PSYC330 overall notes

Lecture 1:

History of Drugs in NZ
- before the arrival of Europeans, Maori were one of the few societies that had no recreational intoxicants. Rather, they used psychoactive substances as medicine. Kawakawa, Pukatea. Rather drugs were used medicinally.

In the late 1700’s Europeans brought alcohol and tobacco to New Zealand. Many Maori leaders discourage the use of however they soon became currency in trade. Because they have been used in trade it makes it harder to get rid of.

Tobacco

·        Along with men, Maori women began to use tobacco extensively in the early 1800’s. in contrast the use of tobacco by European women was frowned on.

·        There were oppositions to the use of tobacco among Maori, in the early 20^th century some leaders banned it from their communities.

·        Maori Councils act of 1900’s prohibited the use of tobacco by children.

·        By the time the dangers of smoking were recognised (mid 1900’s) it was entrenched in Maori communities.

·        Was common among non-Maori but at much lower rates.

Rates of smoking in 1962:

Ø  Maori > 58% in men and 70% In women

Ø  General population > 38% in men and 31% in women

Ø  In 1990, over 50% of Maori were smokers

Ø  In 2009 Maori women aged 20-24 has the highest smoking rates in NZ (61%)

Ø  In 2011/12, rates of smoking in Maori declined to 41%

Ø  2021/22 rates of smoking in Maori were 19.9% compared to 8% of all NZ adults.

Alcohol

·        Was brought to NZ by European settlers, soon used in trade

·        Initially not preferred by many Maoris, Waipiro “stinking water” or “strong water”.

·        Became incorporated into Maori life (1850s)

·        The first Maori doctors described drinking as a major social problem

Impacts of alcohol were only apparent when lots of people were using it.

·        After World War 2 most of the regulations were repealed and drinking became more normalised for many Maoris.

·        The patterns of drinking between Maori and Non-Maori differed; although consuming on average the same amount of alcohol, Maori drink less frequently but consumed twice as much per a drinking session.

·        Maori twice as likely to suffer severe alcohol-related problems and 4x more to die from alcohol conditions.

Other Drugs

·        Chinese miners brought opium (1860s)

·        Patent medicines containing cannabis and morphine were popular

·        Cannabis cigs widely advertised in 19^th century as a cure for asthma and insomnia.

Drug control measures between 1866-1965:

·        1866; Sales of Poison act label opium as a poison

·        1871; required vendors of opium to be registered

·        1901; Opium Prohibition Act prohibited the smoking and importation of opium

·        1908; Quackery Prevention Act; tried to restrict patent medicines

Drugs remained relatively unrestricted until the early 1900s when international pressure forced NZ to restrict drugs.

·        1927; Dangerous Drugs act, established a list of dangerous drugs including cannabis. Could be imported but only under license and purchased legally.

·        Late 1940s, NZ had one of the world’s highest heroin use rates due to (prescription of the drug by doctors)

Vast majority of people who use drugs, recreationally do not experience problems for their use. Only a small minority of people who use drugs have problems as a result of drug use.

·        Misuse of Drugs Act 1975.

Cannabis

·        1960s whereby baby boomers, Vietnam war and psychedelic “hippie’ music/culture had a large influence increasing cannabis use.

·        NZ has one of the highest rates of cannabis in the world.

Hard Drugs

·        NZ has unusual patterns of use due to geographic isolation and border control

·        High profile drugs are less common (cocaine, heroin).

·        Opiate use is low (confined to “home bake”) but prescription opiate use ^.

·        Opiate use is driven by prescription opiates in NZ these rates are increasing but NZ is still isolated from a lot of the factors that drive large consumption patterns globally. NZ is not immune, tad behind but is still impacted.

Synthetic Drugs

·        E.g., amphetamine, ecstasy are used more often, as they are synthetic can be made easier do not need to be imported.

·        Hallucinogens; low rates of LSD, mushrooms, and ketamine

·        Party pills; was once widely used but banned in 2007.

Misuse of Drugs Act 1975

·        An attempt to bring NZ in line with general international consensus on drugs using a comprehensive drug legislation scheme.

·        Established a schedule for drugs; schedule = determine what the criminal penalties for using or distributing certain drugs will be based on depending on the danger they may pose.

·        This underwent revision in 1978/1992 but is still used as the overarching framework for NZ drug policy.

The legislations for these drugs need to be evidence based otherwise they can do more harm than good on society. Alcohol is considered a class A drug but not in this act.

Substance use is one of the leading causes of disease burden in NZ

·        Projected DALY for 2016 was 1.085 million, for drugs was 150,700

·        1.8 billion per year spent on drug related costs, $350 million on drug laws money mostly goes towards criminal justice rather than habitation.

What is a drug? A medicine or other substance which has a physiological effect when ingested or otherwise introduced to the body.

Names of Drugs

Drug Dose

·        Impact of drug is related to its concentration in the body, not the absolute amount of the drug, the dose is according to body weight (mg/kg)

Drug Effect

·        To establish a true picture of a drug effect can look at a dose-response curve.

e.g., effect of caffeine on the rate of responding by a mouse

·        Anaesthesia; not a graded response either asleep or not

·        ED50 median effective dose; the dose that is effective in 50% of the subjects tested.

·        LD50 median lethal dose; the dose that was lethal in 50% of subjects tested.

Drug Safety

·        The further the distance between ED50 and LD50 the better

·        Therapeutic index is an objective way to describe the safety of a drug TI=LD50/ED50. The higher the TI the safer the drug.

·        Potency: differences in ED50 of the two drugs that have the same effect

·        Effectiveness: difference in the maximum effect that drugs will produce at any dose.

Primary and side effects

Primary effects are the intended result in treatment whereas side effects unintended effects that is anything else, can be harmful. Arbitrary depends on when you’re taking the drug.

Lecture 2:

Drug interactions: how do combinations of drugs interact together and against the body?

·        Additive effect: adding an addition drug and the effect it has on the original drug. The combination effect of two or more chemicals equal to the sum of the effect of each agent acting independently(additive). Shifts dose response curve to the left.

·        Drug antagonism: one drug diminished the effect of the other, can decrease the potency and effectiveness. If you are taking a drug for a particular reason, anything else that occurs that is not the primary reason is considered a side effect, unintended.

·        Super additive effected/potentiation: combining drugs increases the effect, need more of the first drug when another is added in order to achieve the effect of the original drug on its own. Drug that is being added is antagonising the effect of the 1^st drug.

Pharmacokinetics

1.        Absorption- how a drug gets into the blood

2.        Distribution- where it goes in the body

3.        Elimination- how the drug leaves the body

Routes of administration

·        Parental; injection under the skin

·        Inhalation; breathed into the lungs

·        Oral; ingested into the digestive system

·        Transdermal; absorbed through the skin

·        Vehicle (before a drug can be injected it must be a liquid)

·        Subcutaneous (needle inserted under the skin or cutaneous tissue

·        Intramuscular (needle inserted into the muscle)

·        Intraperitoneal (needle inserted into the peritoneal cavity)

·        Intravenous (needle inserted into the vein)

Other routes (non-human, invasive)

·        Intrathecal (inserted between the base of the skull and the first vertebra)

*Drug gets left in the CFS

·        Intracerebroventricular (inserted directly in the brain’s ventricles)

·        Intracerebral (inserted directly into brain tissue) often through cannula

Absorption from parental sites; To be effective drugs must be absorbed into the bloodstream this is done by:

Capillaries- permeate most body tissues, drugs move through capillaries into blood through diffusion.

Veins- carry blood to the heart

Arteries- carry blood away from the heart to the rest of the body, and brain

Depot injection: drug is given slowly dissolves into the body over a long period of time. Good if you want to have a stable level of drug over a long period of time.

Inhalation

Gases

·         absorbed quickly through the capillaries in the lungs into the blood

·        Drugs in the form of gases, vapours, or fine mists get into the blood very rapidly via the lungs

·        Blood goes directly from the lungs to the heart

·        One of the arteries goes directly to the brain, so inhaled drugs can pass to the brain without being metabolised in the liver first.

Smoke and solids

·        Burning dry material releases the drug into the air in smoke

·        Absorbed in the lungs (tobacco, opium, and marijuana ingested this way)

·        Drugs ingested in this way can’t be exhaled (must be eliminated through other means)

·        Risk damage to all tissues in the respiratory system

·        Refined drugs can be heated until they vaporise, and the vapours inhaled

·        Powdered drugs also inhaled (snorted) e.g., cocaine, heroin, tobacco (can impact the nasal cavity) not as efficient in getting drug to the blood.

Oral administration

·        Taken in the mouth and swallowed (per oral) absorbed into the digestive system

·        Drugs may also be taken into the mouth but not swallowed, still oral but through buccal membrane.

·        Also, can be taken as suppositories (enters through intrarectal)

Transdermal administration

·        Absorbed through the skin; slow process (unless break in skin)

·        (+) good if you want drug to be absorbed slowly

All tissue in the body is composed of cells that form membranes. In order to get inside the cell, drugs have to cross the phospholipid bilayer, two layers of fat molecules.  Drugs that can dissolve in fat (lipid soluble) are more readily absorbed.

Lipid solubility and absorption

·        All tissue in the body is composed of cells that form membranes

·        In order to get inside the cell, drugs have to cross the phospholipid bilayer

·        Drugs that can dissolve in fat (lipid soluble) are more readily absorbed.

Distribution in the central nervous system:

Blood brain barrier

·        In order to get into the brain, drugs have to cross the blood brain barrier this barrier has protective mechanisms to keep bad things out promoting vitality and health. HOWEVER, some areas of the brain lack blood brain barrier due to the brain area requiring access to the blood stream.

·        Substances can not cross the BBB if they are: too highly charged, too large, or not lipid soluble.

Passive transport: diffusion; most basic and least efficient way “moving from areas of higher concentration to low concentration”. Does NOT require energy. Moves with diffusion gradient. Takes a long time.

Active transport: works against diffusion gradient, DOES require energy. Costly process.

Placental barrier: similar to blood-brain-barrier. Drug concentration in the blood of the foetus reaches 75-100% of that in the mother in roughly 5 minutes. Drugs cross the barrier quite easily, very little protection for the fetes from drugs administered to the mother.

Metabolism and excretion:

·        Metabolism restructuring molecules that can be filtered out of the blood into the kidneys. Requires enzymes. Catalysts that control chemical reactions.

·        Where drugs are involved, sometimes called detoxification.

·        Drugs are metabolized primarily in the liver and excreted through the kidneys, with the rate of elimination often described by half-life. requires enzymes and uses catalysts that control chemical reactions.

First-pass metabolism

·        Drugs thar are absorbed through the digestive system pass through the liver first. some metabolism takes place that this time via the liver enzymes. Likely responsible for a significant amount of drug metabolism.

The kidneys

·        Functions as a complex filtering system that physically removes certain substances from the blood.

·        Filter everything out of the blood and then selectively reabsorb what is needed by the body.

·        Metabolites (from the liver) are generally more likely to ionise, making them more difficult to be absorbed back into the bloodstream. Ionised makes it harder to get into the cells across barriers.

Rate of elimination

·        Half-life: the amount of time it takes to eliminate half of a given blood level of a drug.

Exception to this general rule is alcohol

·        You get rid of drugs rapidly and this curve flattens overtime

·        Other drugs are taken in miniscule amounts and can be metabolised quickly

·        Alcohol is taken is consumed in larger quantities saturating enzymes quickly.

Factors that alter drug metabolism

·        Stimulation of enzyme systems; excess alcohol dehydrogenase in livers of heavy drinkers.

·        Depression of enzyme systems; disulfiram (Antabuse) blocks aldehyde dehydrogenase. Makes you sick if you drink.

·        Age- enzyme production and function, and therefore metabolism, changes with age. Liver function is less efficient in elderly people

·        Species- levels of certain enzymes differ between species.

Combining absorption and excretion functions

·        Effect of drug change overtime

Therapeutic window

·        To be effective the right level of drug must be maintained in the blood for an extended period of time. Too much will produce side effects, too little will not produce the wanted therapeutic effect.

Lecture 3: 22^nd July

 Behavioural analysis of drug effects

How do we scientifically study the effect of drugs on behaviour?

·        Early accounts of the impact of drugs on behaviour were verbal description or written accounts of subjective experience.

Earliest known account of experiences on drugs was taken by Thoman De Quincy who wrote about his experience with opium. Along with Club des Hachichins.

Jacques-Joseph Moreau

·        Became interested in doing systematic analysis of the effect of marijuana on CNS.

·        Used himself and others as test subjects, documenting his results in 1945

·        Was the first doctor to publish effect of drugs on the CNS, with some of his work anticipating modern psychiatry.

What took place as part of evolution science in the development and use of drugs:

1)        Modern chemical techniques for synthesising the active chemical in drugs

2)        Modern refinements in the study of behaviour.

It is hard to pinpoint what is responsible for a behaviour so synthesising help with that.

Introspection- the observation of one’s own mental and emotional processes. Aim was to break down consciousness into its component parts. Structuralism. Focus predominantly on the subjective experience of an individual.

John B. Watson

·        Behaviourists movements (1940-50’s)

·        Felt that science, psychology should study only observable behaviour rather than subjective experience.

·        Subjective experiences not helping us to understand why people behave the way they do, can only see what the person does and the environment around them.

Early studies of drugs on behaviour

·        Mostly carried out by pharmacologists

·        Involved unstructured observations of laboratory animals after given drugs (monitored running, sleeping, convulsions, etc)

·        If the drug increased locomotor activity, it was taken to indicate it as a CNS stimulant. “Stimulated activity”

·        If the drug decreased locomotor activity, it was taken as a CNS depressant

Behavioural Pharmacology

·        Wasn’t until the 1950’s were their separate disciplines for the study of effects of drugs on behaviour.

Two contributors:

1)        Chlorpromazine

2)        Operant analysis of drug effects

Chlorpromazine

·        in 1951 chlorpromazine was synthesised, where it was first thought of as a potentiator or general anaesthesia.

·        Produced a cooling of the body temperature of disinterested without a loss of consciousness. Similar to disassociation.

·        Drug was taken by psychiatric patients, people with severe mental illnesses who were institutionalised were able to resume “normal life” shortly after the drug was taken. Huge development.

·        In 1952, drug was marketed as an antipsychotic (Thorazine)

Peter Dews

·        Was unsatisfied with the current methods of effect of drugs on behaviour

·        Decided to study the effects of drugs on pigeon pecking for grain reinforcement in operant chamber.

Pigeon study: trained pigeons on two different schedules of reinforcement: schedules of reinforcement set the conditions upon which behaviour will be rewarded.

·        FR 50; fixed ratio meant a specific number of pecks (50) produced high rates of responding.

·        FI 15 min; fixed interval, fixed period of time produced low rates of responding

Pigeon was then given pentobarbital where Dew measured the change in responding that occurs after the drug.

Results: comparatively FI15 to FR50 schedule produced a lower rate of responding. 

Statement about drug increasing behaviour = stimulant, drug decreasing behaviour = depressant. What about the same drug on the same behaviour? the same dose of the same drug can impact behaviour significant depending on what occurs before the drug.

Joseph V. Brady

·        Believed neuroscience could be useful in understanding the effect of drugs on behaviour. Also drugs and behavioural pharmacology research could tell us a lot about the function of the brain.

·        Conducted important research on relationship between stress and ulcers, stress was a physical illness, producing physiological problems.

Research Design

Ø  all scientific experimentation is a search for relationships between events

Ø  in behavioural pharmacology, trying to discover the relationship between the presence (or dose) of a drug and changes in behaviour.

·        Independent variable, what the researcher manipulates (drug or dose)

·        dependent variable, the outcome that is measured (behavioural measure)

Experimental Research Design

·        experimental control; need to have experimental control. Ensure effect that is being shown is a result of manipulation within the experiment and not some other factor/mediator.

·        within-subjects design; compare behaviour in the presence and absence of the drug in the same individual.

·        between subjects’ design, compare behaviour in different groups (one drug, one control)

·        placebo controls: using a control condition that involves the administration of something to both groups (sugar pill/injection of saline) effect of expectation.

·        placebo effects- means careful experimental control is a necessity as there can be an effect of an expectation.

Fillmore and Vogel-Sprott (1992)

Studied the placebo effect using coffee and a performance task.

Ø  Different groups were told that the caffeine would improve or impair their performance.

Ø  No one got any caffeine, but expectations had an impact on behaviour.

Balanced placebo design: developed in the mid 70’s (still considered gold standard)

4 groups:

1.        Expect a drug, get a drug

2.        Expect a drug, get a placebo

3.        Don’t expect to get a drug, get a drug

4.        Don’t expect to get a drug, get a placebo

Three-group design: used when a drug is undergoing a clinical trial.

1.        experimental drug

2.        placebo

3.        established treatment drug (to test new drug for its affects against established treatment).

Experimenter bias

Ø  can have an impact on the results so it is common for the experimenter and the subjects to not know the nature of the treatment (double blind) or masked procedure.

Non-experimental research

·        looks for a relationship between two measured events

·        can only look for correlations, can’t establish causality

Unconditioned behaviour- doesn’t take any learning for behaviour to manifest

·        simplest measure of behaviour in nonhuman e.g., spontaneous motor activity (SMA)

·        open field test, administer the drug see how much the animal moves

·        inclined plane test, measures muscle tone

·        elevated plus maze, measures the time spent in closed vs open arms of the maze.

·        Lick latency test, place mouse in metal plate, gradually heat it up to the point where the mouse is uncomfortable, mouse will begin to lick paws. Analgesia

Classical conditioning

·        Developed by Pavlov

·        Conditioning theory was greatly used to understand tolerance & addiction

Conditioned drug effects

Ø  In early experiments, Pavlov showed that a stimulus that preceded a drug US could become a CS that elicited conditioned drug-like effects.  The drug is the unconditioned stimulus as the body prepares to act in a way without any training.

Ø  Response starts to look like a drug has been administered in the absence of a drug.

Operant conditioning

Ø  Thorndike & Skinner

Ø  Behaviour is a function of its consequences

Ø  Meaning any behaviour that is exhibited depends on the consequences of that behaviour in the pass. Therefore, we understand behaviour in terms of its prior consequences.

Anytime reinforcement is being evoked it means behaviour is always going up.

Schedules of reinforcement = rules or contingencies that govern the presentation of reinforcement for appropriate behaviour. Setting up a situation where you can control how often a subject is being rewarded.

Two types:

1)        Ratio = behaviour reinforced at a specific number of responses

2)        Interval = behaviour is reinforced after the first response to occur after a specific amount of time.

Ratio schedules

Ø  Fixed ration (FR) = reinforcement delivered after fixed number of responses

Ø  Variable ratio (VR) = reinforcement delivered after a specified average (slot machines)

Interval schedules

Ø  Fixed interval (FI) = reinforcement delivered for the first response after a fixed amount of time has elapsed.

Ø  Variable interval (VI) = reinforcement is delivered for the first response after an amount of time that varies around a specified average.

Avoidance-escape task

Animal can be taught to avoid/escape aversive stimuli

Ø  Threat conditioning- chamber with two rooms/compartments in one you can deliver a CS (tone) teach animal to know that the sound may result in a shock.

Ø  When the subject is given a shock, they then run out of compartment where they are safe. Escape.

Ø  Pair CS with shock 

Leaving chamber when shock is on, they are escaping, leaving chamber when CS is on, they are avoiding. Important distinction as it has to do with a lot of aspects of anxiety disorders.

Sensitive screen for antipsychotic drugs working in people.

·        Blocks the ability to avoid shock, but not the ability to escape.

Lecture 4: 24^th July

Drugs as discriminative stimuli- A discriminative stimulus is a stimulus in the presence of which a specific response will be reinforced. For example, stop sign is a stimulus to tell you that in the presence of the stops sign, if you don’t stop you might get a ticket. Stop sign is a discriminative stimulus in the presence of which stopping is rewarded.

e.g., light will illumination, given the rodent turns counterclockwise it will be rewarded, if it turns clockwise without the light, it will be rewarded. Given the wanted behaviour is shown the rodent will be rewarded.

Drug discrimination procedure 

• Train the rat to press on a specific lever depending on what drug is on board  

• Give the rat an injection of some drug

• Depending on how that drug makes them feel it learns which lever to press 

• Rat is learning to base its responding on how whatever it has been injected with make it feel 

• Good at associating that feeling with what type of behavior it should admit, can further test this with other drugs, similar or different to the training drug. 

Can you train a rat to base its behavior on that feeling? 

Training rats to discriminate ethanol:

As ethanol increases, responding more and more with the lever for ethanol 

• Then can give other drugs that share similar chemical properties with ethanol or are different 

• In this case memantine and ketamine 

• With increasing doses of these two drugs the rats are pressing the ethanol lever, means these drugs also feel like ethanol to the rats. 

Reinforcing Properties of Drugs

Important to consider whether/not a particular drug has abuse liability- drugs used in a non-medical situation.

Response rate

·        With traditional reinforcers, the greater the reinforcement, the faster the animal will respond.

·        Drugs have different durations of action (unlike food)

·        Some drugs at some doses may interfere with the ability to respond. May increase responding due to hyperactivity, hard to tell if the increase in responding is due to drug itself being rewarding, or to the physical effects of the drug.

Progressive-ratio schedule

·        If a drug is rewarding to an animal, they should be willing to work hard for it

·        Blue tics represent level pressers

·        More effort is being required each trial (with drug presentation)

·        Thought to be an index of how rewarding a drug is.

·        Total responses, comparing sacchrine with cocaine, Earned more rewards with cocaine.

Break point- ratio at which they give up, no longer that rewarding, measure of the amount of effort the animal is willing to put forth.

Choice procedures

Ø  Mice are trained to make two different responses for two different drugs

Training animal to understand that by pressing different levers = infusion of different drugs

Conditioned place preference

Ø  Tests the extent to which the reinforcing effects of a drug will condition preference for the location in which those effects were experienced.

Pavlov study - stimuli paired with effects of particular outcome.

Ø  Occurs in people as well, taking drugs in a particular environment, (regular location) pairing effects of drugs with those stimuli around you. Stimuli in that context will take on some of the rewarding effects in the drug self. Given a choice where you would like to spend your time spend more in the place associated with the drug than where it hasn't. 

e.g., rodent trial; at the end of training spend more time in chamber associated with morphine or in the centre. Evidence that morphine is a reinforcing drug, rats prefer spending time in place that has become associated with the administration of morphine.

Human behaviour

Subjective effects; personal accounts of subjective experience on drugs

Introspection: of no value to scientists by themselves, inspire systematic research

Rating Scales

Ø  Visual analog scale (VAS) facial chart of how one may feel

Ø  Profile of mood state (POMS) 5-point scale with 72 adjectives indicator of how a drug makes a person feel at that moment.

Ø  Addiction research centre inventory (ARCI) 550 “true-false” items

Drug state discrimination

·        Given a series of exposure to drug or placebo, then tested and asked to identify which condition they are in. see how good people are at discriminating what drug they have on board.

·        No difference between nonhumans and humans in ability to discriminate drugs

Sensation & Perception

How do drugs impact sensation and perceptions?

Tests of thresholds

1)        Absolute threshold- lowest value of stimulus that can be detected by sensory organ. Below this will not be detected

2)        Difference threshold- e.g., two-point sensitivity test, used on various parts of the body to see how close the callipers have to be where a subject stops feeling two points and only feels one.

Critical frequency at fusion- flashing light will begin to look like a solid light as the frequency increases. The frequency in which this occurs. Drugs will shift when this appears to be stable/flashing.

Motor performance

Ø  Simple reaction time- person must make a response (pressing a lever) once a signal (light or noise) is given.

Ø  Complex reaction time- there are several responses and several signals e.g., pursuit rotor hand/eye co-ordination

Attention and vigilance

Ø  Mackworth clock test- watch the red target, click space bar when red circle skips a position.

Memory

·        Short-term memory (working memory) – can hold a limited amount of information whilst it is being actively used.

Ø  N-back task, shown a sequence of cards “remember and tell me stimuli 3 back”

·        Long-term memory- permanent, can last for years

Ø  Implicit (procedural) memory- memory of how to do things, often without conscious awareness. Learned how to/ingrained.

Ø  Explicit (declarative) memory- memory that involves specific pieces of information. Names, dates, facts.

·        Episodic memory: case of explicit memory where we remember things that have happened to us.

Ø  Free recall- asked to remember a list then repeat items from list.

Ø  Cues recall- asked to identify which items were in memorised list

·        Memories are transferred from short to long term memory by consolidation processes, drugs can interfere with this.

Response inhibition

·        Some drugs interfere with the ability to inhibit, or withhold responses

·        Disinhibition, loss of impulse control

Go-no go task and Go-stop task

Driving: it is important to know how drugs impact driving, can use computer driving simulators

Development and testing of psychotherapeutic drugs

Ø  Long process whereby drugs must go through numerous clinical trials and safety checks before being approved for use.

Initial screening and therapeutic testing

Ø  Pharmaceutical companies synthesize compounds they think might be effective.

Ø  Tested in nonhumans for safety and potential therapeutic benefit ED50 and LD50

Off label use

Ø  Drugs prescribed to treat conditions other than those they were license for. Might be as high as 31%.

·        Bupropion; for major depression and smoking cessation, off label for bipolar

A lot of drugs are prescribed of label (not enough money to conduct clinical trials etc.)

A lot of drug companies getting into trouble (US especially) as they can market their drugs to doctors directly. Drugs lack scientific evidence so forth.

29^th July

How do we adapt to drugs tolerance, sensitisation, and expectation

Tolerance

Ø  Decreased effectiveness of a drug that results from repeated administration

Ø  Different effects of drugs undergo tolerance at different rates

Ø  Many mechanisms likely involved intolerance to different drug effects

Acute tolerance

·        Usually talk about tolerance developing after repeated drug administrations

·        Possible for tolerance to a drug’s effects to develop in a single administration.

ascending curve indicates increase absorption of the drug. Descending curve represents metabolism and excretion of the drug.

Ø  Solid line = drug level in the blood.

On ascending part of the curve at time A, level X of the drug in the blood, drug effect almost at peak.

On ascending part of the curve still have same drug level X in blood. Dashed line representing drug effect is less on the descending portion of the curve than the ascending portion even though drug level in blood is the same in both cases. Indication of how tolerance can occur, the way the body is interacting with drug.

·        Tolerance is transient; will disappear with time if drug use is discontinued

·        use of one drug may also diminish the effects of other drugs

·        cross tolerance; usually seen between members of the same drug class. Sometimes taken as evidence that effects are due to common mechanisms.

Mechanisms of tolerance

Ø  pharmacokinetics tolerance- caused by an increase in the rate or ability of the body to metabolise the drug.

·        usually result from enzyme induction, less of the drug available at the site of action

·        with higher tolerance, more available enzymes in the body, break down the drugs easier, less of the given drug makes it past metabolic step.

Ø  pharmacodynamic tolerance – arises from adjustments made by the body to compensate for an effect of the drug. > homeostasis

Homeostasis

·        many of the bodies physiological processes are controlled by feedback loops

·        when a drug is administered, the body works to restore homeostasis

·        with repeated administration, the homeostasis mechanisms adapt more quickly

·        drug will have a smaller and smaller effect the more it is administered

·        when drug administration is discontinued, the compensatory process weakens, but can take some time before disappearing completely.

E.g., pharmacodynamic tolerance is upregulation and downregulation of neurotransmitter receptors.

- down regulation of receptors, getting rid of some receptors on post-synaptic neuron.

-upregulation, body manufactures more receptors.

Withdrawal

·        physiological changes that occur when use of a drug is stopped, or the dosage is decreased. Takes some time to reestablish homeostasis at a new level.

·        Different drugs produce different withdrawal symptoms, but drugs from the same family generally produce similar withdrawals.

·        Withdrawal can be stopped almost immediately by giving the drug (cross dependence)

·        Degree of withdrawals vary across drugs (microscopic or fatal), can occur hours after drug has been discontinued or produced in minutes if antagonist drug is administered. E.g., giving naloxone to morphine dependent humans/nonhumans.

Dependence

Historically has meant both:

·        A state in which discontinuation of a drug causes withdrawal

·        A state in which a person compulsively takes a drug

Ø  The relationship between dependence and addiction is complex

·        People can take a drug compulsively in the absence of withdrawal

·        People can have withdrawal without taking the drug compulsively

Ø  Dependence, physical dependence, and physiological dependence

·        Used to describe a state where withdrawal will occur if use of a drug is discontinued.

Opponent Process Theory

Proposed by Solomon & Corbit (1974)

Process A, which produces euphoria (high), represents disturbance in homeostasis. Body realises this starts compensatory B process.

Process B, which is compensatory, produces dysphoria.

Barret & Smith (2005)

Trained rats in a drug discrimination procedure

·        Chlordiazepoxide (CDP)- tranquilizer – anxiolytic

·        Pentylenetetrazol (PTZ) – causes tension – anxiogenic

Training them to detect the difference between anti-anxiety drug, and a pro anxiety drug. Once the discrimination was learned, tested rats with one injection of CDP then observed response overtime.

-            Further and further from the dose they feel something else such as PTZ on board

Opponent Process Theory & Withdrawal

If you take a drug continuously for weeks or months you:

·        Maintain enough of the drug in the body so that withdrawal symptoms never occur

·        The compensatory response, however, builds in strength (tolerance)

Classical Conditioning

Conditioning of drug effects:

·        Principles of classical condition pertain to drug effects as well.

·        Drug effects can be classically conditioned

-anything that consistently signals a drug is about to be taken can become a conditioned stimulus (CS). the effects triggered by CS are usually weaker than the actual drug effects.

·        Conditioned effects tend to be somewhat less in magnitude than when the drug is administered.

Classical Conditioning of Compensatory Responses

sometimes the body’s response to CS mimics drug effects but other times it does the opposite.

·        Sometimes the conditioned response to the drug is the same as the effect of the drug

·        Sometimes the conditioned response to the drug is the opposite of the drug

-            In rats, the unconditioned response to morphine is analgesia; however, when body anticipates the drug (CS) the conditioned response is hyperalgesia.

·        What is being conditioned is not the effect of the drug, but the body’s attempt to resist the effect of the drug, the compensatory response.

Classical Condition of Tolerance

·        The environment and preparations for drug administration become paired with the effects of the drug. Specific place, specific friends.

Can these stimuli be responsible for tolerance?

Siegel (1975)

Assessed whether drug-associated environmental cues could come to produce tolerance. Tested rats on the paw lick test.

4 groups:

1)        S – received saline injections before hot plate test

2)        M-HP received morphine injections in the test room before hot plate test

3)        M-CP morphine injections in the test room before cold plate test

4)        M-CAGE morphine injections in cage room before hot plate test

Results:

S = no tolerance

M-HP = tolerance

M-CP = tolerance

M-CAGE = no tolerance

Ø  Tolerance did not develop when morphine was injected outside of the testing context

Ø  The environmental stimuli in the testing context become associated with the drug

Ø  These stimuli become CSs, capable of eliciting the compensatory responses on their own.

Ø  Even though rats in group M-CAGE were exposed to the same injection schedule, tolerance did not develop because the injection occurred in a different room.

Conditioning and overdose

·        Classical conditioning of compensatory effects likely plays a role in some cases of overdose

·        Cues and stimuli associated with drug administration come to control compensatory responses. These responses get the body ready for drug administration.

·        A significant number of cases of overdose involve death after administration of a well-tolerated dose

·        One common factor in some of these deaths is that they take place in a location that is different from usual.

Siegel et al. (1982)

Tested whether conditioned tolerance (or lack thereof) could play a role in overdose

·        Injected different groups of rats with heroin or sugar in different rooms

Heroin dose was increased across days to produce tolerance to a larger dose.

3 groups

·        Control – injected with a sugar solution equally in both rooms

·        Group 1- injected with sugar in room 1 and heroin in room 2

·        Group 2- injected with sugar in room 2 and heroin in room 1

-            All rats received a large dose of heroin

Trying to see if the place the rat is getting dosed in will protect them from overdosing

(See figure)

Classical conditioning of withdrawal

-            Drugs associated stimuli become CSs

-            They elicit compensatory responses

-            In the absence of drug, these responses are withdrawal

-            Can produce relapse to drug use

O’brien (1976) (summary)

-            The body has been free of the drug for months; physiological withdrawal was not possible.

-            Conditioned withdrawal does not abate with time

-            They only way to get rid of it is for it to undergo extinction, the presentation of conditioned stimuli in the absence of drug administration.

Cue exposure therapy

Ø  Expose addicted individuals to drug cues while at the same time addressing withdrawal, craving, and anxiety that occur in their presence.

Ø  The hope is that extinction will eliminate conditioned withdrawal and craving, allowing patients to return to normal life.

Virtual reality               

-            Early treatment presented actual cues in the clinic

-            Patients had trouble maintaining abstinence when they returned back to their original environments.

-            More recently, clinicians have been using VR to present more realistic cues and environments.

Ø  So far results are promising, the combined use of traditional therapy and VR treatment better at maintaining abstinence than just those that undergo traditional therapy.

Lecture (30^th)

Rewiring drug memory- contemporary knowledge about memory processes is leading to potential treatment breakthroughs.

*If you recall a memory back to an active state, it is then fluid and can be manipulated.

Xue et al. (2012)

Took advantage of the labile nature of recalled memories and tested treatment efficacy in both rats and humans. Wanted to test treatment efficacy using this idea.

Exposed to condition placed preference (CPP) baseline test 

• Give rat a choice between going into two different places. Then inject them with morphine in one of the places. 

• Thought that euphoric experience that morphine produces gets associated with the place they receive the morphine in. 

• When given a choice between the two locations they will choose to go the place where they had morphine. 

- only way you can get rid of drug associated memories is by extinguishing them (presenting stimuli without drug reward). 

Sequence of events:

Conditioned place preference baseline -> Morphine CPP training -> Placed preference test 

Clinical Relevance

Does it work in patients? Reactivating drug associated memories before extinction therapy results in much more effective and long-lasting treatment gains.

-            Suggests what is done in treatment paradigm has fundamentally changed the nature of the association, memory. Can recall it into an active state and then get rid of it.

Operant Conditioning and Drug Effects

·        For a long time, it was thought that drug effects were independent of the environment and depended only on physiological changes.

·        It is now clear that the type of behaviour that is occurring when the drug is taken has a big impact on the drug’s effect.

Campbell and Seiden (1973)

Ø  Trained rats to press a lever for food on a differential reinforcement of low rate (DRL) schedule.

-            Rewards lever presses that occur after a specified amount of time (18 seconds), penalised responses that occurred before that time.

Ø  Chronically administered amphetamine for 28 days

Two groups:

-            Group 1: dosed before experimental session

-            Group 2: dosed after experimental session

Both groups then dosed with pre-session amphetamine and tested on the DRL.

Group 1: Bio model distribution where rats will make a certain proportion of responses with brief latency. Nice distribution centred over the value of the DRL that they learn. By the end of training are doing pretty well on schedule.

Group 2: amphetamine never did anything to their ability to earn rewards in the test environment, didn't become tolerant to those effects so when they got the drug before the session their behaviour fell apart. Had not learnt how to change behaviour in the presence of amphetamine.

Wolgin (2000) reviewed the work on amphetamine hypophagia

-            Rats given amphetamine don’t consume available foods

-            Wolgin showed that this was due to hyperactivity that interferes with consummatory behaviour.

Lots of research indicates that if the primary effect of a drug interferes with an organism’s ability to obtain rewards, tolerance will develop to those effects. Doesn’t have anything to do with the physiological effects of the drug.

-            physiological effects for the two groups in Campbell & Seiden (1973) were the same. Wolgin’s rats only showed tolerance when the amphetamine interfered with their consumption.

Sensitisation

Most of the time a drug is given, tolerance develops. In some cases, the effect of a drug can increase with repeated administration (sensitisation).

 Benedetti et al. (1995) mechanisms involved in placebo effect.

-            Tested the effects of a pain killer (proglumide) and placebo on post-operative pain

-            Gave patients injections of either proglumide or placebo (saline)

-            Patient groups differed in their awareness of the treatment they had received.

-            Even if you give somebody a pain killer, if they don’t expect to have the effect of the drug, this data shows there is no effect on this pain.

Mechanisms

·        Little is known about specific mechanisms that underlie the placebo effect

·        What is clear is the expectation of a drug effect can significantly alter the experienced effect of drugs.

·        The most important factor in the placebo effect is the strength of the expectation

·        Placebo drugs can even generate side effects based on the expectation of the patient (nocebo effect).

The case of Eltroxin

-            Thyroid medication used to treat hypothyroidism

-            In 2007 drugmaker GlaxoSmithKline moved their manufacturing process from Canada to Germany and altered some of the drugs inert qualities (size. Colour, markings).

-            Reports of adverse reactions associated with the drug rose

What was going on?

-            Media began to directly attribute adverse effects to the drug change

-            Areas of the country that had more media coverage reported more adverse incidents

-            Incidents were real, but in most cases had nothing to the with the properties or drug

Monday 5^th August- Neurophysiology, neurotransmitters, and the nervous system

The Nervous System

-            All behaviour is under control of the nervous system

-            Effects of behaviourally active drugs can be traced to direct or indirect effects on this system

Consists of two types of cells glia and neurons

Ø  Neurons are the information transmitting cells

-            Excitable, receive sensory information from the outside world, storing transmitting that information and controlling the function of muscles and glands.

Ø  Glia are the support cells, are also protective and supply neurons with energy. Active communicators with neurons via chemical transmission.

How does the nervous system communicate?

-            Electrical activity

-            First discovered by Luigi Galvani where he experimented on “animal electricity” which paved the way for techniques of electrophysiology. From there electrical properties of neurons were uncovered.

Luigi Galvani

-            Had copper wore attached to nerves in spinal cord of frog, when he touched the wire to nerves in the legs it would cause the legs to move. This was a result of the generation of an electrical impulse.

How are electrical signals generated?

Resting potential

Action potential

Ø  Hyperpolarization- when the charge becomes even more negative

Ø  Depolarization- when the charge becomes less negative

If the neuron is depolarised to around -55mV (threshold), the delicate balance that maintains the resting potential breaks down.

neuronal spike, graph showed what it looks like when measuring electrical properties of a neuron. Step (1-6)

at resting potential neurons (-70mV)

(-55mV) action potential is triggered.

refractory- resistance or stubborn

Conduction of action potentials along the cell

Action potential is generated at the axon hillock and travels down the cell. Successive portions of the cell are depolarised and generate their own action potential at the Nodes of Ranvier. Action potentials are non-decremental they reach the axon terminal with the same strength as which they were initiated near the axon hillock.

Action potentials are always the same, they do not vary in strength with the strength of the depolarizing stimulus. Information about stimuli is transmitted by changed in the rate of action potential firing.

Rate law

weak stimulus = lower rate of firing

strong stimulus = higher rate of firing

weak stimulus is more uneven, slower and spread out. Whereas strong stimulus will push system to limits of what it can do. Firing as fast as possible, as fast as the system can reset and generate another action potential.

Stimulation of the dendrites and cell body

·        Action potentials can only be generated at the axon hillock

-            All or none- always the same

-            Only contains voltage-gated channels

·        The dendrites and cell body contain many other proteins and enzymes that modulate cell excitability

-            Allows for modulation by a number of factors

·        Unlike the all-or-none action potential, disturbance of the resting potential of dendrites and cell bodies has variable effects.

Post-Synaptic Potentials (PSPs) (have an effect after the synapse of cell producing signal)

Excitation- open voltage gated Na+ channels

-Depolarisation (less negative)

-Excitatory post-synaptic potential (EPSP)

-increases potential in cell, making it closer to firing an action potential

Inhibition – opens voltage gated K+ channels

-Hyperpolarisation post synaptic potential (IPSP)

-More difficult to fire action potentials

At any given moment in time the neuron is receiving input from both excitatory & inhibitory, if sum of total input from excitatory is bigger than inhibitory than cells will fire.

PSPs (many thousands at a time) are integrated by neurons to determine the rate at which action potentials are generated

-            Two types of integration include (temporal summation & spatial summation)

Temporal summation- a certain number of signals come in, in small enough time window. Two IPSPs elicited in rapid succession sum to produce larger ISPS.

Spatial summation- stimuli appear at the same time, but in different areas

What causes neurons to be depolarised and fire action potentials?

Sensory Neurons- take in information about the external world, communicate to brain

-            Skin (pressure, head, cold, pain)

-            Ears (vibration)

-            Muscles (movement)

-            Nose (odours)

-            Tongue (tastes)

-            Eyes (light, motion, colour)

These stimuli produce signals in our brain to produce action potentials, to transmit information in efficient and rapid way, to behave adaptably.

How doe neurons communicate with one another?

Ø  There is no direct way for an action potential in one neuron to directly depolarise the membrane potential of another neuron. Not connected.

Ø  Communication takes place at the synapse between adjacent neurons

Types of Receptors

have one of these receptors. When neurotransmitter is not docked with receptor, channel is closed, ions can’t travel from extracellular space into the cell.

When neurotransmitter docks with receptor, ion channel opens.

Opens up channel allows ion to come in.

Has a receptor for a neurotransmitter, also connected to G protein (chemical messenger).

-not a channel

When receptor is activated G protein breaks off, goes elsewhere in cell to signal biochemical processes.

When metabotropic receptor gets activated, it starts a chain reaction, producing other biochemical processes in the cell.

Signalling cascades- A series of chemical reactions that occur within a cell when initiated by stimulus (G protein).

Ø  Metabotropic receptors tend to control signalling cascades that can lead to long lasting, sometimes permanent changes in cell function and structure.

Presynaptic effects of neurotransmitters

Ø  Auto receptors

-            Contains a binding site for neurotransmitters

-            Regulate the amount of neurotransmitter released from presynaptic neuron 

Ø  Heteroreceptors

-            Like auto receptors, but respond to chemicals released by the post-synaptic cell

-            Regulate the amount of neurotransmitter released from presynaptic neuron

Terminating the signal ­– two main ways signal gets terminated

Ø  Reuptake- cell takes neurotransmitter back into presynaptic neuron for repacking and retransmission. Most common method done by proteins ‘transporters’

Ø  Deactivation- synapse may contain an enzyme which breaks down the neurotransmitter. Parts may be taken back into the presynaptic cell for remanufacturing

The Nervous System

-            Two main divisions:

Ø  CNS is the brain and spinal cord, cell bodies called nuclei (grey matter), axons called tracts (white matter).

Ø  PNS is everything outside the brain and spinal cord; cell bodies called ganglia; axons called nerved.  (somatic, autonomic, parasympathetic, sympathetic)

Somatic nervous system is made up of all the sensory nerves from conscious sense. Allows us to interact with our environment (sensory as well as motor). Uses acetylcholine as its primary neurotransmitter.

Autonomic nervous system sensory systems we are not fully aware of (blood pressure, functioning of organs, levels of hormones). Parasympathetic & sympathetic systems.

Ø  Parasympathetic is in charge most of the time, rest and digest system. Keeps the internal functioning of the body running smoothy. uses acetylcholine

Ø  Sympathetic connected to the same organs as parasympathetic division, and in times of danger it takes over to help the body prepare for a sudden expenditure of energy. (fight or flight response) uses adrenaline.

Spinal cord serves as a relay station between sensory and motor neurons in the brain. Transmits sensory signals to the brain, and motors signals from the brain to the muscles.

7^th July

The Brain- estimated to contain 100 billion neurons

-            Each neuron synapses onto 1000 other neurons

-            Each neuron receives an average of 10,000 synapses

Hindbrain

Medulla oblongata- involved in proper functioning of the autonomic nervous system. Keeping systems that body needs to maintain normal functioning online.

Respiratory centre- depressed by several types of drugs (barbiturates, opioids, alcohol) death by overdose and brain damage are caused by depression of this centre. If this gets depressed for a long time can have extensive brain damage.

Pons- relay motor information from the cortex to the cerebellum (movement, balance, orientation).

Locus coeruleus- contains majority of norepinephrine neurons in the brain. Projects to higher cortical areas through the medial forebrain bundle. Associated with depression.

Cerebellum- “little brain” functions primarily as a component of the motor system.

-            Damage impacts co-ordination, memory, and fine muscle movements

-            Plays a role in certain cognitive tasks and possibly some diseases

-            Alcohol impacts this structure

Midbrain

Reticular formation-

Ø  Descending reticular formation- projects axons down through spinal cord & is involved in autonomic responses (breathing & heart rate, swallowing, coughing)

Ø  Ascending reticular formation- controls level of arousal, selective attention, and wakefulness.

Ø  Raphe nuclei- important source of serotonin in the brain. If a particular drug targets raphe nuclei, will do something with serotonin in the brain.

Periaqueductal Gray (PAG)- pain sensation and defensive behaviour. Stimulation of PAG produces and immediate reduction in pain (opioid receptors, analgesia). Received input from amygdala. ­analgesia

substantia nigra- sends dopamine projections to the basal ganglia (involved in motor behaviour). Deterioration of this pathway associated with Parkinson’s disease.

Ventral tegmental area (VTA)- sends dopamine projections to limbic and cortical areas and is involved in reward circuits for natural rewards and drugs.

Forebrain

Basal ganglia- involved in voluntary movement, action selection, motor behaviour and habits, eye movements. Participates in activity “loops” with thalamus and cortex.

-            A subdivision, the nucleus accumbens, is part of the reward pathway.

Limbic system- large network of interconnected nuclei

-            Hippocampus; learning and memory, spatial learning

-            Amygdala; processing of emotions

Thalamus- relays sensory information to cortex. All information from body senses (except smell) gets processed in thalamus prior to cortex. Interacts with reticular formation to regulate arousal.

Hypothalamus- primary recipient of limbic input. Maintains homeostasis.

-            Controls metabolism, hormonal balance, circadian rhythms, instinctual behaviour, and emotions.

Cortex- integrates information from other brain areas & decides on appropriate behaviour

Controls behaviour by sending outputs to motor neurons. Is responsible for higher order cognitive process. (PFC heavily impacted by alcohol as impacts judgement & impulsivity)

Drug effects during development

Nervous system development is extremely susceptible to drug effects. With many drugs resulting in developmental dysfunction

-            Teratogens

-            Deformed babies – thalidomide, given as anti-nausea during pregnancy

-            Brain malformation and severe mental retardation – FAS; fetal alcohol syndrome

Neurotransmitters

To be considered a neurotransmitter a substance has to:

1)        Be synthesised within the neuron by coexisting enzymes

2)        Be released in response to cell depolarization

3)        Bind to receptors to alter the functioning of the post-synaptic cell

4)        Be removed or deactivated from within the synaptic cleft

Can hyperpolarize cells (IPSP) or depolarize cells (EPSP), depending on the type of receptors they bind to.

Drugs and neurotransmitters

·        Drugs can impact the process of neurotransmission at any one of these steps

·        Agonistic effects: drug effects that facilitate the action of a specific neurotransmitter

·        Antagonistic effects: drug effects that impede the action of a specific neurotransmitter

Acetylcholine

First neurotransmitter to be discovered, synthesised by combining acetate and choline/choline acetyltransferase.

-            Degraded by acetylcholinesterase

-            Major cholinergic neurons are in the basal forebrain

-            Originally thought to the involved in arousal, but actually plays a crucial role in cognition

In PNS is involved in automatic nervous system.

Work via two types of receptors: Nicotine – ion channels & Muscarinic – g – protein coupled

Monoamines

Synthesised from one amino acid

-            Broken down by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)

-            Catecholamines all synthesised from the precursor tyrosine (dopamine, norepinephrine, epinephrine).

Dopamine (DA)

Synthesis steps:

-            Tyrosine is converted into dihydroxphenylalanine (DOPA) by tyrosine hydroxylase

-            DOPA is converted to DA by DOPA decarboxylase

·        Involved in numerous psychological processes (e.g., learning & memory)

·        The mesolimbic tract is implicated in drug abuse and addiction, and diseases such as schizophrenia

Norepinephrine (NE)

Synthesised from DA by dopamine-beta-hydroxylase. Plays a role in attention, sleep, wakefulness, feeding behaviours, and emotions.

Serotonin (5-HT)

Synthesis steps:

-            Tryptophan is converted to 5-hydroxytrytophan by tryptophan hydroxylase

-            5- hydroxytryptophan converted to 5-HT by aromatic amino acid decarboxylase

Drugs used to treat depression target the reuptake of 5-HT

Amino acid transmitters

Ø  Glutamate is the major excitatory neurotransmitter in the brain

-            Synthesised from glutamine by glutaminase

·        Widespread projections throughout the brain

·        Binds to a number of metabotropic and ionotropic receptors

·        Actions at NMDA receptors thought to be critical for learning and memory

Ø  Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain

-            Synthesised from glutamate by glutamic acid decarboxylase (GAD) also requires vitamin B6.

·        Broken down by GABA aminotransferase.

Other neurotransmitters

Adenosine

Endocannabinoids

MONDAY 12^th August

Peptides- more than 100 have been identified that act as neurotransmitters, neuromodulators, and neurohormones.

Five general categories:

-            Brain-gut peptides

-            Pituitary peptides

-            Hypothalamic peptides

-            Opioid peptides

-            Miscellaneous peptides

Brain imaging techniques (PET, SPECT, MRI, fMRI)

PET

Advantages:

-            Allows researchers to directly measure the brain distribution of various drugs

-            Can measure local concentrations of receptor sites, determined by giving tiny doses of radiotracers that contain pharmacologically inactive amounts of drug

-            Can be used to assess competition for binding sites

-            Can be used to isolate areas of the brain that are active during a mental activity, such as drug craving

-            When used with lab animals, can help in preclinical assessment on newly developed drugs.

Problems:

-            Low degree of resolution compared to other methods (difficult to distinguish between small structures of the brain)

-            Expensive

-            Because radioisotopes (tracers) decay quickly, they must be made on site (need a cyclotron, more $$$)

Single photon emission compute tomography

-            Similar to PET

-            Uses radioisotopes that have much longer half-lives, meaning they last longer

Can measure more long-lasting brain functions, cheaper

Problems:

-            Technically challenging (more prone to error)

-            Even poorer resolution than PET

Magnetic resonance imaging

Medical imaging device commonly used to examine soft tissue of human body

-            Key components; magnetic, radio waves, gradient, computer

-            Machine focuses on low energy water molecules to create an image of the brain

fMRI

functional MRI shows which areas of the brain are active whilst performing a specific task

-            Lots of images of the brain are taken very quickly, creating a map of brain activity

advantages

-            Very high resolution (can differentiate structure, small structural abnormalities)

-            Safe-does not require injection or radioisotopes

Problems

-            Expensive

-            People feel highly anxious inside the magnet, need to hold still in order to not mess up the image.

-            No metal can be present - including in the body

-            Changes in BOLD signals can result from daydreaming, boredom, or thinking about something outside of the experiment.

-            Lag times between signals and task events make it difficult to correlate events with brain signals. Is the signal that you are seeing related to the process of interest

-            Results are highly subject to distortion by data analytic techniques

Neuromarketing

Ø  People who want to make money of consumers have leveraged techniques, how to make consumer want to buy their products.

Ø  Is the measure of physiological and neural signals to gain insight into customers.

Alcohol

Describes a wide range of substances, only a few of which are consumed.

Ø  Isopropyl (rubbing alcohol) don’t drink!

Ø  Methanol (wood alcohol) don’t drink!

Ø  Ethanol (drinking alcohol)

Fermentation

Ø  Is a way of making alcohol, it is the combination of sugar and yeast = fermentation leading to (alcohol & co2)

Ø  Generally speaking, fermentation leads to about 10-15% alcohol

Distillation- the process of separating the components of a liquid’s mixture through selective evaporation and condensation. (40-50%)

Origin and History of Alcohol

-            Alcohol has likely been associated throughout evolutionary with food and nourishment

-            Found as early as 9000 years ago in China

-            Earliest law codes contain laws for regulating fair commerce of alcohol

-            Egyptians, Greeks, Romans, all drank moderately. Later Rome descended into insobriety; drunkenness increased.

-            British Isles has a long tradition of drinking. Mostly mead, ale, and cider as grapes don’t grow well in climate

-            Distilled alcohol became popular in 1600s (whiskey)

Gin Epidemic- period in first half of 18^th century when consumption of gin increased rapidly in Great Britain. Along with this came increase in drunkenness and social disorder.

Unite States

-            Colonists brought their inclinations for strong drink with them from England

-            Harvard University has a brewery, drafted rules to avoids “excesses, immoralities, and disorders” at commencement (graduation ceremonies)

-            Workmen received part of their wages in rum, and employers would set aside certain days for total inebriety.

-            Alcohol apart of US culture from way back

Temperance Movement

-            After the American Revolution, alcohol consumption increased until the Temperance Movement in the 1800s.

-            Urged moderation, then encouraged drinkers to help other resist temptation, demanded local, state, and national government to prohibit alcohol outright.

-            The temperance movement gained political traction

Prohibition (1917-1933) passed at 18^th amendment; to prohibit alcohol in US, no longer legal

Ø  Black marketing of alcohol and escalation of criminal activity

Repeal in 1933 to revoke or withdraw alcohol prohibition

Neuropharmacology

-            Alcohol in the body is complex and involves a number of different systems

-            Alcohol intoxication occurs at concentration 1,000 to 1,000,000 times greater than other drugs.

-            Stimulates multiple pathways at once. Alcohol at a high concentration is interacting with different systems, before feeling intoxicated.

-            Most effects are mediated through GABA and glutamate. Effects other transmitters as well.

GABA

 receptors in brain are responsible for maintaining a constant inhibitory tone (across the brain when  receptors are active, the brain areas are inhibited, at a reduced level of functioning. When brain areas need to be used the inhibition is released).

Ethanol binds and increases the inhibitory action of GABA.

-        Alcohol sensitive  receptors are located in cerebellum. The action of alcohol here is responsible for many of the motor impairments associated with intoxication.

Glutamate

-            Alcohol binds to NMDA receptors and blocks the ion channel

Ø  Alcohol on one hand is increasing the inhibitory action of GABA and blocking the excitatory activity of glutamate. The effects of alcohol on GABA and glutamate converge.

Ø  Alcohol stimulates GABA receptors, which inhibit neural activity

-            Alcohol also blocks normal functioning of glutamate (NMDA) receptors, which also inhibits neural activity.

-            Together, these effects throw off the delicate GABA/glutamate balance that is necessary for normal functioning of the CNS. Dysfunction of CNS.

-            Prolonged blockage od NMDA receptors leads to compensatory upregulation. May be involved in alcohol withdrawal symptoms. Excitatory activity all over the brain causes seizures, generalised excitation all across the brain.

Dopamine

Alcohol impacts dopamine produces some reinforcing effects through increasing dopamine activity in the mesolimbic dopamine system. Causes the brains reward system to release the motivational chemical dopamine.

 Ethanol stimulates dopamine release in the NAC, and it is suggested that this neurochemical event is involved in the initiation of alcohol reinforcement. the disinhibition of GABAergic neurons appears to be one major contributory mechanism. End goal: more dopamine in NAC (nucleus accumbens).

Effects of alcohol on human behaviour and performance

BAC level (blood level alcohol) the amount of alcohol in blood from drinking:

-            50-100 = become more talkative; use a higher pitched voice; mild excitement

-            100-150 = more talkative and cheerful; often loud, boisterous, later sleep

-            >150 = nausea, lethargy, stupor

-            200-290 = loss of understanding, memory blackout, unconsciousness

Blackouts

Heaving drinking may cause periods of amnesia for events that occurred during intoxication

Two types:

Ø  Gray out- drinker remembers only bits and pieces of events that occurred while drinking. Can recall if prompted or if they return to the location of the event. Indicates that problem is with retrieval, memories are stored intact but unable to be accessed without being prompted, or with cues.

Ø  Blackout (En bloc)– drinker remembers nothing that occurred during a drinking episode. Memories are stored, but never return. Behaviour may appear to be quite normal during blackout period.

Effects of alcohol on driving:

Alcohol produces severe deficits in processes involved in driving. These effects are likely mediated by decreases in cortical activation. Cortex involved in executive function, attention, decision-making etc.

Age and risk of accident data from NZ, risk of accident increases with both increasing blood alcohol concentration as a function of age also.

Withdrawal- complex and varies across individuals.

Stage 1- 6 to 8 hours after last drink

-            Causes increased blood pressure, and pulse as well as fever

-            Exaggerated startle; headache; nausea; restlessness; easily distracted

Stage 2 – 24 to 72 hours after last drink

-            Worsening symptoms of stage 1

-            Hallucinations (visual, auditory, tactile)

Stage 3- within first 48 hours after last drink

-            Seizures (short duration tonic/clonic seizures)

Stage 4- 48 hrs to 14 days after last drink

-            Delirium tremens; Delirium, paranoid delusions

-            5% mortality rate

Harmful effects of an acute administration

Ø  Alcohol poisoning

-            300-400 BAC will cause loss of consciousness

-            500 BAC usually results in death within a couple hours, Death generally is caused by respiratory failure.

Harmful effects of chronic consumption (watch video)

Ø  Cirrhosis of the liver (scarring of the liver caused by long-term liver damage)

Ø  Cancer; proven to increase risk of 8 types of cancer, causal.

Ø  Reproductive effects in both males and females

Ø  Foetal alcohol syndrome (FAS)

Ø  Heart disease

Ø  CNS disease

-            Wernicke-Korsakoff psychosis is the loss of memory or inability to remember new things

-            Epilepsy

-            Cerebellar syndrome is inco-ordination of voluntary movements

-            Alcoholic dementia

-            Major brain atrophy which is the over activity of glutamate system (too much excitatory activity is toxic to neurons)

Benefits of alcohol consumption (not any)

-            Moderate alcohol consumption has health benefits j-shaped curve for mortality from a number of conditions and alcohol use. Analysis is correlation in nature, correlation is not causation!

-            Unclear whether alcohol is causal in health benefits or what lifestyles benefit most from drinking

Risk threshold for alcohol consumption, interested in how the level of drinking is associated with various risks for adverse outcomes. Meta-analysis of data from 83 studies. Calculated risk as a function of grams of alcohol consumed per week, separated risk for all mortality from CVD.

How do we reduce harm?

Ø  Increase the price of alcohol (tax alcohol by content, and alcohol discounts “happy hour”

Ø  Restrict availability of alcohol (removal from supermarkets, limit hours that bars and pubs are open, limit deals/promotions)

Ø  Treat it like a health issue (treat dependence of alcohol as a health issue, prioritise government funding for programs)

Ø  Stop people binge drinking (requires concerted effort from many groups and is difficult as alcohol is a huge source of revenue).

Wednesday 14^th Lecture

Cocaine

Cocaine and Psychomotor stimulants

All stimulants stimulate transmission of monoamines

-            Epinephrine

-            Norepinephrine

-            Dopamine

-            Serotonin

Sympathomimetic

Ø  Mimic sympathetic arousal

-            Epinephrine is the primary transmitter in the sympathetic nervous system

Source and History

Some stimulants are naturally occurring (have been used for centuries), others are new synthetic drugs.

Amphetamines

Synthetic meaning they do not occur naturally, two types: amphetamine & methamphetamine

Used to treat ADHD, narcolepsy, and obesity. Methamphetamine can be synthesized for legally available materials (sold as crystal meth, ice, crystal)

Ephedrine (found in the herb ma huang) has been used in China for more than 5,000 years. Was isolated from the herb in 1880. Properties investigated in 1924 by Ko Kuei Chen and C.F. Schmidt. Found the structure and action was very similar to ephedrine.

More stable than epinephrine (then used to treat asthma)

-            Could be administered in pill form and had a longer duration of action, less toxic

Ø  Use became so widespread that supplies were feared to run out

Search for synthetic substitute had already been discovered by L.Edeleano for epinephrine he has synthesised amphetamine in 1887. Remained untested until 1910, suggested a substitute for ephedrine in 1927.

-            In 1937, the American Medical Association authorised use of amphetamine for treatment of narcolepsy and as a stimulate for depression

-            By 1943, at least half of the sales were prescribed for weight loss and diet control, antidepressants and stimulant effects, and extended periods of alertness.

-            Today many countries strictly regulate the manufacture and marketing of amphetamines generally prescribed nowadays only for ADHD and narcolepsy.

-            Not widely used for medicinal purposes today, most amphetamine & methamphetamine are made in illicit labs.

Cocaine

Extracted from the leaves of the coca bush, native to South America, for centuries these leaves have been chewed by various South American tribes.

Incas began using the plant when they conquered the region in the tenth century. Coca was sacred and used by priests and nobility. Also used in ritual human sacrifice.

When the Spanish conquered the Incas, they first banned coca use.

-            Picked up on it after they found it useful in commerce

-            Also found they could work slaves for longer and harder and needed to feed them less if on coca.

Ø  Postosi silver mine; some 8 million Incan and African slaves died during the Spanish colonial period.

-            Cocaine itself was classified in 1749

-            Europeans had no interest in the drug until it was isolated (didn’t want to chew it)

-            Albert Neimann isolated and named cocaine in 1860

-            Used by professionals and intellectuals (Freud, Robert Louis Stephson, Sherlock Holmes)

-            Sigmund Freud proposed cocaine as a cure for many conditions (addiction and depression). His colleague, Karl Koller found it useful as an anaesthetic (numbing properties)

-            Cocaine became widely available in general purpose formulations (cocaine toothache drops, said to be good for scalp, soothing syrup for babies, nervine tablets, in wine).

-            1886 John S. Pemberton made a drink out of the kola nut extract, added soda water and called it coca cola, to this day coca cola is made from coco leaves.

-            Early 20^th century, there was growing backlash against cocaine, Harrison Narcotic Act of 1914 banning its use.

-            Cocaine began being used underground by artists, musicians, wealthy upper class

-            After WW2, the idea of stimulants was common, cocaine use spread and increased

Ø  Cocaine use has gone down in recent years, appears to be creeping up in NZ.

Neurophysiology of Cocaine

All stimulants have a common effect on synapses that use the monoamine transmitters.

-            They achieve this affect in different ways:

Ø  reuptake inhibition (neurons clear out transmitter from the synapse so it isn’t active anymore)

Ø  substrate-type release (in a normal neuron have a neurotransmitter that is released, it gets taken back up into the synapse by monoamine transporters) when you have a transporter blockade, drug blocks the transporter, so the neurotransmitter is in the synapse longer and is more active. Creates increased neurotransmission.

-            Amphetamine re-engineer’s transporters to go the opposite way. Pumping neurotransmitters out.

Different stimulants have different affinity for different types of MATs

·        Cocaine- NETs, DATs, and SERTs

·        Amphetamine – NETs > DATs > SERTs

Cocaine blocks SERTS in the same way as antidepressants but does not alleviate depression. Reason for this is unknown!

Stimulants effects on the body

-            Increase heart rate and blood pressure, and vasodilation

-            Increase bronchodilation (making breathing easier, by relaxing muscles and opening up airways), reason why amphetamines were developed in the first place

-            Reduced appetite and food consumption, mostly stimulating other incompatible behaviours (why sometimes used in obesity). However important to note missed food consumption is made up for by excessive food consumption later in lab demonstrations.

Effects on sleep

·        Produce insomnia (used widespread during WW2 and in 1950s)

·        Amphetamine, methylphenidate, and modafinil are used to treat narcolepsy

Effects on behaviour of humans

·        Subjective effects: intense “rush” or “high” often described as being sexual in nature

-            Feelings of well-being, happiness, being talkative and friendly

·        Stereotyped behaviour: “Punding” repeated useless activities for extended period of time.

·        Psychosis- at higher doses and after repeated use, stimulants produce behaviour that is indistinguishable from paranoid schizophrenia (hallucination’s “bugs crawling under skin”, delusions and paranoia, hostility and aggression)

-            Can occur in individuals with no history of psychosis

·        Violent behaviour: caused by changes in users’ personality, which become hostile, paranoid, and defensive.

*The drug itself do nor produce aggression, but paranoia may cause someone to lash out.

·        Sensory effects: increase in visual and auditory perception, passage of time is overestimated.

Effects on performance

In low doses stimulants improve performance on a number of tasks and skill

-            Improves reaction time

-            May improve short term memory

-            Improves vigilance and attention- however may impair divided attention

-            Overcome fatigue

Ø  In higher doses, produces performance deficits in tasks that require flexibility and the ability to adopt new strategies.

Used to treat ADHD, (Ritalin and Adderall are the most commonly prescribed stimulants)

-            Rate of diagnosis for ADHD from 1995-2015 shows an increasing trend overtime with biggest increase from age 10-14 years. is higher in boys/men than girls/women.

Effects on driving

-            People under amphetamine are 2.3 times more likely to be killed in automobile accidents likely due to a narrowing of attentional focus.

Athletic performance                                                                                                                            

-            Improve athletic performance, therefore banned by most national sport federations.

-            Urine is screened for stimulants (certain cold medications can cause positive result)

.

14^th August Part 2

Withdrawal

Stimulants are not associated with a medically serious withdrawal

Depression may be quite severe when withdrawal sets in, may last for months

Withdrawal also associated with performance decrements

Self-administration in humans

Cocaine; long history of use with oral consumption

-            Pure cocaine is usually administered in binges, separated by abstinence

-            Often mixed with other drugs (heroin- speedball, benzodiazepines, ketamine, or PCP)

Amphetamines; also, self-administered in run-abstinence cycles

When used to get high, often taken continuously for days a time until the user is exhausted or runs out of drugs.

-            Don’t eat, sleep, psychosis symptoms

-            Running out causes a crash, sleeping for long periods of time

-            Upon awakening, eat ravenously before searching for more drugs

Harmful effects

Ø  Cocaine is costly, affects many parts of the body when consumed chronically

Ø  Amphetamine much more harmful to the body, adverse effects.

Indirect effects

-            Hepatitis, HIV and AIDs from sharing needles

-            Death rate among amphetamine and cocaine users in 6x higher than general population

Reproduction

Both amphetamine and cocaine have been reported to enhance sexual desire and pleasure (prolonged use leads to a decrease in sex drive and disruption of sexual activity in males)

Not clear whether cocaine or amphetamine during pregnancy causes birth defects (it is clear that prenatal cocaine exposure leads to more behavioural problems in children).

Overdose

Cocaine “sudden death” syndrome

Two phases:

-            Initial excitement followed by severe headache, nausea, vomiting, and severe convulsions.

-            Loss of consciousness, cardiac arrest, respiratory depression, death

-            Can occur in as little as 2-3 min, as long as 30

Lab animals will self-administer lethal doses of cocaine. There is considerable variability in the sensitivity to the euphoric vs. cardiovascular effects of cocaine in lab animals. (drug high, but also has stimulant effects that effect cardiovascular system) If there is variability in humans as well, this could contribute to “sudden death” syndrome.

Cocaine in NZ.

-            Cocaine not commonly use, amphetamine is more commonly used

Monday 19^th August Opiates

Opiate[1]- originally, was any medicine containing opium, typically used to relieve pain or encourage sleep. More recently has come to mean any natural drug extracted from opium plant, heroin, morphine and codeine.

Opioids

Synthetic narcotic drug with physiological effects. Also called narcotics, which causes sleep and produces analgesia.

-            The term narcotics has come to be synonymous with drug addiction and law enforcement. Opiate or opioid is preferred.

Opium

·        Natural source is Papaver somniferum

·        Originally from Asia, but now cultivated in similar climates all over the world.

·        Active ingredients are morphine and codeine thebaine is present in much lower quantities.

·        Has been used as a painkiller for thousands of years

Harvesting Opium

·        Poppy plants produce opium for 10 days in its life cycle

·        Opium is the sap that seeps out of seedpod after the petals fall off

·        Pods are scores, then sap is allowed to dry, is gathered and formed into cakes

Other Opioids

Naturally occurring opium from poppy plants can be used to synthesise other opioids. Thebaine is used to make other opioids

-            Oxycodone- Percocet, Percodan

OxyContin is a slow-release formulation, but can be crushed and injected

-            Buprenorphine

-            Nalorphine

-            Naloxone

-            Hydrocodone - Vicodin

Synthetic Opioids

·        Drugs that do not resemble morphine but have similar pharmacological and behavioural profiles.

-            Meperidine (Demerol)

-            Methadone – used as a heroin maintenance drug to keep someone off heroin without bad withdrawals.

-            Fentanyl: problem is that it is cheaper more efficient to make. Cutting different types of drugs with fentanyl is done to stretch the supply.

Designer drugs “China white” are synthesised based on fentanyl

History of Opioids!

Routes of Administration

Opioids are given orally as analgesics (pain killers), but this route is not used when they are taken for euphoric effects.

·        Morphine is not lipid soluble, under-goes significant first-pass metabolism (gets rid of a significant amount of drug).

·        Heroin is morphine but more lipid soluble; becomes morphine in the brain

Using these drugs for euphoric effects is done by injection or smoked. but can be snuffed or vaporised and inhaled “chasing the dragon”

As morphine is not lipids soluble meaning it does not get into the brain quickly people may heroin as it is morphine but made more lipid soluble. When it goes to the brain it turns into morphine. But is more potent since it can get into the brain easier.

Neurophysiology

Brain has receptors for opioids! Identified in 1973 by Candice Pert, & Solomon Snyder

Brains of most vertebrates have opioid receptors. Brain has endogenous opioids that it used to regulate various processes (endorphins, enkephalins).

Opioids Receptors

There are three types:

1.        Mu

2.        Kappa

3.        Delta

These are G-protein coupled receptors which can initiate long term signalling cascades, more far-reaching effects on some cellular properties.

One Mechanism of Opioid Action:

When an opioid binds to an opioid receptor in the membrane of a neuron.

1)        Calcium channels close, blocking positively charged calcium ions from entering the cell

2)        In addition, cAMP levels decrease and potassium channels open

3)        Allowing positive potassium ions to exit the cell. These events hyperpolarise the cell, increasing the charge difference between the cell’s interior and extracellular environment making the neuron less likely to fire an action potential. Quieting neurons along pain pathways with opioids dampens the transmission of pain signals and results in analgesia. However, for chronic pain opioids are not super helpful

Opioid Action

Why do different opioids have different effects?

All opioids have the same effects on cells, but the overall effects depend on the affinity for each receptor type and the cell type and regional distribution of the receptors. (all receptor’s subtypes have distinct expression profiles).

Most effects of opioids that we know of are mediated by the mu receptor. Different opioids bind with different affinities. In general, the opioids with less affinity produce the strongest effects.

Opioid Receptors in the Body:

·        Brain: Opioids bind to receptors in parts of brain including cerebellum, nucleus accumbens, and hypothalamus. Regions involved in pain perception, emotion, reward, and addiction.

·        Brain stem:  Opioid receptors are found in the brainstem, also where respiratory centres are. Opioid activity in brainstem can affect breathing, respiratory depression is a dangerous side effect of opioid drug and is commonly cited as the cause of death in opioid drug OD.

·        Spinal cord: the transmission of pain signals in the spinal cord, “dorsal horn” is dampened by opioids binding to receptors on these cells, this is one intended target of opioid treatment and a mechanism of the drugs analgesic property.

·        Peripheral neurons: pain sensing neurons send messages from periphery to spinal cord. Binding opioid receptors in these neurons another way drugs can curb pain sensations.

·        Intestine: receptors are expressed in neurons regulating peristalsis. Inhibition of these cells upon opioid binding leads to constipation (side effect of opioid medication).

Opioids and Dopamine

Any drug that inducing high, euphoria or rewarding sensation has an effect on dopamine.

Morphine’s activation of the opioid receptor in neurons of the nucleus accumbens in the brain.

 1. reigns in the release of the neurotransmitter (GABA)

2. GABA’s main role in the brain is to inhibit other neurons if inhibited: causes a drop in GABA meaning neighbouring cells expel dopamine

3. in turn elicits the euphoria associated with opioids.

Ø  Opioids effects on body:

-            drowsiness, confusion, memory loss, fatigue, hallucinations, convulsions

-            respiratory depression

-            dilation of blood vessels causing increased pressure on brain

-            pupil constriction, slurred speech

-            nausea, vomiting, weight loss

-            sexual dysfunction

-            constipation

Ø  Opioids effects on sleep: insomnia

Ø  Effects on human behaviour: subjective effects. Many literary figures were known to be opium users.

Ø  Effects on mental faculties:  opium users are convinced that using drugs enhanced their creativity these ideas were said to not have become without using. Taking the drug orally produces intense feelings of euphoria, but only injecting produces immediate intense “rush”.

Ø  Systematic effects on mood:

-            there is a disconnect between subjective accounts and what people are experiencing in comparison to lab studies asking people to account their experience.

-             positive feelings don’t last and are replaced by mood changes and negative feelings. Effects also depend on whether users are new or experienced (17 out of 30 former addicts wanted to use morphine again but only 2 out of 20 non-users would use again). Lasagana et al. (1955).

Performance: psychometer may be slowed, cognitive performance is mostly intact. Tolerance also develops to performance effects. If someone is in pain the effects on performance diminish, don’t have reduced deficits.

Tolerance

If you’re taking opioids chronically will develop tolerance. Within 3 to 4 months, consumption increases 10-fold, therefore doses much higher can be handled by non-users.

-            Changes in opioid receptors and metabolism contribute to tolerance.

Cross tolerance- when tolerance to the effects of a certain drug produces tolerance to another drug. tolerance extends to all mu opioid agonists. Does not extend to depressants, stimulants, or hallucinogens. Some cross tolerance to alcohol (indicates some communication with opioid receptors and alcohol intoxication at much higher concentrations).

Opioid Withdrawal

One of the most misunderstood aspects of drug use. May have been more severe in 1920-30’s addicts had access to cheaper and more heroin taking it in greater quantities. Even in its most severe form, heroin withdrawal is not as severe as barbiturate or alcohol withdrawal (fatal).

Timeline and Symptoms:

Ø  Begins 6 to 12 hours after last drug use, peaks at 26 to 72 hours, and is over within a week.

e.g., restlessness, pacing, chills & hot flashes, goose bumps, vomiting, diarrhoea, cramps, sweating.

·        Severity of withdrawal depends on the daily dose. For most people, it resembles a bad case of the flu and is not life-threatening but uncomfortable.

·        Similar for all mu opioid agonists can be immediately stopped by agonist and generated immediately by antagonist.

Self-administration in humans

Not all are addicts but the being a heroin addict can be classified by:

-            using at least once a day

-            preoccupied with obtaining drug

-             physical dependency

-            little time or money for other activities and around people who also use.

·        First exposure is usually via a friend

·        Many people “mature out” of use

Laboratory studies on Opioids

Opioids act as reinforcers in users (in terms of subjective effects and enhanced mood), but not in nonusers. Few studies of self-administration in non-users, opioids are only reinforcers in non-users in the presence of pain.

Harmful effects

Acute effects- often occur relatively quickly after exposure. severe depression of respiration and eventually death.

-            Overdose is the leading cause of death among heroin users (potentially due to quinine, loss of tolerance, mixing drugs)

Chronic effects

Ø  Health; constipation, cancer promotor

Ø  CNS; does not alter structure of the brain, reduced activation of cortical areas

Ø  reproduction:

-             in males – decreased testosterone, decreased fertility).

-            In females – changes in menstrual cycle, decreased fertility, use during pregnancy may cause harm to foetus. Abies born to addicted mothers have lower birth weight, illness, also have to go through withdrawal.

Lifestyle effects

Ø  Costs a lot of money (people may neglect important needs, health, housing, nutrition)

Ø  Clean needles are not common (exposure to hepatitis, HIV/AIDS

Ø  Years of potential life lose risk of other causations of death

Rate of death is 50 to 100x the rate in general population.

In a study heroin addicts followed over a 33-year period took note of where they were at various point of their life.

• Of 581 heroin addicts admitted to compulsory drug treatment between 1962 and 1964, Half had died by 1997. 

• Of the surviving 242 addicts who were interviewed in 1996-1997, 1 in 5 were currently using heroin. 

Prescription Opiate Addiction

Since 1990s, prescription opiates (oxycodone) have skyrocketed in popularity. Prescription of morphine maintained relatively flat in terms of trajectory, but oxycodone has increased. When broken down by age, at every age group there has been an increase in opiates being prescribed particularly young-mid adult.

Over prescribed is a result of drug company marketing and kickbacks for doctors.

Addictive nature is purposefully downplayed; PurduePharma guilty of a crime misbranding and fined $634 million when they make $3 billion a year on oxycontin alone.

Funnelled into illicit use.

-            Pharmacy robberies

-            Prescription forgeries

-            Doctor shopping

Opiates in NZ

Produce the highest number of overdoses casualties despite more prevalent use of meth and other drugs (429 deaths between 2004 and 2010- half due to overdosed). Prescription opiate use on the rise.

Opiate conclusion: Carrying out normal activities under opiates is challenging, not recommended for driving etc. some are highly addictive and repeated use leads to physical dependence and withdrawal symptoms. Main harm to body causes nausea, vomiting and chronic constipation. Not good for chronic pain yet are widely used for it.

Acute vs chronic:[2]

26^th-28^th August Tobacco and Vaping

Tobacco

Tobacco is the only known natural source of nicotine. The plant belongs to the nightshade family (Solanaceae). Nicotiana tabacum is cultivated widely all over the world and was originally cultivated and used in North and South America.

History

Jean Nicot

-            French ambassador to Portugal

-            Convinced of the medical usefulness of the tobacco plant

-            Presented the tobacco plant to the French royal family

-            The genus Nicotiana was named after him

-            Tobacco was widely used for “medicinal” purposes

The English were among the last to take up smoking

·        By the end of the 16^th century, the demand for tobacco began to worry some.

·        In 1604 King James 1 published A counterblast to Tobacco.

Disproved claims for medical benefits of smoking

Tobacco in North America

·        Colonists began cultivating tobacco in a last effort before quitting

·        Hugely successful by 1720, Virginia tobacco was the primary source for England

·        Primary reason for slave labour early on

·        Smoking had been the most popular method of tobacco use in Europe

·        Snuffing was popular for a time, particularly among clergy. Not outlawed in churches, easy to hide from disapproving parishioners.

·        Tobacco chewing was an American export which was first observed as a habit of native people but never popular in Europe

·        Following the Revolutionary War, the new United States deliberately rejected European habits and fashions.

·        Snuff was rejected, tobacco chewing was adopted with patriotic zeal. Chewing was democratic, snuff was aristocratic.

·        Westward expansion brought chewing tobacco with it

·        Baseball players use of chewing tobacco popularised it, and is still common today

Cigarettes

·        Early explorers noted that “Mexican Indians” smoked tobacco through reeds (plant)

·        A small percentage of people in Spain and Portugal smoked cigarettes through the next couple of centuries.

·        In 1840, cigarette smoking become very popular in France

-            Mostly among French ladies

-            Enthusiasm women showed led to general acceptance

·        About the same time in North Carolina, flue-cured, or “bright” tobacco was discovered

-            Stephen, a slave on the plantation of Abisha Slade, credited with discovery.

Heat cured with charcoal, rather than smoked, more mild taste and aroma perfect for cigarettes and perfect for arid, infertile soil.

·        Cigarette smoking skyrocketed (advertisements)

·        In 1964, the US Surgeon General’s Report linked smoking to cancer and other diseases.

·        In 1971, the Royal College of Physicians of London published a similar report

Since smoking has declined among adults in developed nations.

However, Smoking has increased dramatically in developing nations

Ø  By mid 2020s, around 85% of smokers will be in developing countries

Neurophysiology

Nicotine acts on the nicotine acetylcholine receptor (nAChR), located in both the PNS and CNS. In the PNS, they are located at neuromuscular junctions and control voluntary muscle action.

-            Blocked by curare[3], a poison used on dart and arrow tips by some South American tribes.

-            This blocks the ability of nerves to cause muscle contractions. Causes paralysis and death by asphyxiation (deprived of oxygen)

nAChRs in the CNS

·        Found throughout the brain, participates in a variety of brain functions

·        Ionotropic receptors (allow ions to flow from extracellular to intracellular) space, compromised of 5 subunits

·        When activated, allow Na+ and K+ to pass through, creates an excitatory post synaptic potential.

Receptors present in three different states; closed, open, desensitised.

Effects on the behaviour and performance of humans

Acute effects:

-            Many people report that smoking is a pleasurable experience

-            Pure nicotine is reinforcing to smokers, but not to non-smokers

·        Chronic effects

-            Smokers have lower levels of physiological well-being than non-smokers

-            Mood worsens following quitting, but then improved to better than it was during smoking.

Effects of performance

Largely inconsistent results over the years.

Poor experimental design meant there has been no control for nicotine withdrawal effects, no placebo smoking condition.

Heishman et al. (2010) concluded based on a meta-analysis of studies that:

-            Fine motor abilities; improved performance

-            Alerting attention; improved both accuracy and speed of attention

-            Orienting attention; did not improve accuracy, but improved speed

-            Short term and long-term episodic memory; improves short term, but not long term

-            Working memory – no effect, improved response times.

Withdrawal Symptoms

-            Anxiety, irritability, decreased heart rate, difficultly concentration, increased appetite & weight gain, restlessness, cigarette cravings. Depression and dysphoria report in 31% of no prior history whereas 75% of people with history of depression.

-            Withdrawal symptom score goes up weeks after quitting

Self-administration in non-humans

·        Notoriously difficult to get lab animals to self-administer nicotine. Questions as to whether nicotine is a reinforcer at all. Very narrow range of reinforcing doses (too much nicotine makes people ill).

·        Present of conditioned stimuli that have been paired with nicotine is critical. You will not get a rat to self-administer nicotine unless there is a set up stimuli paired with delivery of nicotine.

Caggiula et al. (2001)

Graph shows cues with nicotine results in high rates of nicotine self-administration. When taking away cues causes rates to drop down a lot. Putting cues back + nicotine they go back up to previous level. Something important about the cues.

Reinstatement condition:

Putting back nicotine only bumps it up slightly

Cues + saline = further increase

Cues + nicotine results in the most responding.

Self-administration in humans

Nicotine is a reinforcer in human smokers; they are sensitive to changes in concentration (how much nicotine is onboard) and can work to change doses so it is rewarding to them. The change in blood-nicotine levels responsible for this is not clear.

Two theories:

Ø  Constant blood theory

Ø  Nicotine bolus theory

Constant blood level theory

Suggests that smokers will adjust their smoking behaviour to maintain a more or less constant level of nicotine in the blood.

-            Smokers change their puffing depending on the level of nicotine in the cigarette

-            Smokers change their puffing over the course of the cigarette

-            Smokers smoke first thing in the morning.

BUT…

-            Not good at titrating blood level

-            Nicotine replacement theory is not as effective as one would assume

Nicotine bolus theory

·        Sudden high concentration of nicotine in the brain enhances its reinforcing effect and increase pleasure. Accounts for the addictive nature of smoking, but not other means of nicotine administration.

·        The kinetics of nAChRs support this model; a bolus of nicotine followed by a concentration decrease could activate nAChRs and then return them to their basal state before desensitisation.

BUT…

-            There is no spike in nicotine concentration with each puff

Both theories don’t work!

Non-nicotine factors

-            People engaging in behaviour that is supported by nicotine. stimuli that are associated with smoking can acquire reinforcing properties

-            These stimuli may be important in maintaining smoking and in relapse

-            Some taste and tactile aspects of smoking may also be important in the reinforcing effects of smoking.

Dual reinforcement model

Suggests that nicotine:

1.        Is a primary reinforcer

2.        Enhances the reinforcing value of other stimuli. Associative learning. Responding produces a visual stimulus in order for nicotine to enhance the reinforcing value.

Nicotine does not have to be contingent on behaviour. as long as nicotine is on board will increase reinforcing value of that stimulus.

Nicotine as a conditioned stimulus:

·        People engage in other reinforcing activities while smoking

·        Perhaps the subjective effects of nicotine become associated with other stimuli

Besheer et al. (2004)

Two treatment conditions: saline, nicotine

Rats received free sucrose presentations when nicotine was on board. No rewards when injected with saline.

Will rats learn a conditioned response during nicotine sessions? Data shows this is the case.

Other components of cigarettes besides nicotine contribute to addiction:

Brenna et al. (2015) tested whether rats found nicotine, cigarette tobacco particulate matter, or roll-you-own particulate matter more reinforcing. Using a self-administered & progressive ratio paradigm (get rat to press level, see how long they go before they give up)

Ø  Nicotine = TPM < roll your own

Ø  Pressed level less for nicotine & TPM in comparison to roll your own

·        Nicotine by itself is does not support a lot of behaviour. Probably not that reinforcing!

·        Nicotine is mixed in with a lot of other ingredients in cigarettes, could these other aspects contribute to tobacco addiction?

Roll your own tobacco has a higher proportion of MAO inhibitors. Inhibits the breakdown of monoamine neurotransmitters including dopamine.

·        More MAOIs, more dopamine

Clemens et al. (2009)

4 groups:

-            Saline

-            Saline + alkaloid cocktail

-            Nicotine

-            Nicotine + alkaloid cocktail

Tested rats on self-administration & progressive ratio. Found higher responses for nicotine + alkaloid cocktail.

·        Some of these alkaloids (nornicotine, anabasine, continine) increases dopamine release in striatum.

Rose et al. (2010)

Trained participants (smokers) to self-administer

·        Denicotinized puffs + IV nicotine (feels like a cigarette with no nicotine)

·        Denic puffs + IV saline

·        Sham puff (filter blocked smoke) + IV nicotine

·        Sham puffs + IV saline

The gave a choice between IV saline, IV nicotine, Denic puffs, sham puffs

Ø  People prefer denicotinised puffs over everything else. People find act of smoking with taste and tactile sensations more reinforcing than just getting nicotine by itself.

Cigarette smoke contains over 4000 chemicals can be combined in 8,000,000 ways. We have only begun to understand the psychoactive and reinforcing properties of tobacco smoking.

Wednesday 28^th August

Harmful effects of smoking- smoking can damage every part of the body from cancers to chronic diseases.

Environmental tobacco smoke

·        Second hand smoke; spending a lot of time around people who smoked, can also lead to exposure to a number of implications.

Being around smoke can also lead to significant health problems even when not actively participating in smoking, hence the ban.

Smoking in New Zealand

Mid to older teens are smoking low rates. This increases till mid 30’s than tails off.

Little difference between male/females

Maori & Pacific groups smoke at higher rates than Asians & Pakeha in NZ.

Vaping

Another way of getting nicotine into system is from e-cigarettes:  this works by heating a liquid until it vaporises, person inhales the vapour.

Ø  the e-liquid contains many chemicals: nicotine, flavours, catalysing agents (glycerol, propylene glycol).

Ø  Also contain many of the same toxic agents as found in cigarettes, just at a much lower level.

Ø  Some new toxic agents (metals) can be found in e-liquids.

Ø  Unclear how chemicals combine when vaporised, not sure of the impacts.

Only now are vapes beginning to be regulated and studied.

Are they safe and healthy?

-            To early to say but they are much healthier than cigarettes (95% less harmful)

-            Were first introduced as a smoking cessation, to stop smoking.

-            As they are not burned & smoked avoid many of the health risks associated with cigarettes (inhaling burnt particular matter & smoke into respiratory system)

-            Due to huge increase in teen use, many studies look at potential adverse effects.

Potential harmful effects that have been identified:

·        Inflammation to vaping

·        Impaired organ development and function

·        Risk of cancer due to gene expression changes

·        Hypertension

·        Cardiovascular effects

·        Immunosuppression

·        Acute toxicity

·        Asthma

·        Reduced wound-healing ability

Appeared in literature but has not been identified as casual from vaping. Some of these effects are due to the nicotine content, some to other content.

Looking to difference between people smoking & vaping, is psychological phenomena the same?

Gateway to cigarette smoking? Because e-cigarettes are being increasingly used by teens, some worry that they are a gateway to cigarette smoking. Many teens who are vaping have never smoked, not using it as a smoking cessation aid, but is it possible that by starting vaping will it lead to individuals picking up smoking cigarettes.

Bauld et al. (2017)

Surveyed over 60,000 youth ages 11-16 for cigarette and e-cigarette use.

Included 3 different groups designations.

 -never smoked

-ever smoked

-regular smoked

-never e-cigarette use,

-ever e-cigarette use

- regular use

Wanted to see what the relationship between smokers & vapers was. The difference colours of bars represent different groups in different places.

-            People who had ever smoked were higher than people who were regularly smoking.

-            People who have ever smoked have a high chance of vaping.

-            Increasing numbers of people vaping in the absence of use of cigarettes

(There is a relationship between smoking & vaping, does appear people who vape have a higher incidence of ever smoking, or regularly smoking than people who haven’t).

E-cigarettes in New Zealand

·        Estimated around 100,000-200,000 vapers across the country

·        Government legalised e-cigarettes in hopes to help with smoke free NZ 2025 initiative

·        E-cigarettes will be restricted and regulated; only available for 18+, prohibited indoors & restricted advertising.

Recent data from NZ showing age group broken down by daily vapers & smokers.

 Increase in daily vaping and decrease in daily smoking in mid age range. As age increases so does smoking but not vaping.

For Yr10 student’s percent of daily smoking has gone down but daily vaping has gone up.

*Increase of proportion of people who vape daily have never smoked

*Snapshot of vaping landscape in NZ in particularly looking at youth

*Indication that vaping is harmful is increase in lung and respiratory infections. Increased incidence of bacterial infections in those who vape. Can be minor – serious.

 Psychedelics

Also called hallucinogens.

-            Broadly refers to a class of drugs that can cause hallucinations how ever is often not taken in high enough doses to cause them.

-            Have profound subjective and emotional effects (in touch with themselves or others

Other names for hallucinogens include phantasticants, psychedelic, entactogens, empathogens.

·        Due to the nature of the subjective effects, some suggest that these drugs may be useful in therapy.

·        Some of these drugs produce a mental state that is similar to certain forms of psychosis (psychotomimetic- psychosis mimics).

·        Some have more recently been associated with the club scene to enhance music etc.

LSD- lysergic acid diethylamide

Derivative of ergot fungus grows on grains especially rye. In the Middle Ages, outbreaks of ergot poisoning (ergotism) were common. Two effects caused by different fungi

-            Constricted blood flow to extremities making limbs feel warm

-            Convulsions, hallucinations, delusions

·        Albert Hoffman synthesised LSD in 1938 in Switzerland

-            Working for Sandoz pharmaceutical company trying to find a respiratory and circulatory stimulant.

-            Returned to LSD in 1943 felt strange after synthesising a new batch at work, a day later deliberately ingested 0.25mg had a very strong trip.

-            Sandoz did not know what to do with the drug, so they gave it to research laboratories in Europe and the US.

Used in experiments in mental health hospitals until mid-1960s, when it broke out into the streets. Also used in military experiments. Project MKUltra,

Popularised by Timothy Leary, Harvard professor has a psychedelic experience in Mexico in 1960. Came back to the US an became an advocate for psychedelics.

LSD reaches its height in the hippie era of the late 1960s and early 1970s. outlawed in 1966, harsh criminal penalties imposed under Nixon’s War on Drugs. Classified as a schedule 1 drug (no medical use, high abuse liability).

-            By putting laws on specific drugs Nixon could disrupt political groups.

Use decreased in 70s and 80s, resurged in 90s, but decreased throughout the 2000s. relatively low compared to other drugs.

·        2.5% in NZ reported using psychedelics in 2023.

Dosage and sources of LSD

“Hits” of LSD contain between 0 – 300 ug.

 Minimum dose for a full psychedelic experience is around 200 ug

Effects on the body

for example: increased temperature, dilated pupils, dryness of mouth, increased blood pressure and heart rate,nausea.

Neurophysiology of LSD

•        Even though it’s been around a long time, its neural action is still not well understood

•        LSD is similar in structure to serotonin and binds to the 5-HT2A receptor

•        Binding in the cortex is sufficient to produce the hallucinogenic effects

Other brain areas involved

Locus coeruleus

Stimulation of 5-HT2A receptors in LC enhances novelty detection. (Presenting an animal with an array of stimuli, change something small figure out whether or not the animal can recognise something has changed). By stimulating these receptors, the animals are better at looking at these novel changes.

·        Users claim to “see things for the first time”

Raphe nuclei

Release serotonin throughout the brain

- LSD inhibits serotonin release

- May be a precursor to the effects in the LC

‘Subjective’ effects of LSD

·        Euphoria

·        Tactile enhancement

·        Visual perception changes

·        Time distortion

·        General stimulation

·        Increased sense of humour

·        Expanded consciousness and insight, unearthing and understanding trauma

·        Encounters with entities

Behaviour & Performance in association with LSD

There is trouble with measuring human performance under hallucinogens because they make people inattentive to tasks

-            LSD impairs reaction time and intellectual performance

-            Deficit in working memory

-            Other impairments in problem solving and other cognitive functions

-            Claims of improved creativity

-            Difficult to substantiate; changes the sort of work produced by artists. Are these improvements?

Withdrawal from LSD

There are no withdrawal symptoms. Probably because drug use is not continued long enough to develop physical dependence. However, flashbacks or residual distortions can persist after use is discontinued.

Self-administration of LSD

Non-humans

-            Hallucinogens are not self-administered

-             Are aversive; animals will work to avoid an LSD injection

-            Some evidence that a history of drug use (MDMA) results in self-administration of hallucinogens.

Humans

-            Self-administered throughout history 

-            Never continuously used; used on special and sporadic occasions

-            Religious ceremonies; shaman communicating with the dead or divining spirits

-             LSD use in teenagers in the US was fairly high throughout the 1990s, but has been steadily declining

-            In New Zealand, LSD use has remained relatively minimal but has seen some growth because the quality of MDMA has declined in recent year

Harmful effects of LSD

·        Hallucinogens are not very toxic

-  No recorded cases of fatalities due to overdose

- Media focuses on extreme but rare behaviours (jumping out windows, committing murders)

·        Acute psychotic reaction or psychedelic crisis

- Occurs during a bad trip

- User forgets their subjective experience in caused by a drug

- Can become extremely fearful or anxious

- Can usually be talked down by someone who reminds them that their state is drug-induced

·        Flashbacks - Can occur long after the drug use is discontinued; Hallucinogen Persisting Perception Disorder (HPPD)

Once you open the lid, there’s no going back, can result in difficult psychological processing of trauma or precipitate major life crises or revaluation

Ecstasy

The most well-known derivative of the mescaline molecule, these drugs are a combination of hallucinogens and amphetamines.

·        Ecstasy usually refers to MDMA (3,4-methylenedioxyamphetamine)

-            Originally synthesized by Merck and patented in 1914

-            Never developed or used until 1960

-            Many other drugs were synthesized (“designer drugs”)

-            Many have virtually disappeared, but MDMA remains popular

Prior to July 1985, some psychotherapists gave MDMA to patients because of the close relationship between patient and therapist it fostered

-            Reported by some therapists one dose equivalent to “4 years of therapy”

Banned in 1985 even from psychotherapeutic use because of its “neurotoxic effects” (data not reliable).

-            High doses produced a massive depletion of serotonin in the brain

Ecstasy is sold in white or coloured tablets contain up to 100 mg or more of MDMA and is often mixed with other synthetics.

Purity for ecstasy was relatively low in the late 1990s but has increased into the 2000s

Neurophysiology of Ecstasy

Stimulants release of serotonin & blocks reuptake. Serotonin hanging out in the synapse more.

also increases release of oxytocin, a hormone involved in bonding and building trust.

May be the cause of its empathogenic and entactogenic properties.

Behaviour & Performance in relation to Ecstasy

A dose of 75 to 100 mg induces a state of enhanced awareness of emotions and sensations

·         Produces increase in wakefulness, endurance, energy, a sense of euphoria, increased sense of well-being, sharpened sensory perception, greater sociability and extroversion, heightened sense of closeness to people

·        Rapid tolerance which dissipates within a few days

Short-term physiological effects

-            Increased body temperature

-            Perspiration

-            Headache

-            Pupil dilation

-            Muscular tension; teeth grinding and jaw clenching

After effects

-            Difficulty concentrating

-            Irritability

-            Insomnia

-            Fatigue

-            Depression or crash

Self-administration of ecstasy 

Nonhumans

-            Readily self-administered by monkeys and mice

-            Reinforcing effects are highest at moderate doses

-            Blocked by blocking 5-HT2A receptors

Humans

-            Highest use in 1990s followed by drastic decline

-            Use is resurging in US and Canada, declining in the UK

-            Increasing in NZ

MDMA in New Zealand

Latest results indicate it is one of the most commonly used drugs in NZ

-             3.6% of adults reported use in 2023

 Although typically associated with nightclubs and dancing, it is also used in homes and private parties, with house parties were reported as the most common setting in a recent survey

·        Often combined with other drugs, particularly alcohol leading to increased risk of harm

Withdrawal in terms of Ecstasy

Due to rapid tolerance, it is not taken chronically!

-            No physical dependence; therefore, no withdrawal

-            May produce psychological dependence due to the post-use crash in mood.

Harmful effects of Ecstasy

-            Chronic use can deplete serotonin in the brain. Not clear the extent of this damage, but some evidence suggests it can be long-lasting

-            More recent evidence indicates that there is not lasting damage on neurons and function

-            still not settled

Chronic users show symptoms associated with serotonin depletion:

- Sleep disorders

-Persistent anxiety

- Impulsiveness

-Hostility

- Impairments in attention and working memory

Cognitive deficits dissipate after about 6 months after use is stopped. However, Anxiety and hostility may remain for years. Improvement likely due to upregulation of serotonin receptors or some other compensatory mechanism.

Some data suggests ecstasy may contribute to depression however:

·         Data are not conclusive

·        MDMA is rarely used in isolation; difficult to analyse factors involved in polydrug abuse

 One of most troubling effects is loss of heat regulation and increased temperature

-            In dance or club settings this is particularly dangerous

-            Can produce heatstroke-like symptoms and severe dehydration, hyperthermia and death.

Lethal Effects of Ecstasy

-            Hyperthermia or hyponatraemia (low sodium in blood) drinking too much water

-            Heart or liver damage

-            Swelling of brain resulting from blood dilution

-            Overheating

-            Suicide – although latest data suggest the association is weak

-            Purity of MDMA cannot be quality-controlled; Pills may contain other, very harmful drugs

-            Also, can be lethal if used with other drugs, Alcohol, GHB

Others

·        Psilocybin (magic mushrooms) – organic; used worldwide for millennia

-            Produce many of the typical psychedelic effects

-            Currently undergoing clinical trials for depression/anxiety and PTSD

·        Phencyclidine (PCP)-synthetic drug marketed in the 1960s as an analgesic

-            Does not depress respiration or heart rate

-            Produces a trance-like state

-            Termed a “dissociative anaesthetic”

-            Sold on the street as crystal, angel dust, hob

·        Ketamine-marketed in 1969 as a safe alternative to PCP

-            Still used as an anaesthetic for children and by veterinarians

-            Sold on the street as K, Special K, kitkat

-            Popular at clubs and raves

-            Recent trials for depression and anxiety

·        Dextromethorphan

-            Cough suppressant-taken in high doses acts as a dissociative anaesthetic

-             Effects similar to PCP and ketamine

-            Low affinity NMDA receptor agonist

·        GHB-gamma-hydroxybutyrate

-            Widely marketed as a medicine or dietary supplement

-            Sedative-gained popularity as a club drug; gained notoriety as a “date-rape” drug

-            At low doses, produces alcohol-like intoxication without hangover

-            At high doses, produces a non-responsive and anaesthetic state

-            Has action at its own receptor and at GABA B receptors

·        Mephedrone-belongs to the amphetamine and cathinone classes

-             Similar effects as MDMA

-            Blocks reuptake of dopamine and serotonin

-            Gained popularity as a club drug

[1] All opiates are opioids, but not all opioid are opiates!

[2] Acute = rapid onset, short duration, chronic = long lasting

[3] Curare – a plant-derived substance that affects voluntary muscles by blocking the motor end plate, leading to muscle paralysis