Drugs and addiction, ecstasy and cannabis

This essay was written by Nigel Birdsall and was first published in the 2002 Mill Hill Essays.

Cocaine isn’t habit-forming. I should know – I’ve been using it for years

Tallulah Bankhead (1903 – 1968)

‘Taking drugs’ – What image is conjured up when you see the phrase? Do you think of going to a doctor and being cured of an illness? Or perhaps taking an aspirin for a headache? Maybe you have the image of a terminally ill patient with chronic unremitting pain receiving morphine? Or do you picture young people dancing in a club, or a huddled, quivering figure in a doorway? But possibly you don’t immediately think of somebody smoking a cigarette, having a cup of coffee, or drinking a pint of beer or certain well-known carbonated beverages.

The word ‘drug’ is used in phrases which can often elicit very different reactions, depending on the person and the situation: ‘recreational drugs’, ‘drugs of abuse’, ‘hard and soft drugs’, ‘side-effects of drugs’, ‘wonder drug’, ‘the drug industry’ are examples. However all ‘drugs’, independent of the context in which the word is used, do have similar mechanisms of action; they attach themselves to specific target molecules that have a natural function in the body and change that function. Often these target molecules are proteins on the surface of specific cells in the body that are important for enabling communication between the outside and the inside of cells, and between cells. These proteins are called receptors, which control the function of the brain by binding naturally occurring signalling molecules that are released from nerve cells. Binding activates the transfer of electrical information along pathways linking the billions of nerve cells that form the nervous system.

There is a very large number of different signalling molecules and receptors in the body but each signalling molecule only activates one type of receptor. The result is exquisite specificity and diversity in the overall signalling processes that are dependent on where the signalling molecules are released, where the receptors are located in the body, and which nerve cells and pathways that they form in the body are activated. Certain drugs mimic the actions of the natural signalling molecules. For example, nicotine, components of cannabis, and morphine act on different natural receptors. In fact, receptors are the targets for about half of the drugs that are used clinically for the treatment of disease.

Other targets for drugs are called transporter proteins. Like receptors, these are present on the cell surface. Their role is to recapture specific signalling molecules by pumping them back into a cell after they have been released and thereby ‘switch off’ the signal. Drugs that bind to transporters block the reuptake of the signalling molecules and prevent them from being rapidly removed from the vicinity of their receptors. This means that the receptors continue signalling for longer than they would otherwise. Many antidepressant drugs produce their therapeutic actions by blocking the transporters responsible for the uptake of the important signalling molecule called serotonin.

Drugs are not only used to treat disease but they are also used in social or cultural situations. Non-medical use can range from the occasional consumption of alcohol to the uncontrolled use of opiates. Social use may start out as experimenting with a drug because of curiosity or peer pressure. Their use may then increase to a casual or ‘recreational’ use where moderate amounts are taken because of their positive pleasurable effects or in attempts to overcome negative feelings, such as ‘life’s problems’ or ‘feeling low’. Some drug effects are also sought after because they are viewed as useful in certain circumstances; an example is the use of amphetamines by drivers and students in order to stay awake and decrease the feeling of tiredness. Each of these three different forms of non-medical use can lead to taking increased quantities of the drugs.

Obviously, drugs produce effects. But in order to produce the ‘correct’ effect the dose must be right. Too little and the drug has no effect; too much and the drug has too big an effect or it starts to produce additional side-effects. The way the drug is taken is also important for its effect and how long it lasts. If a drug is injected into a vein or inhaled, then its action is almost immediate and high levels of the drug are achieved momentarily. This high level often decreases rapidly as the drug is cleared from the bloodstream. For example, if you smoke a cigarette, it takes less than 8 seconds for the nicotine to reach and affect the brain. If a drug is taken by mouth, say as a tablet, then the time taken for it to be absorbed into the bloodstream via the stomach and intestines is much slower. A more prolonged action is observed but you don’t get the initial surge or ‘rush’ that accompanies inhalation or intravenous injection.

People who take a drug for a long time may need increasing doses to produce the original effect. This phenomenon is called tolerance. The body adjusts itself to the continued presence and increased level of the drug in such a way that not taking the drug leads to a whole range of new, generally bad, symptoms. These are withdrawal effects and are generally associated with a craving for the restoration of the newly established ‘normality’, that is, the presence of the drug. A dependence on the drug has now been established. It may be instructive to re-read this paragraph, replacing ‘drug’ by ‘alcohol’ and ‘dose’ by ‘number of drinks’.

The taking of increased amounts of drugs for non-medical use can lead to patterns of dependence and uncontrollable drug use. This is one of the hazards of certain drugs that alter mood and feelings. Continued taking of the drug can lead to adverse social and health consequences, both to the person taking the drug and those who come in contact with them. The drug is needed to maintain the sensation of well-being. The intensity of the ‘need’ varies dramatically between individuals and, especially, between drugs. There may be just a mild desire to continue taking the drug or, at the other extreme, the dependence progresses towards a lack of control over the use of the drug. In the worst examples, the intense craving to obtain and take a drug dominates all aspects of life. In addition to a physiological drive to take a drug, there is often a psychological component in drug dependence where mood or environment trigger the craving. The sight or smell of alcohol can sometimes be sufficient to produce the sensations of withdrawal in abstinent alcoholics.

Tolerance and dependence on a drug need not always be a cause for great concern. For example caffeine is the most widely used behaviourally active drug in the world. It belongs to a class of drugs known as ‘psychostimulants’ which cause a heightened mood, awareness and activity. Caffeine makes one feel alert because it blocks the receptors for a signalling molecule, adenosine, that normally dampens down brain activity.

People get used to drinking coffee, tea or soft drinks. If 200-400 mg of caffeine is taken in drinks during a day, there can initially be difficulty in sleeping. But this effect ‘wears off’ after a few days – one becomes tolerant. Anybody who wakes up in the morning and ‘needs’ a coffee to ‘get going’ may be considered to show signs of dependence and withdrawal. Withdrawal effects do occur but they are relatively limited as regards their severity. They can take the form of feeling tired, having a headache, or having difficulty in concentrating. They can even be observed in some people who drink just one cup of instant coffee a day. The withdrawal effects can often be suppressed by taking low levels of caffeine. This characteristic, together with the fact that high doses of caffeine cause unpleasant effects and limit how much caffeine can be taken, contributes to the relatively benign actions of caffeine as a drug. Caffeine levels present in food and drinks vary from 30-50 mg in a typical cola drink or in a tea bag, up to 540 mg for a large strong ‘grande’ coffee from a coffee house. This high level of caffeine, ingested over a short period of time, will make a person very jumpy if they are unused to drinking coffee but has no such effect on regular coffee drinkers.

So far the word ‘addiction’ has not been mentioned. Drug addiction can be considered as a highly complex process by which the drugs alter the functioning of the brain circuits that are responsible for the behaviour associated with the drugs’ actions, the consequence being that the circuits become more, or less, responsive to the drugs. A limiting definition of addiction is that of a persistently recurring brain disorder in which the addict experiences an uncontrollable urge to take the drug, whilst all behaviour unrelated to drug seeking, taking and recovery declines severely. A more global definition says that drug dependence is the hallmark of addiction. In fact, the definition of addiction has become a focal point of contention in legal cases because some drugs fall into the category of being addictive under the second, but not the first, definition. It is often possible to describe more precisely many of the effects of the non-medical use of drugs in terms of tolerance, physical dependence, withdrawal, cues, uncontrollable drug use and craving.

Every form of addiction is bad, no matter whether the narcotic be alcohol or morphine or idealism

Karl Gustav Jung

What do we know about the neural pathways in the brain that are altered in drug tolerance and dependence? Is there just one pathway that is affected and, if so, why do different drugs differ in their ‘addiction ability’? Do they change the pathway by different mechanisms?

Dopamine is the molecule that is most centrally implicated in the pleasurable, rewarding and reinforcing effects of most drugs used for non-medical purposes. It is thought that an increased release of this signalling molecule from nerve terminals in a specific region of the brain is mainly responsible for the reinforcing effects of drugs such as amphetamine, cocaine, heroin, nicotine, and alcohol, but not moderate doses of caffeine. Dopamine release is triggered by stimulation of a natural ‘reward pathway’ of dopamine-containing neurons that connect a discrete region at the base of the brain to this specific region. However it seems that it is not just a simple reward pathway that is activated but also new learning pathways can be initiated. When the drug is taken for the first time, the dopamine-containing nerves in the base of the brain initially respond to the unpredicted reward but, on repetition, this response is changed to one where the reward is anticipated. The system first says ‘Wow, that was nice! ‘ and then progressively learns to change that response to a subconscious decision: ‘I know it is going to be nice. I really, really need some more’. The brain reward system is very ancient. One finds the same molecules having the similar functions in different species, from fruit flies to humans! The system evolved originally to respond to rewards from external stimuli such as food, water, or sex, but humans have discovered how to use drugs to hijack and perturb this system directly.

When teenagers, or in fact anybody else, smoke their first cigarette, they often cough, feel dizzy or nauseous, and they may immediately think ‘never again’. However, at the same time that they are feeling rotten, the nicotine has sent a positive reinforcement ‘teaching’ signal down the reward pathway to make the smoking of another cigarette more likely. The more cigarettes that are smoked, the less severe the adverse effects become and the stronger is the reinforcement to continue smoking. In addition to this positive reinforcement, smoking is also negatively reinforced by the urge to get relief from the withdrawal effects. The Office for National Statistics reports that 30% of regular smokers (over 20 cigarettes a day) have a cigarette within the first 5 minutes of waking.

Cocaine and amphetamines are very much less ‘benign’ psychostimulants than caffeine. The main target for their actions is the transporter for dopamine. Amphetamines are taken up into nerve fibres and nerve terminals via the transporter and trigger the sudden release or surge of dopamine. Cocaine also acts on the same transporter but its mechanism of action is somewhat different from that of amphetamine. Cocaine blocks the transporter but is not taken up into the cell. It just prevents dopamine getting back into the cell once it is released. Both drugs give increased levels of dopamine but the time course and extent of increased release are different. Cocaine and amphetamine can also block the transporters for serotonin and other signalling molecules to differing extents.

It is important to realise that the different transporters and receptors that psychoactive drugs act on are not just associated with the reward pathway but are present in many other brain regions. Although there may be similarities in the action of these drugs on this one pathway, these do not extend to other pathways. The ‘wiring’ patterns of different nerve cell pathways are not the same and not all the drug targets may be present on a given pathway. Therefore each of these drugs has a different range of additional effects caused by their affecting different targets and other pathways. Two very different examples of the effect of a drug on other pathways are the beneficial pain-killing action of morphine and its lethal effects on respiration associated with overdosing. The latter effect hit the headlines in October 2002 when a morphine-like drug was used during the rescue of hostages being held in a Moscow theatre.

Alcohol stimulates the reward pathway and dopamine release but, unlike psychostimulants and heroin, the release is not further increased on repeated doses and can even decrease. Only limited tolerance to alcohol is generated, but the levels of dependence and withdrawal can be profound. Different neuronal mechanisms seem to be important for the maintenance of alcohol drinking. These are not fully understood at present, due in part to alcohol acting on many different signalling systems in several brain circuits. The continued use of large amounts of alcohol also has the well-known detrimental effects on the liver, heart and gut as well as affecting the functioning of the receptors for many signalling molecules and enzymes in the brain. It can also generate severe nutritional deficiencies. If smoking is excluded, alcoholism is viewed by many as by far the most serious drug problem in the USA and Western countries in terms of accidents, crime, damaged health and social costs.

Work is the curse of the drinking classes

Oscar Wilde

So where, if at all, do ecstasy and cannabis fit into the picture of tolerance, withdrawal and addiction? How do ecstasy and cannabis work and do their actions in the brain fit in with what we know of the actions of other ‘drugs’? Are these drugs ‘safe’, both in the short and in the long term? There is public concern regarding the widespread use of both drugs and the dangers they may present to the users who are often young people. It is estimated that 44% of 16 to 29 year olds in the UK have tried cannabis at least once and 500,000 people regularly use ecstasy. The media frequently report concerns about the dangers of these currently illegal practices. Cannabis is also in the news because the government is considering legislation to re-categorise it from a class B drug, like amphetamines, to a class C drug such as anabolic steroids and benzodiazepine tranquillisers such as Valium or Librium. At present, ecstasy is a class A drug, like cocaine and heroin.

There is no convincing evidence that ecstasy amplifies the effects of dopamine and the activation of the reward pathway. Its main action is to stimulate the release of the signalling molecule, serotonin, in the brain by targeting the serotonin transporter. This initially causes excess levels of serotonin to circulate in the brain, followed by depletion of serotonin stores in nerve cells in the base of the brain. Serotonin is a small molecule which is released throughout the brain and plays a major role in many different neurobiological processes. It helps to regulate our moods and is associated with the effects of several drugs that are used in medical practice to treat anxiety, depression, migraine and nausea. By releasing serotonin, ecstasy promotes feelings of euphoria, emotional closeness and warmth. Higher doses can cause anxiety, panic and confusion. In a small number of cases, taking ecstasy results in death: 27 ecstasy-related deaths were reported in the UK in 2000. However nineteen of these people had other drugs in their bodies so it is not clear which drug killed them or whether it was the combination of drugs. For comparison, there were no deaths attributable to the recreational or medical use of cannabis, 64 deaths from solvent abuse, 87 deaths from cocaine, 94 deaths from paracetamol overdose, and 754 deaths from heroin. In terms of simple numbers, all these figures pale in comparison with at least 30,000 deaths related to alcohol use and over 120,000 to smoking. Another way of viewing these statistics is that 0.5-1.5% of alcohol, tobacco and heroin users and about 0.005% of ecstasy users die each year.

Ecstasy can cause an increase in body temperature that can eventually lead to heatstroke. The danger is enhanced by ecstasy making the drug users oblivious of the fact that their continued dancing is causing overheating and dehydration. Paradoxically, another effect of ecstasy can be that the kidneys stop producing urine, even though a person may be drinking litres of water. This latter combination of circumstances has led to a swelling of the brain and death. So it is important to have an appropriate intake of water. In a further small number of fatal cases, ecstasy users have suffered from the ‘toxic serotonin syndrome’ caused by overstimulation of the serotonin-signalling systems in the brain. Deaths from the use of ecstasy are tragic and sometimes unpredictable, but the incidence is very low, possibly lower than many other ‘risk taking’ pastimes. A focus on the number of deaths can obscure the question of whether there are serious short and long-term effects that might affect much larger numbers of users. Psychological studies have shown that ecstasy users perform worse than non-users in some tests, but equally well, or occasionally even better, in other tests. There are some controversial reports that ecstasy use may give rise to permanent brain damage and a decrease in the levels of the serotonin transporter in the human brain. However there seem to be flaws in the way these data were analysed. So any long-term changes in humans would appear to be quite subtle and may be difficult to attribute to ecstasy itself as many users take other drugs. However an important cautionary note is that exposure to ecstasy has been found to cause damage to serotonin-containing nerve fibres in the brains of animals.

Ecstasy use does not seem to be associated with a great degree of tolerance, dependence or withdrawal, at least in comparison with the effects of cocaine and heroin. Ecstasy users often spend much of the following day sleeping and can have a mild depression – the ecstasy blues – during the next week. This may be a consequence of the ecstasy-induced depletion of the serotonin stores in some of the nerve endings of the brain.

I tried marijuana once. I did not inhale.

Willam J. Clinton

The main psychoactive ingredient in cannabis acts on cannabinoid receptors that are located in many brain regions. Tolerance arises primarily in heavy users and seems to be much less important in casual users or people using small amounts for medical purposes. However regular users run the risk of becoming dependent and allowing the drug to dominate their lives. They can become depressed, unable to function, and severely cognitively impaired. Withdrawal symptoms are only unpleasant in those users who are highly dependent. As might be expected from this general pattern of behaviour of tolerance, dependence and withdrawal, cannabis stimulates the reward pathway and the release of dopamine. However cannabis users seem less predisposed than cigarette smokers to being hooked and find it easier to give up their drug. Many people become lifetime cigarette smokers after a short exposure to nicotine whereas most marijuana users in Western Europe and North America give up before they reach the age of 30. In other regions of the world, where smoking cannabis is incorporated into religious rites or is an accepted part of the culture, there is less fall-off in the use of cannabis with increasing age.

Drugs related to the main active ingredient of cannabis have been used to treat the nausea and vomiting that occurs during cancer chemotherapy but they have now been superseded by more effective drugs with other mechanisms of action and fewer psychoactive side effects. Cannabinoids have also been reported to be of use in alleviating the painful muscle spasms and improving urinary control in multiple sclerosis. However many of the reports are anecdotal and well-designed clinical trials need to be done to demonstrate efficacy.

As with cigarettes, cannabis smoking is also associated with the well-known hazards to the lungs, caused by inhalation of the carcinogens and irritants in the smoke. Otherwise, cannabis has low toxicity. Small doses can have effects on the heart and circulation but regular users become tolerant to these effects. There is no convincing evidence of long term structural damage to the brain. Nevertheless there is concern that cannabis may trigger a latent psychopathic condition such as schizophrenia in a small number of users, but again definitive evidence of a causative link is lacking. The unwanted psychoactive effects of cannabis are also of concern if it, or a related drug, is going to be used therapeutically. Cannabis impairs short-term memory, reduces the ability to concentrate, to remain alert, and to process complex information. Driving is impaired, as are balance and dexterity. In addition the active constituents of cannabis are effectively absorbed in fat stores in the body and are only slowly released from them. This means that they have a prolonged duration of action. All these effects are unacceptable clinically unless a drug can be administered in such a way, and at a dose, that only the desired therapeutic effects are achieved.

In this brief excursion through the world of psychoactive drugs, I have attempted to point out the ways in which they act when they are used for non-medical purposes in a social setting. Some of these effects have been related to those that are also found when drugs are used in a clinical setting.

Many psychoactive drugs have different specific targets in the brain and therefore have different actions. Despite these differences, they appear to trigger a common pathway associated with the development of tolerance and dependence. However the nature, extent and time course of these and other adaptive changes depend on the drug. The sheer complexity of the brain provides the challenge to our understanding the mechanisms of adaptive changes. In the future, the ability to intervene therapeutically to reverse or modify the adaptive changes in the brain may make it possible to treat the craving, the compulsive drug seeking and the other unwanted symptoms of dependence and withdrawal.

I can stop anytime I want to, only I don’t want to

Marilyn Monroe in ‘Some Like it Hot’


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