How do psychoactive drugs work?
Drugs have many different effects. Here we are thinking of drugs that have a psychoactive effect. People do not get addicted to aspirin - it has no psychoactive effect.
The nervous system is divided into two main parts:
The Central Nervous System is comprised of the brain and spinal cord; it processes sensory information, coordinates responses and it is where where thoughts and feelings happen. The effects of psychoactive drugs are mainly experienced here.
The Peripheral Nervous System consists of all nerves outside the brain, which are sub-divided into the somatic system for voluntary movements and the autonomic system for involuntary functions like breathing and heart beat.
It is estimated that there are 86 billion cells, called neurons, in the brain. They make neurotransmitters in the cell body which are then passed down the long axon and released at the axon terminal to communicate with another cell across what is called a synapse.
First let's see how the nervous system works...
Drugs act on receptors either to stimulate or to block them - like enabling or disabling something on a computer. Neurones manufacture their transmitter and store it in vesicles (small packets). The graphic illustrates vesicles passing down an axon to be released across the synapse (the gap between cells) and activate receptors which are located on an adjoining cell. Excess transmitter is destroyed in the synapse or transported back into the cell that released it (reuptake).
To understand receptors is to understand how drugs work
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.
It would be nice if drug effects were the result of action on a single neurotransmitter pathway. Of course the real world is more complicated: there may well be a dominant pathway explaining the main drug effect but drugs may also act on multiple pathways with lesser effects and on receptors outside of the brain causing physical effects.
All drugs, whether pharmaceutical or ‘street’ drugs, have unwanted effects. For some people knowing the risks of taking a drug is a potent deterrent to its use. For others the immediate, pleasurable effects of a drug outweigh the possible, often long-term, risks of taking it and for these people harm reduction strategies are a crucial part of their drug use.
What are the neurotransmitters called?
What goes on at receptors
Watch this YouTube video from Utah University's Genetic Science Centre's Mouse Party. It is a cartoon explaining how receptors work, what are the different kinds of receptor, and how do they connect with different kinds of drugs.
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.
The names of the parts of the brain are unimportant. What matters are the functions of these dopamine pathways…
Mesocortical - cognition, memory, attention, emotions and learning
Nigrostriatal - movement and sensory input
Mesolimbic - pleasure, emotion and perception
Now let’s look at psychoactive drugs
Note that the Drugs Venn was designed by Fiona Measham (founding Director of The Loop), Guy Jones (senior chemist with The Loop, senior advisor on the Drugs Wheel, and technical lead at Reagent Tests UK) and made available with a Creative Commons Attribution-Non Commercial-ShareAlike 4.0 International License.
There are many ways that drugs can be categorised. One approach would be to look at the pharmacological structure, another would be to consider drug effects, another might be to rank their harmfulness. No particular way is right or wrong - it all depends on what purpose a taxonomy has. Here we are interested in which drugs have similar effects and understanding how medications can help…
Key concept
naturally occurring and synthetic drugs
Benzodiazepines and cannabis are both depressant drugs but their real world effects are very different. This is because drugs, like benzodiazepines, have one big effect, while others, like cannabis, have a lot of small effects because they are made up of many active compounds called alkaloids.
Pharmaceutical companies seek to diminish side-effects and maximise the desired therapeutic effect by creating drugs that work across a particular profile of receptors. Alkaloids are naturally occurring substances produced by many plants and fungi. They are the basis of traditional medicine and the production of pharmaceutical medicines. 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.
Depressants - 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.
Pharmacotherapies for alcohol
💊 Disulfiram does not have an effect at receptors. It blocks an enzyme which normally breaks down alcohol and this results in a build up of a toxic metabolite which causes an unpleasant reaction and so changes a person's expectations of what will happen if they drink.
💊 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.
Depressants - benzodiazepines
Medical uses of benzodiazepines include treatment of anxiety, panic attacks, sleeplessness, epilepsy, alcohol withdrawal.
Side effects include drowsiness, unsteadiness, memory difficulties, dizziness.
Unlike alcohol, benzodiazepines have a potent effect at a single receptor type: GABA.
The differences between benzodiazepines are because of different pharmacokinetics.
Depressants - cannabis
Cannabis, like alcohol, is well suited to recreational use. It 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 over 100 alkaloids.
The alkaloid cannabidiol, CBD, tend to have the opposite effects to THC and this is reflected in its receptor profile.
Effects of synthetics 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. Potency ranges 50-300x THC. Duration varies: JWH-018 = 1–2 hours CP47497-C8 5–6 hours. Synthetic cannabinoids are sprayed onto or mixed with exotic herbs or flowers - typically these plants have some reputation for psychoactive effects themselves, such as indian warrior.
What are synthetic cannabinoids
The first synthetic 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.
Depressants - opioids
Opiates are potent pain killers. They also create a strong sense of euphoria and wellbeing associated with feeling detached from surroundings. There are three main opiate transmitters which have distinct effects at their respective receptor sites: endorphin (mu), enkephalin (delta), dynorphin(kappa)
Mu pain relief, respiratory depression, constipation, euphoria, pin point pupils
Delta pain relief, anti-depressant, lowers seizure threshold
Kappa pain relief, sedation, depression, anti-convulsant, pin point pupils
⚠️ Potent synthetic opioids
Fentanyl and its many derivatives are 50+ times more potent than heroin, nitazines are 100+ times more potent and may be used to boost the effect of street drugs. They are associated with fatal overdoses.
Opium is the naturally occurring ’milk’ that comes from the poppy seed heads containing some 80 alkaloids. It used to be smoked in opium dens as a relaxant.
Classic full agonist opioids eg heroin, morphine, tramadol, codeine
Partial agonist opioids eg buprenorphine
Pharmacotherapies for opioids
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.
Stimulants
Stimulant drugs are both derived from plants and produced synthetically. Potency varies enormously from a cup of coffee (caffeine) to get you going in the morning to cocaine.
Typically stimulants are potent dopamine reuptake blockers. The increase in dopamine causes euphoriant and ‘feel good’ effects but 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’.
Ecstasy (MDMA) causes much greater release of 5HT than other stimulants. Drugs that do this are called entactogens and they cause a sense of togetherness and strong emotions when dancing or having sex, complementing the stimulant effects.
A number of stimulants have an agonist effect at just the one receptor type. These include caffeine and nicotine.
Psychedelics
NDMA receptors activated by glutamate stimulate CNS and keep the brain awake: they are concerned with memory and learning. 5HT has effects on perception and 'flashbacks'
For hallucinogenic drugs, LSD, psylocibin, mescaline NMDA receptors are powerfully activated
For dissociative drugs, ketamine, phencyclidine, NMDA receptors are powerfully blocked
more about addiction…
