psychoactive-drugs

psychoactive-drugs

1. Receptor types and neurotransmitters 2. Dopamine theory of addiction 3. Depressant drugs benzodiazepines, alcohol, cannabis 4. Opioid drugs

How do drugs work?

classic and partial agonists

5. Stimulant drugs

Duncan Raistrick has put together this step by step guide...

cocaine, ecstasy, nicotine 6. Hallucinogenic drugs

LSD, ketamine

In summary of the nervous system...

The graphics on this page demonstrate neurones communicate through receptors.

In pharmacology a receptor is a protein molecule that receives signals from outside the cell. If the signals are strong enough then the cell causes some action to occur. Depending on the cell the action may be, for example, to ‘feel good’ or it may be to make a muscle contract.

We will now look at receptor types.

Receptor types… The body has many receptor types. In order to understand how psychoactive drugs work, seven receptor types are relevant:

GABA gamma amino butyric acid Cannabis

Dopamine

Autonomic adrenergic and nicotinic

5 HT 5 hydroxy tryptamine NMDA n-methyl d-aspartate

Opioid

Each receptor type has a number of subtypes – this is important, because different drugs of the same group (eg opiates) have an effect at different receptor subtypes. We will describe the effects from each receptor type later.

Dopamine The dopamine theory of addiction…

Dopamine is a neurotransmitter which binds to dopamine receptors. It has a role in controlling movement. It is particularly relevant in addiction as most addictive drugs and some behaviours, sex and exercise for example, increase dopamine release causing activation of the ‘pleasure centre’, a primitive part of the brain, thereby reinforcing the activity.

Dopamine is often released indirectly by other neurotransmitter types that extend into the ‘pleasure centre’

Another six receptor types are particularly important in understanding the effects of drugs. How many can you remember ?

Do you know what their neurotransmitters are called ?

Other neurotransmitters…

GABA is a general CNS depressant at GABA receptors

Glutamate is a general CNS stimulant at NMDA receptors

GABA and glutamate are the most abundant neurotransmitters found in the nervous system.

Anandamide is the neurotransmitter at cannabis receptors

Enkephalin, endorphin, and dynorphin are neurotransmitters at mu, delta and kappa opiate receptors

Serotonin is the neurotransmitterat 5HT receptors

Adrenalin, noradrenalin, and acetylcholine are the neurotransmitters at adrenergic and nicotinic receptors

If a drug activates a receptor it is said to be an agonist eg a drug acting at dopamine receptors could be shown as DA++ A drug blocking a receptor is called an antagonist eg a drug blocking serotonin receptors could be shown as 5HT - -

Key concept…

Agonist and Antagonist Effects Both the body’s own neurotransmitters (known as endogenous substances) and psychoactive drugs have an effect at receptors. This determines a person’s experience of the drug.

In summary...

So a neurotransmitter is made by the body and it is, therefore, said to be endogenous.

Pharmaceutical and recreational drugs and neurotransmitters all target receptors where they have agonist or antagonist effects.

Different substances can bind to different parts of the same receptor thereby multiplying the effect.

It is always a good idea to keep things as simple as possible. There are lots of drugs of misuse and many have similar effects to each other.

Can you think of a way of categorising drugs according to their effects?

A Useful Way to Group Drugs From an observational point of view psychoactive drugs can be divided into four categories which are characterised by having similar effects and similar withdrawal or abstinence states. These are… Depressants Stimulants Opioids Hallucinogens

Key concept…

Most drugs influence multiple neurotransmitters but two or three are dominant and the drug effect can broadly be understood from its neurotransmitter profile.

Once you are sure you understand the basics of ‘How do drugs work’ , technically called pharmacodynamics, then you are ready to learn about drugs.

We have represented drugs with a graphic of a molecule showing which receptors it affects and where these activate the pleasure centre

the coloured dot represents a receptor type

Other GABA agonists Zopiclone Zolpidem Barbiturates Chlormethiazole

Depressant drugs...

Benzodiazepine GABA agonists Fast onset Diazepam Medium onset Chlordiazepoxide

Mixed receptor agonists Alcohol GBL & GHB Cannabis and synthetic cannabinoids

Lorazepam Alprazolam Slow onset Oxazepam Clonazepam

Effects of benzodiazepines...

Medical uses of benzodiazepines include treatment of anxiety, panic attacks, sleeplessness, epilepsy, alcohol withdrawal. Side effects include drowsiness, unsteadiness, memory difficulties, dizziness.

Benzodiazepines work by fixing onto the GABA receptor and increasing the effects of GABA. Differences between benzodiazepines are to do with their speed of onset and duration of effects.

Benzodiazepines: strong action at single receptor

GABA +++

Effects of alcohol...

Alcohol is well suited to use as a recreational drug: it comes in different forms in terms of the volume of a drink, its taste and strength. Congeners are chemicals other than alcohol which give drinks their particular character.

Alcohol is commonly used in social situations both for the effect of being intoxicated and to reduce social anxiety. Like benzodiazepines, alcohol can help to relieve anxiety, panic attacks, and sleeplessness – the benefits are soon lost with regular use. Intoxication leads to impaired judgment, unsteadiness and accidents – at higher levels memory loss, drowsiness and unconsciousness.

So benzodiazepines and alcohol are both depressant drugs but the real world effects of alcohol are different to benzodiazepines.

Which receptor was activated by benzodiazepines ?

Can you see from the next slide how alcohol is different…

Alcohol: small actions at multiple receptors...

NMDA-

opioid mu+

GABA+

cannabis+

Key concept…

Effects on Multiple Pathways Unlike benzodiazepines many drugs have an effect on more than one neurotransmitter pathway albeit that only one or two pathways are really important. Ketamine, for example, affects 27 receptor subtypes but only two are very significant. Clozapine, an anti- psychotic medication, affects 39 receptors subtypes. Alcohol is another example.

Why is it important? Pharmaceutical companies seek to diminish side-effects and maximise the desired therapeutic effect by creating drugs that work across a particular profile of receptors. Similarly with recreational drugs a spread of effects is usually more desirable than a potent single receptor effect.

Pharmacotherapies… Knowing how drugs work informs the development of pharmacotherapies. For alcohol there are three medications aimed at preventing or reducing drinking

💊 Disulfiram does not affect receptors. It causes an unpleasant reaction with alcohol and so changes expectations from drinking. 💊 Naltrexone and nalmefene block the effect of alcohol at the opioid receptors making drinking less pleasurable. Other effects are not blocked. 💊 Acamprosate enhances GABA and reduces NMDA effects which it is claimed reduces craving. Other effects are not blocked.

In summary - depressant drugs so far...

Benzodiazepines are a pharmaceutical product and alcohol is produced by brewers and distillers – they are synthetic.

Many drugs, including those taken for recreational purposes, are naturally occurring in plants.

There are very big differences between synthetic and naturally occurring drugs. Cannabis illustrates the point…

Effects of cannabis... Effects include relaxation, mild euphoria, introspection, amusement, and, later, physiological effects including hunger and increased heart rate. Medically it is used to relieve chronic pain and muscle spasms. Side effects include dizziness, nausea, anxiety, hallucinations and paranoia.

Like alcohol, cannabis comes in different forms and strengths: herbal cannabis (flowering tops and leaves): 1-18% THC; cannabis resin 1-17% THC; oil 60% THC and with different mixes of alkaloids.

Alkaloids Alkaloids are naturally occurring substances produced by many plants and fungi. They are the basis of traditional medicine and the production of pharmaceutical medicines. For example Papaver somniferum yields morphine, thebaine, codeine, papaverine, dihydroetorphine; Erythroxylum coca yields cocaine, benzoylecognine, nicotine; Cannabis sativa yields tetrahydrocannabinol and cannabidiol among 113 alkaloids.

Key concept…

Why is it important? Naturally occurring substances tend to be less potent and so less addictive than their purified counterparts. Moreover the mix of alkaloids from plants grown in different locations and in different conditions gives a richness and variability to drugs.

Cannabis: effects of its two main alkaloids...

tetrahydro-cannabinol THC

NMDA-

5HT+

cannabidiol CBD

cannabis++

cannabis-

What are synthetic cannabinoids? The first cannabinoids were developed in the 1960s. All are full CB1 agonists and can be smoked or vaped. There are three classes of drug: HU-210 (‘HU’ for Hebrew University) has 100 times the potency of THC. Nabilone, Dronabinol and many other pharmaceutical preparations are HU drugs. Noladin is a CB1 antagonist.

In the 1970s, Pfizer developed the cyclohexylphenol(CP) series including CP59540, CP47497. In the 1990s Clemson University, USA created a large series of benzoylindoles (JWH compounds — after the name of their inventor), eg JWH-015, identified in ‘spice’ products.

Synthetic cannabinoids are sprayed onto or mixed with exotic herbs or flowers - typically these plants have some reputation for psychoactive effects themselves.

Blue water lily

Synthetics are full agonists at CB1 (THC partial) and CB2 with knock on effects to other transmitters. Potency ranges 50- 300x THC. Duration varies: JWH-018 = 1–2 hours CP47497- C8 5–6 hours

Indian warrior

Effects are much more intense than for natural cannabis. Adverse reactions include: hallucinations, suicidal and homicidal thoughts and actions, intense fear and paranoia, catatonia, seizures, diarrhoea, vomiting, craving, and persistent perceptual disturbance.

Beach bean

Synthetic cannabinoids: potent at single receptor...

cannabis++++

We have looked at depressant drugs which are widely used both as recreational and pharmaceutical drugs. You should now have a good understanding of the terminology and the key concepts of pharmacodynamics.

Now for drugs which generally are less suitable for recreational use.

coloured dot represents a receptor type

Opioid drugs...

Partial opioid agonists Buprenorphine Pentazocine

Full opioid agonists Morphine Diamorphine(heroin) Codeine Methadone Fentanyl Tramadol

Opioid antagonists Naloxone

Naltrexone Nalmefene

Where do opioid drugs work ?

At opioid receptors the body's transmitters are: endorphin (mu) enkephalin(delta) dynorphin(kappa)

The three main opiate receptor types have distinct effects: Mu μ : pain relief, respiratory depression, constipation, euphoria, pin point pupils Delta δ : pain relief, anti-depressant, lowers seizure threshold Kappa κ : pain relief, sedation, depression, anti-convulsant, pin point pupils

At GABA receptors the body's transmitter is GABA

Opioids are strong inhibitors of GABA which reduces dopamine neurone inhibition causing an increase in dopamine and its euphoriant effects.

Effects of opioids...

Opiates are potent pain killers. They also create a strong sense of euphoria and wellbeing associated with feeling detached from surroundings. Side effects include nausea (initially), drowsiness and physiological effects including anorexia, constipation, and amenorrhea. Opium is the naturally occurring substance that is produced by the opium poppy – its use is easier to control and pleasanter than purified opiates such as heroin. Opium dens were visited by people from all walks of life

Classic opioids: potent at single receptor...

GABA--

opioid kappa+

opioid delta+

opioid mu+++

Partial opioids: medium initial effect at single receptor then receptor block...

GABA--

opioid kappa+

opioid mu--

opioid delta+

opioid mu++

Pharmacotherapies… Medications are aimed at substituting more addictive drugs eg heroin, with less addictive ones, or blocking the effects of taking opioids at all.

💊 Methadone is a Mu receptor agonist and so has similar effects to heroin and other opioids. It is less addictive because it is less potent and longer acting. Buprenorphine is less potent still and also has a receptor blocking effect.

💊 Naltrexone totally blocks the effect of opioids at the Mu, Kappa and Delta receptors so that if any opioid drug is taken very little happens.

Stimulant drugs...

Mono receptor agonists Ephedrine Phenyl-propanolamine Pseudoephedrine

Dual receptor agonists Amphetamine Meth-amphetamine Cocaine Mephadrone Khat Methylphenidate

Caffeine Nicotine

Mixed receptor agonists MDMA (ecstasy)

Where do stimulant drugs work?

At dopamine receptors the body's transmitter is dopamine

Typically stimulants are potent dopamine reuptake blockers. The increase in dopamine causes euphoriant and ‘feel good’ effects but also excess dopamine effects, including paranoia and psychosis, are common. Dopamine is involved in control of movement causing repetitive or jerky motion. The autonomic nervous system takes care of bodily functions that happen automatically such as heart rate, digestion, breathing. There are two parts: the sympathetic, triggered by adrenalin-like drugs, is for ‘fight and flight’ –the parasympathetic, triggered by acetylcholine-like drugs, is for ‘rest and digest’. At autonomic receptors the body's transmitters are noradrenalin and acetylcholine

Effects of stimulants...

Energy, feeling of physical wellbeing, improved concentration and wakefulness are

Ecstasy (MDMA) causes much greater release of 5HT than other stimulants. Drugs that do this are called entactogensand they cause a sense of togetherness and strong emotions when dancing or having sex, complementing the stimulant effects.

hallmark features. Side effects include

irritability, anxiety and paranoia. Physiological effects include anorexia, sleep deprivation, and high blood pressure.

Cocaine: a dopamine reuptake inhibitor...

α -Adrenergic++

5HT+

dopamine+++

Ecstacy (mdma): a dopamine reuptake inhibitor...

α -Adrenergic++

5HT+++

dopamine+++

Nicotine: potent single receptor...

NMDA-

acetylcholine+++

Hallucinogenic drugs...

Psychedelics LSD

Dissociatives Ketamine Phencyclidine SalvinorinA Muscimol

Psylocibin Mescaline DMT

Where do hallucinogenic drugs work ?

At NMDA receptors the body's transmitter is glutamate

NDMA receptors activated by glutamate stimulate CNS and keep the brain awake: concerned with memory and learning.

For psychedelic drugs NMDA receptors are powerfully activated For dissociative drugs NMDA receptors are powerfully blocked

At 5HT receptors the body's transmitter is serotonin

Serotonin is concerned with mood, social behaviours, learning, memory, sleep, thermoregulation. It is a target for hallucinogens and mood altering drugs.

Effects of hallucinogens...

Vivid visual, auditory, and tactile experiences. Mood changes depend on circumstances: may be frightening or enjoyable. Side effects include disorganised thoughts, anxiety, insomnia, and changes in body temperature.

Feeling of detachment: depersonalisation, out of body experiences, dream-like state, with hallucinations and delusions. Side effects include impaired ability to feel noxious stimuli and an inability to move.

LSD: other psychedelics are similar...

NMDA++

5HT+++

dopamine+

Ketamine: other dissociatives are similar...

NMDA---

dopamine+

Learning points...

Knowing about different receptor types is important for practitioners so that they have a simple framework for understanding drug effects 1 2 Delivering effective pharmacotherapies depends upon understanding receptors and how medications will change drug effects