Drugs PDF

Drugs Aims: In this session we will look at:  Revisit normal neuronal transmission  Look at how a psychoactive drug may act on the brain to change behaviour  Discuss how a drug may act on both the body and the brain, using the recreational drug ecstasy as our example ...

Drugs Aims: In this session we will look at:  Revisit normal neuronal transmission  Look at how a psychoactive drug may act on the brain to change behaviour  Discuss how a drug may act on both the body and the brain, using the recreational drug ecstasy as our example  Consider the possible harmful effects of taking drugs Psychoactive Drugs We have already been introduced to psychoactive (or psychotropic) drugs in last week’s session. These are drugs that affect the brain to produce alterations in mood, thinking, perception and behaviour, and we looked at a particular example of a type of psychoactive drug: caffeine. It is worth remembering two things: 1. Not all drugs we take are psychoactive (not all reach the brain because they can’t all cross the blood-brain barrier – this is the case with many medicines). 2. Not all psychoactive drugs are illegal – there are a number of legal substances that we use that change the way we interact with our world (some are medicines and are often used in a mental health context, such as antipsychotics or antidepressants; others we use precisely because of the way they make us feel, such as caffeine or alcohol.) Psychoactive drugs have their effects by disrupting normal neural transmission. They induce chemical imbalances within our brains and bodies that we experience as physical effects of taking a drug (this might be increased heart rate) and that perceive subjectively (for example feelings of euphoria). Again, don’t forget that even psychoactive drugs, are having an effect on Dr Lynne Marrow the rest of the body as well as the brain and they will often be exerting an influence over more than one neurotransmitter system, both centrally and peripherally. It is this variance in action that leads to the effects we associate with different drugs; so cocaine is stimulating, it makes you feel euphoric and full of energy, whilst heroin gives a sense of well-being and escape from the world – different drugs produce different effects because they are affecting different brain systems. There are many different psychoactive drugs and these can be broken down into a number of different types. Drugs can be broadly categorised in a way that helps with understanding how a person might be affected when using them: Depressants – these slow down the central nervous system, affecting co-ordination and reaction times (they do not necessarily make you feel depressed!). Stimulants - increase the heart rate and give the user a sense of increased alertness and energy. Hallucinogens - change the way people think, feel and perceive their surroundings. Drug Action and Drug Effect Drug action refers to the specific interaction between drugs and their target sites or receptors. Psychoactive drugs act in a variety of ways to have their effect, but in general terms, there are two main effects that a drug might have on synaptic transmission: 1. An agonist is a drug that mimics or facilitates the effect of a neurotransmitter. 2. An antagonist is a drug that blocks or inhibits the action of a neurotransmitter. So, for example, drugs may excite neurones to produce more action potentials (e.g. alcohol, heroin, and nicotine) or may directly activate postsynaptic receptors (e.g. THC (marijuana) and morphine). These would be classed as agonistic effects. Others may block post-synaptic receptors (e.g. caffeine). This would be an antagonistic effect. Dr Lynne Marrow Drug effect, in the other hand, refers to the widespread changes in physiological or psychological function that occur as a result of taking the drug. When we take a drug, we have an acute response to that substance, however, as we become experienced with a particular drug, our body changes to counteract that drug’s effects; we adapt to our drugs. The Body’s Adaptation To Drug When we take a drug, be it caffeine, alcohol, nicotine, cannabis, cocaine, it alters our body’s natural balance and the response to this is try to re-establish that normal state or homeostasis. Over time, if we continue to take drug, our body will make subtle changes that accommodate the chemical, because now, the drugged state becomes the normal state, so our body learns to function with the drug by minimising its effect. This is known as tolerance. “Tolerance: A decrease in response to a drug dose that occurs with continued use. Increased doses of alcohol or other drugs are required to achieve the effects originally produced by lower doses.” (WHO lexicon of alcohol and drug terms) We see the effects of tolerance in our own drug taking behaviour. Many of us drink alcohol to a greater or lesser degree. If you do drink alcohol, think back to your first experience with this common drug. How much alcohol did you drink before you started to feel its effects; perhaps a little giddy, talkative, light-headed? Half a glass? How much do you have to drink now to achieve that same state? This change is due to the effect of tolerance. If we stop taking our drug, then gradually we will lose our tolerance to it. This can be a problem for some drug users who have been drug free for a long time, but then return to their drug- taking habit. Thinking it perfectly safe, they may take a dose of drug that they previously used to take without problem, not realising that when they were regular drug users they had developed tolerance to their drug. Now imagine that drug is heroin. The amount of drug (the dose) we take is important and is very individual, depending on many factors including gender, weight, genetics and prior experience. Getting the dose wrong can be fatal. That is why doctors Dr Lynne Marrow will often prescribe a low dose of a drug then adjust in small increments until they find the lowest effective dose for the individual. It is interesting to note that, contrary to expectation, tolerance does not necessarily occur to all aspects of the drug taking experience. Indeed, some drug effects become more evident following continued drug use. This phenomenon is known as sensitisation. So you may become tolerant to some effects and sensitised to others – for the same drug! Sensitisation is produced by many different drugs of abuse including amphetamines, cocaine, opiates, ethanol (alcohol) and nicotine. A drug user who suddenly stops taking their drug can trigger withdrawal symptoms – an adverse physiological reaction to no longer having drug in the body. Remember tolerance, caused by adaptations to continued drug use? These changes are thought to be responsible for withdrawal symptoms when the drug is no longer present. Evidence to support this view comes from the observation that withdrawal symptoms are almost always the opposite of the effects of the drug. Withdrawal symptoms can be incredibly unpleasant, depending on the drug and level of prior drug use. Individuals who experience adverse physical symptoms when they stop taking their drug are said to be physically dependent on that substance. Not all drugs induce great physical distress when the user stops taking them, in some cases an overwhelming desire to take a drug, to the point that the user can think of nothing else, is a greater cause of distress. This would be a psychological dependence on a substance. Dr Lynne Marrow Drugs of Abuse Psychoactive drugs that we take recreationally, for pleasure, share a common action: they act on the brain’s reward system. An important part of the reward pathway is shown in this picture and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex it sends information to these structures via its neurones. The neurones of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex. Drugs that we abuse increase the levels of dopamine in the nucleus accumbens and this almost certainly accounts for the rewarding (pleasurable) effects of abused drugs. Of course, we must remember that the effects of drugs are not limited to the reward pathway in the brain. Drugs can act in various regions of the brain to exert their effects. However, their ability to alter dopamine neurotransmission within the reward system is one of the most important factors that drives continued drug use. Ecstasy The drug 3,4, methylenedioxymethamphetamine, better known as MDMA or ecstasy, is a derivative of amphetamine, and like amphetamine, ecstasy is a synthetic substance, produced in clandestine laboratories. In fact, there are several “designer drugs” that are made by altering the structure of the amphetamine molecule. Ecstasy is usually sold in either tablet or capsule form and is taken orally. When taken by mouth, effects begin in about 30 minutes and usually last somewhere between 3 to 6 hours. On the street its purity can vary dependant on where it is made, and other compounds are easily combined into the same tablet (contaminants often include caffeine, ephedrine, ketamine - a mild hallucinogen and methamphetamine). Ecstasy's Dr Lynne Marrow stimulant action, gives the user the energy to dance for hours, and its subjective effects makes the user feel more 'in tune' with their surroundings, more sociable and trusting. These factors ensured the popularity of this drug at clubs and parties. According to Home Office statistics for 2015/16 1.5%, or 492,000 people aged 16 to 59 reported that they had taken ecstasy. The proportion of 16 to 24 year olds reporting ecstasy use was 4.5%, equating to around 279,000 young adults. There have been many reports in the media that ecstasy is getting stronger. A study from the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA) from April 2016 looked at this issue. They state that in the 1990s and 2000s the average MDMA content of tablets was somewhere between 50–80 mg, as reported by drug checking services and forensic institutes. Currently, however, the averages are closer to 125 mg of MDMA per tablet, while there are also ‘super pills’ found on the market in some European countries with a reported range of 270–340 mg. How does it work? Ecstasy's primary effect is on the serotonin (5-hydroxytriptamine, or 5-HT) systems within the brain. Serotonin neurones originate from the Raphe nuclei in the brainstem and send projections throughout the brain where they affect several processes including mood, Dr Lynne Marrow emotions, aggression, sleep, appetite, anxiety, memory, and perceptions. In particular, serotonin neurones project to the neocortex (regulating cognition, memory, and perceptions); the limbic system, including the amygdala (mood and emotions), hippocampus (memory) and hypothalamus (regulating heart rate and blood pressure, fluid retention and kidney function, and body temperature); and the basal ganglia. A 2nd serotonin pathway descends down the spinal cord; these neurons control muscle activity. Consequently, ecstasy affects cognition (thinking), mood, and memory. It also can cause anxiety and altered perceptions (similar to, but not quite the same, as hallucinations). One of the more desirable effects of ecstasy is its ability to provide feelings of warmth and empathy. Ecstasy has it's effects by binding to the serotonin transporter molecules (re-uptake pump) that usually remove serotonin molecules from the synaptic gap, transporting them back into the neurones where they can be recycled for reuse. When Ecstasy binds to the serotonin transporters it has two effects: 1. Ecstasy prevents the transporters from carrying serotonin back into the terminal. 2. Ecstasy causes the transporters to work in reverse transporting serotonin from the terminal into the synaptic space. Consequently, more serotonin is present in the synaptic gap and therefore more serotonin receptors become activated. What does it do? The immediate effects of using ecstasy include elevated mood and feelings of empathy, heightened perceptions, stimulation and reduced appetite. Ecstasy is also reinforcing, acting through an effect on the dopamine system; this means that its pleasurable properties increase the likelihood that the person will take it again. Among its many effects, ecstasy is often described as increasing feelings of empathy, however, this is actually a controversial claim. Bedi, Hyman and de Wit (2010) found that the drug MDMA increased “empathogenic” feelings, or feelings that were interpreted by the user as Dr Lynne Marrow feelings of empathy, but actually reduced accurate identification of threat-related facial emotional signals in others, findings consistent with increased social approach behaviour rather than empathy. In other words, rather than feeling more empathic, MDMA users were more likely to make inappropriate social approaches, because they were unable to recognize the signals that indicated those advances were unwanted, thus placing themselves in risky social situations when on the drug. Whilst taking ecstasy might sound like a lovely experience, not all reported experiences are positive, for example, Davison and Parrott (1997) found that 25% of users reported having at least one adverse reaction, when unpleasant feelings and bodily sensations predominate. Negative psychological effects may include clouded thinking, agitation and disturbed behaviour (mediated by the neocortex, and limbic structures). Other adverse effects include sweating, dry mouth, increased heart rate, fatigue, muscle spasms (especially jaw-clenching) and hyperthermia (over heating). The development of thirst and the hyperthermia are due to the actions of ecstasy at the hypothalamus, which controls drinking behaviour and body temperature. Hyperthermia is especially problematic when the user is in a hot environment and/or engaging in intense physical activity such as dancing in clubs or at parties. The muscle spasms and jaw-clenching are due to ecstasy’s action on the motor neurons in the spinal cord, which send signals to the muscles to contract. Increased, or multiple, doses increase the severity of these adverse effects, some of which can become life-threatening. Repeated doses or an extremely high dose of Ecstasy can cause heat injury due to hyperthermia, hypertension (high blood pressure), cardiac arrhythmias (irregular heart beat), muscle breakdown, and renal failure due to salt and fluid depletion. Again, the effect of ecstasy on the hypothalamus is important here. If the body temperature gets too high, it can cause brain damage and in extreme cases can be fatal. The after effects of taking ecstasy include depression-like symptoms that occur about 2 days after having taken the drug. Fortunately these feelings are back to normal seven days after Dr Lynne Marrow taking the drug (Parrott and Lasky, 1998) and occur because of a depletion of serotonin in the central nervous system from weekend drug use. Serotonin levels must then be built back up before mood and levels of sociability improve. Curran (2000) also reported mid-week low moods following weekend ecstasy use. In addition, 80% of her participants also reported concentration difficulties or memory problems. If ecstasy users are reporting memory impairments, what is the risk that these may last over the long term? There is increasing evidence that there may be some long-term effects of ecstasy use. For example, Morgan (1999) found that ecstasy users had lower scores for memory performance than non-ecstasy user controls, suggesting that these deficits self-reported deficits were real deficits. Whilst Gouzoulis-Mayfrank, Thimm, Rezk, Hensen and Daumann (2003) found that heavy ecstasy users had lower memory performance that both nonuser controls and moderate ecstasy users, implying that this effect is dose dependent. They also found that it is not an effect of lower overall cognitive function, but specific to memory performance, suggesting that hippocampus is particularly vulnerable to the neurotoxic effects of ecstasy. More concerning, the authors suggest that hippocampal dysfunction after ecstasy use may be a risk factor for earlier onset and/or more severe age-related memory decline in later years. A drug induced form of dementia perhaps? McAleer et al (2013) addressed the fact that ecstasy is often consumed at weekends rather than across the week, resulting binge-like pattern of consumption. They gave rats free access to MDMA on a “weekend” schedule: 2hrs self-administration on 2 consecutive days followed by 5 drug free days. They found that after just 2 such weekends, the rats’ non-spatial memory was impaired. Long term serotonergic damage caused by MDMA was first demonstrated in laboratory animals during the mid 1980’s. Studies by researchers such as Ricaurte et al (1985) and Schmidt et al (1986), showed that rats treated with successive doses of MDMA developed a pronounced degeneration of serotonin axons whilst the cell bodies were spared and that this effect was Dr Lynne Marrow specific to serotonin neurones and did not affect other neurotransmitter systems. Similar findings have been demonstrated in human studies including: McCann, Szabo, Scheffel, Dannals and Ricaurte (1998), who found that MDMA users showed decreased global and regional brain serotonin transporter binding compared with controls. These decreases in serotonin transporter binding positively correlated with the extent of previous MDMA use. McCann UD, Szabo Z, Seckin E, Rosenblatt P, Mathews WB, Ravert HT, Dannals RF, Ricaurte GA. (2005), used PET scans and two radioactive tracers to measure serotonin transporter availability. Both radioactive tracers showed less serotonin transporter availability in the MDMA users than the controls. Ricaurte et al (2000) analysed brain scans of people who had used ecstasy an average of 200 times over five years. Although the behaviour of these people appeared normal, brain scans showed global brain damage related to serotonin neurotoxicity. The severity of the brain damage was correlated to ecstasy usage. Numerous studies have used PET to measure 5-HTT levels in human recreational MDMA users. While not universally consistent, the bulk of the available evidence indicates that MDMA use is associated with long-lasting reductions in the serotonin transporter molecule. Interestingly, Malberg and Seiden (1998) noted that changes in ambient temperature of as little as 2oC produced changes in the core temperature of MDMA-treated rats, but not of saline- treated rats. These increases in the core temperature of MDMA-treated animals were associated with increased neurotoxicity of MDMA. This has relevance to human recreational use of ecstasy, as many people take this drug in clubs or at parties where they are in hot crowded environments and where they are being physically active. So there is evidence that ecstasy can be neurotoxic and cause damage to serotonin neurones. Reneman, Booij, de Bruin, Reitsma, de Wolff, Gunning, den Heeten & van den Brink (2001), using single-photon emission computed tomography (or SPECT) to visualise the serotonin transporter molecules, found that women were more susceptible to the neurotoxic effects of Dr Lynne Marrow ecstasy than men. However, females who were former users of ecstasy had higher overall densities of serotonin transporters than heavy current users of MDMA (though not as high as controls), a finding, the researchers concluded, that suggests any damage may be reversible. Can these effects be reversed? Certainly there is evidence from the animal literature that suggests some degree of recovery. In the rat neuronal recovery occurs over several months, which amounts to a large proportion of a rat’s normal lifespan of about 2.5 years. In monkeys and primates, recovery appears to be partial at best, even after a prolonged period. In an important study by Hatzidimitriou et al (1999) one group of monkeys were given ecstasy twice a day for 4 days whilst the control group received given saline. Monkeys in the experimental group were then sub-divided in to two groups: 1. brains were analysed for serotonin 2 weeks after receiving ecstasy 2. brains were analysed for serotonin 7 years after receiving ecstasy The monkeys that did not receive any ecstasy had a lot of serotonin and serotonin neurones. Two weeks after a monkey received ecstasy, most of the serotonin was gone from the neocortex, suggesting that the serotonin neurone terminals were destroyed (although there was no destruction of the serotonin cell bodies arising back in the brainstem). This damage appeared to be long-term because 7 years later there was some recovery, but it was not complete and in fact the pattern of regrowth of serotonin terminals was abnormal. The researchers found similar changes in limbic areas of the brain such as the hippocampus and amygdala. What is particularly concerning here is that these monkeys only ecstasy over 4 days and yet the consequences appear to be long lasting. Findings like those of Hatzidimitriou and colleagues have to make us pause for thought. Whilst the the human data is still equivocal, neurocognitive problems are reported in the literature and review of the area by Roberts, Quednow, Montgomery and Parrott (2018) concluded that the evidence suggests that ecstasy use causes changes to the serotonergic system such that Dr Lynne Marrow additional resources need to be recruited to perform cognitive tasks (in other words it takes more energy and or processing power to perform these tasks) in users and former users. Although whether this reflects neurotoxicity or neuroadaptation is a question for further discussion. Consequently, this is a still an area of ongoing investigation. Further Reading  Pinel, J. P. J., and Barnes, S. J. (2018) Biopsychology. Tenth Edition. Pearson Education. Further Study If you are interested in this area check out our M.Sc Applied Psychology (Addictions) programme https://beta.salford.ac.uk/courses/postgraduate/applied-psychology-addictions Dr Lynne Marrow