Decreased intra- cellular AC activities Decreased intra- cellular cAMP activities Increased intra-
cellular K, Ca2
Stimulates
Inhibits
AC Adenylate cyclase
11-OH-THC 11-Hydroxy-D9-tetrahydrocannabinol
cAMP Cyclic adenosine monophosphate
CB1 Central cannabinoid receptor Gi G-protein, inhibitory
GABA c-Aminobutyric acid
Treatment options
Only symptomatic treatments are well established
For psychosis Antipsychotic drugs
For depression Antidepressants
For agitation/tension/anxiety Benzodiazepines
The active compound in herbal cannabis, 9-tetrahydrocannabinol (THC), is contained
in marijuana at a concentration of over 5%. Despite being illegal, cannabis is one of the most widely used intoxicants; almost half of all 18-years-olds in the USA and most European countries admit to having tried it at least once, and about 10% of that age group are regular users. The experience of cannabis use is highly variable, depending on the dose of the drug. Smoking remains the most efficient means of delivering the drug; experienced users can titrate the dose by adjusting the frequency and depth of inhalation. Cannabis can also be taken orally in fat-containing foods or dissolved in a suitable pharmaceutical oil, but absorption is delayed. Apart from being an abused substance, interesting and important cannabis-induced effects are emerging as potential future treatments for psychiatric and neurological conditions.
Notes about the scheme
Cannabis acts as an agonist at the CB1
cannabinoid receptor, which is the only one known to date to be expressed in the brain. It is particularly distributed in the frontal regions, the basal ganglia, the cerebellum, and the limbic forebrain (particularly in the hypothalamus and in the anterior cingulated cortex). The relative scarcity of cannabinoid receptors in the brainstem nuclei may account for the low toxicity of cannabis when given in overdose. A second cannabinoid receptor, CB2, is expressed only in the peripheral immune system. Both cannabinoid receptors are members of the G-protein-coupled class, and their activation is linked to inhibition of adenylate cyclase activity.
There are a series of arachidonic acid derivatives (endogenous cannabinoids) with potent action at cannabinoid receptors. These are
anandamide (N-arachidonylethanolamine)
and 2-arachidonylglyceryl ether. The endogenous cannabinoids known as endocannabinoids are present in only small amounts in the brain or other tissues, and appear to be synthesized and released locally on
demand. Anandamide and other endogenous cannabinoids are rapidly inactivated by a combination of a transporter mechanism and by the enzyme fatty acid amide hydrolase. To date, there are no well-established data regarding the physiological role of the endocannabinoids, although they are assumed to play a role in the regulation of food intake and body weight. The discovery of agents that could interfere with the activation of endogenous cannabinoids may provide a novel means of pharmacologically modifying cannabinoid function in the brain.
Among the well-established effects of acute intoxication with cannabis is an impairment of short-term memory. Some users often report a subjective enhancement of visual and auditory perception, sometimes with synesthesia (where sounds take on visual qualities). One subjective effect that has been confirmed is the sensation that cannabis users experience time as passing more quickly relative to real time.
Many subjective reports suggest that
cannabis intoxication is associated with
increased appetite, particularly for sweet foods.
Cannabis has been demonstrated to have
significant beneficial effects in counteracting the loss of appetite and reduction in body weight in patients suffering from AIDS-related wasting syndrome. This suggests that cannabinoids may play a role in the regulation of food intake and body weight, and this is one of the medical indications for which the drug has official approval in the USA. Moreover, the CB1
antagonist rimonabant has been demonstrated to suppress appetite and to induce weight loss.
The second medical indication for THC use is associated with the ability of the synthetic
cannabinoid nabilone to control the nausea and vomiting associated with cancer chemotherapy.
A temporary form of drug-induced
psychosis can occur in some cannabis users as a result of taking large doses. Cannabis has some addictive properties, but these are much less than amphetamines, for example. The addictive properties, of cannabis are due, probably, to its indirect capacity to enhance dopaminergic transmission in the ‘reward’ pathway (i.e. by suppressing GABAergic neurons that modulate the dopaminergic pathway).46–48
6.8 Abused substances – lysergic acid diethylamide (LSD)
Supposed mechanism of dependence, withdrawal symptoms, and treatment options