Table 3.

Drug classes and their main mechanisms of action

Drug class	Main mechanisms of action
Alcohol	Alcohol affects multiple targets (enhances GABA, mu opioid receptor and cannabinoid signaling), indirectly increasing dopamine in the nucleus accumbens.
Nicotine	Nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs). In particular its binding to the α4β2 nAChR subtype is associated with its reward‐related and reinforcing effects, directly activating dopamine neurons in the ventral tegmental area (also activates modulatory neurons in this area).
Cannabinoids	The rewarding and reinforcing properties of cannabis are due to tetrahydrocannabinol, which is a partial agonist at the CB1R receptors. Cannabidiol is neither rewarding nor addictive. Synthetic cannabinoids’ agonism at CB1R also underlies their rewarding and reinforcing effects. CB1R activation modulates presynaptic release of GABA and glutamate, activating dopamine neurons in the ventral tegmental area.
Cannabis, Synthetic cannabinoids
Stimulants	Amphetamines, whether legally prescribed as medications for ADHD or obtained from illicit or clandestine sources (e.g., meth labs), directly release dopamine from the terminals of dopaminergic neurons via dopamine transporter (DAT) reversal and depletion of vesicular dopamine stores.
Amphetamines, Cocaine
	Cocaine increases dopamine by inhibiting DAT, which prevents dopamine reuptake leading to its synaptic accumulation.
Opioids Morphine, Heroin, Fentanyl	Opioids’ rewarding effects are due to their agonist actions at mu opioid receptors. In the ventral tegmental area, opioid binding to these receptors on GABA cells disinhibits dopaminergic neurons, increasing dopamine in nucleus accumbens, which underlies their reinforcing properties. Opioid drugs differ in potency, with fentanyl >> heroin > morphine.
Inhalants Volatile solvents, Aerosols, Gases, Nitrites	Inhalants have effects on various neurotransmitters and their receptors (NMDA↓ glycine↑, GABAA↑, nACh↓, dopamine↑), enhancing dopamine release.
Sedative/Hypnotics	Benzodiazepines and barbiturates, which are used as therapeutics for anxiety, insomnia, seizures, and sedation in anesthesia, are misused for their rewarding effects. They enhance GABAA receptor function, increasing dopaminergic neuron firing in the ventral tegmental area through disinhibition, which underlies their reinforcing properties.
Benzodiazepines, Barbiturates
Classic hallucinogens	Hallucinogenic drugs act as agonists at the 5‐HT2 receptor. They are predominantly used to alter mental states and do not trigger compulsive drug taking. They are the only drugs in this table not considered to be addictive. They also have effects at other serotonin receptors.
Psilocybin, Lysergic acid diethylamide (LSD), Mescaline, Dimethyltryptamine (DMT)
Dissociative drugs Ketamine, Phencyclidine (PCP)	NMDA receptor antagonism dissociates the cortical control and the gating of thalamus, facilitating transmission of perceptual stimuli to sensory cortices. These drugs have additional targets, including mu opioid receptors, which might underlie their increase of dopamine in nucleus accumbens.
Mixed drugs	MDMA is a blocker of monoamine transporters. Its effects are similar both to those of stimulants (enhancing dopamine) and of hallucinogens (enhancing serotonin).
3,4‐Methylenedioxy‐methamphetamine (MDMA)

ADHD – attention‐deficit/hyperactivity disorder, NMDA – N‐methyl‐D‐aspartate