Fear and anxiety

Addiction is a chronic, relapsing disorder involving changes in brain reward, motivation, learning, stress and executive control systems. While different substances (and behaviours) act through distinct primary mechanisms, they converge on common neurobiological pathways — particularly the mesocorticolimbic dopamine system.

Below is an overview in Australian English of the core mechanisms and then substance-specific and behavioural addiction processes.

Core Neurobiological Pathways in Addiction

1. The Mesocorticolimbic Dopamine System

The central pathway implicated in addiction is the mesocorticolimbic circuit, involving:

• Ventral tegmental area (VTA)
• Nucleus accumbens (NAc)
• Prefrontal cortex (PFC)
• Amygdala
• Hippocampus

All addictive drugs increase dopamine transmission in the nucleus accumbens, either directly or indirectly. Dopamine does not simply produce pleasure — it encodes reward prediction, salience and learning. With repeated exposure:

• Drug-related cues gain exaggerated salience
• Natural rewards become less reinforcing
• Behaviour becomes increasingly habitual and compulsive

2. Neuroadaptation and Allostasis

Repeated substance exposure produces:

Tolerance — Reduced response due to receptor downregulation or neurotransmitter depletion.

Dependence — Neuroadaptations that produce withdrawal when the substance is removed.

Allostatic shift — The brain’s reward set point shifts downward, mediated by stress systems (e.g. corticotropin-releasing factor), resulting in dysphoria during abstinence.

3. Habit Formation and Loss of Control

With repeated use:

• Control shifts from ventral striatum (goal-directed) to dorsal striatum (habit-based)
• Prefrontal cortex regulation weakens
• Impulsivity and compulsivity increase

Substance-Specific Mechanisms

Alcohol

Alcohol acts on multiple neurotransmitter systems:

• Enhances GABA-A receptor function (inhibitory)
• Inhibits NMDA glutamate receptors (excitatory)
• Increases dopamine release in nucleus accumbens
• Affects endogenous opioid systems

Chronic exposure leads to:

• GABA downregulation
• NMDA upregulation
• Hyperexcitable state during withdrawal (risk of seizures, delirium tremens)

Alcohol dependence also involves stress system activation and impaired frontal cortical control.

Methamphetamine

Methamphetamine is a potent psychostimulant that:

• Enters presynaptic terminals
• Reverses the dopamine transporter (DAT), causing carrier-mediated dopamine efflux
• Inhibits vesicular monoamine transporter 2 (VMAT2), releasing dopamine from synaptic vesicles into the cytoplasm
• Causes massive dopamine release into the synapse

It also increases noradrenaline and serotonin.

Chronic use causes:

• Dopamine neurotoxicity (particularly to dopaminergic terminals)
• Reduced dopamine transporter availability
• Structural changes in striatum and PFC
• Persistent cognitive deficits

Methamphetamine produces particularly strong sensitisation of cue-driven craving.

Cocaine

Cocaine:

• Blocks the dopamine transporter (DAT), preventing reuptake
• Increases synaptic dopamine concentration

Unlike methamphetamine, cocaine acts by blocking DAT rather than reversing it, and does not cause large presynaptic vesicular release — the elevation in synaptic dopamine arises from impaired clearance.

Repeated use leads to:

• Dopamine receptor downregulation
• Enhanced cue reactivity
• Rapid cycling between intoxication and crash
• Strong psychological dependence

Opioids (e.g. heroin, morphine, oxycodone)

Opioids act primarily at mu-opioid receptors (MORs), which are expressed throughout the brain, including in the VTA. Their dopaminergic effects arise through multiple mechanisms:

• MORs on GABAergic interneurons in the VTA suppress inhibitory tone, thereby disinhibiting dopamine neurons (the classical disinhibition mechanism)
• MORs are also expressed on VTA dopamine neurons and projection targets directly, contributing additional excitatory drive beyond the disinhibition pathway

They also act in brainstem respiratory centres, which underlies the risk of respiratory depression in overdose.

Chronic use produces:

• Receptor desensitisation and internalisation
• Reduced endogenous opioid production
• Severe physical withdrawal mediated by noradrenergic rebound in the locus coeruleus
• Strong negative reinforcement (use to avoid withdrawal)

Cannabis

Δ9-tetrahydrocannabinol (THC):

• Activates CB1 receptors (the primary psychoactive cannabinoid receptor)
• Modulates GABA and glutamate release at presynaptic terminals
• Indirectly increases dopamine in NAc via disinhibitory mechanisms

Cannabis produces:

• Altered endocannabinoid system function
• CB1 receptor downregulation with chronic use
• A mild to moderate withdrawal syndrome (irritability, sleep disturbance, appetite changes)
• Effects on hippocampal memory circuits

While addiction risk is generally considered lower than for opioids or stimulants, it remains clinically significant and may be underestimated, particularly given the widespread availability of high-potency THC products (e.g. concentrates and high-THC flower), which are associated with greater dependence risk and more severe withdrawal.

MDMA (Ecstasy)

MDMA:

• Reverses the serotonin transporter (SERT), causing massive serotonin efflux — this is its primary mechanism
• Also increases dopamine and noradrenaline

Neurobiological consequences include:

• Acute empathogenic and entactogenic effects driven by serotonin release
• Post-use serotonin depletion, which may contribute to dysphoria in the days following use
• Potential serotonergic neurotoxicity, though this evidence comes largely from high-dose or repeated animal studies; the clinical significance in typical human recreational use remains under debate and is not definitively established
• Moderate addictive potential relative to psychostimulants, partly because dopaminergic effects are less prominent than with cocaine or methamphetamine

Prescription Psychoactive Medications

Certain prescribed medications also have addictive potential:

Benzodiazepines — Enhance GABA-A receptor activity. Cause tolerance via receptor downregulation. Dependence is primarily a GABAergic adaptation. Withdrawal can be protracted and, in cases of high-dose or long-term use, may produce seizures.

Prescription stimulants — Act via similar mechanisms to amphetamine, increasing dopamine and noradrenaline. Risk of misuse exists in susceptible individuals, though therapeutic doses in appropriately diagnosed patients are associated with substantially lower addiction risk than recreational use.

Behavioural (Process) Addictions

Gambling Disorder

Gambling disorder is recognised in DSM-5-TR as a non-substance-related addictive disorder. Although no substance is ingested, similar neurobiological mechanisms are involved.

Dopamine and reward prediction error — Near misses activate the nucleus accumbens similarly to wins. Variable ratio reinforcement schedules (as in poker machines) generate strong, unpredictable dopamine prediction error signalling that powerfully drives continued behaviour.

Cue reactivity — Gambling-related cues activate the same mesocorticolimbic circuitry as drug cues, with increased striatal activation and reduced prefrontal inhibitory control.

Habit circuitry — A shift from ventral to dorsal striatal control contributes to compulsive betting despite continued losses.

Other Emerging Behavioural Addictions

Conditions such as internet gaming disorder, compulsive sexual behaviour disorder, and problematic social media use share overlapping neurobiological features including:

• Dopamine dysregulation and sensitisation to cue salience
• Reduced executive control
• Stress system activation

However, the evidence base for most of these conditions is still developing, and their classification as formal addictive disorders remains an area of active research and debate. Internet gaming disorder is currently listed in DSM-5-TR as a condition for further study.

Shared Neurobiological Themes Across Addictions

Across substances and behaviours, addiction involves:

• Dopamine sensitisation to cues
• Reduced sensitivity to natural rewards
• Impaired prefrontal inhibitory control
• Stress system overactivation (particularly corticotropin-releasing factor)
• Habit circuitry dominance (dorsal striatum)
• Neuroplastic changes in glutamatergic signalling

Why Some Substances Are More Addictive

Addictive potential is influenced by multiple interacting factors. The speed of dopamine rise is one of the most studied — faster onset of dopamine elevation (e.g. via smoking or intravenous administration) is associated with stronger reinforcement. This framework, developed largely through the work of Volkow and colleagues, has strong empirical support, though it represents a mechanistic model rather than an established universal law. Other important factors include:

• Intensity of dopamine release
• Pharmacokinetics (e.g. route of administration)
• Withdrawal severity (which drives negative reinforcement)
• Social and environmental context
• Genetic vulnerability (heritability of addiction is estimated at 40–60% across substances)

Conclusion

Addiction is not simply about pleasure seeking. It reflects maladaptive neuroplasticity in reward, stress, learning and executive control circuits. While alcohol, methamphetamine, cannabis, opioids, cocaine and MDMA each act through different primary molecular mechanisms, they converge on common neural pathways that drive craving, tolerance, withdrawal and compulsive use. Behavioural addictions such as gambling engage these same circuits despite the absence of an ingested substance.

The neurobiological understanding of addiction continues to evolve, and where evidence is still emerging — particularly regarding emerging behavioural addictions and the long-term neurotoxic effects of substances like MDMA — clinical interpretation should be appropriately cautious.

1. Alcohol (ethanol) enters the body through the oral cavity (i.e., the mouth). The inner surface of the oral cavity is mucosal tissue to keep the cavity lubricated and it is capable of absorbing alcohol into the bloodstream. This absorption is considered “insignificant”.

2. Alcohol flows down the oesophagus to the stomach where 10-20% of ethanol will be absorbed into the bloodstream. Alcohol enters the bloodstream via the mucosal tissue of the stomach wall, and travels straight to the liver. Alcohol can take 5-10 minutes to reach the brain because of the ethanol absorbed via the stomach. If you drink alcohol on an empty stomach, the pyloric sphincter [gateway between the stomach and the small intestine] is going to be more open, and the alcohol is going to immediately enter the small intestine after reaching the stomach. If food is also present in the stomach, the sphincter will open and close at a rate that allows food to enter the small intestine gradually, therefore if alcohol is also in the stomach, it will gradually enter the small intestine.

3. Alcohol flows through the pyloric sphincter into the small intestines where most alcohol absorption occurs. Human intestines are attached the to the posterior abdominal wall by a fold of membrane called the mesentery. Alcohol is absorbed into the mesentery via veins and then travels to the liver.

4. One function of the liver is that it detoxifies toxic elements into non-toxic elements before passing it to the heart and then the rest of the body. The liver sustains considerable “abuse” from a variety of toxic elements and chemicals, and therefore it needs to be capable of full regeneration. NOTE: Many diseases and exposures can harm it beyond the point of repair. These include cancer, hepatitis, certain medication overdoses, and fatty liver disease.

In the liver, ethanol is met with an enzyme called alcohol dehydrogenase and converts ethanol into acetaldehyde [ass-eh-tal-de-hide]. This chemical is more toxic than ethanol, so the liver uses another enzyme to convert acetaldehyde into acetate, which is non-toxic to the human body. NOTE: the amount of alcohol consumed + the timeframe it is consumed [and a variety of other factors] will influence the ability of the liver to effectively convert acetaldehyde all the way into acetate. The liver can’t handle the entire workload effectively therefore ethanol (before being metabolised) will go straight from the liver to the bloodstream and make its way directly to the heart.

NOTE: Genetics will play a role! Certain people do not produce the liver enzymes in enough quantity to properly breakdown ethanol.

5. Blood leaves the liver through the hepatic veins. The hepatic veins carry blood to the inferior vena cava—the largest vein in the body—to the right side of the heart. The heart will beat and send the incoming blood to the lungs to oxygenate and expel carbon dioxide as we breath out. This is how ethanol can be on your breath. Inside the lungs, at the very end of the bronchioles, are hollow air sacs called alveoli where there is a gas exchange. Ethanol evaporates through capillaries into the air sacs and exhaled out of the body. Breathalysers can detect the quantity of ethanol in a person’s system based on the quantity of ethanol in our breath.

6. Not all the ethanol will expel from the body via the breath. The rest will flow back to the heart, with newly oxygenated blood, and then get pumped all the way up to the brain and around the body. NOTE: Ethanol is water soluble. It will be distributed to every cell in the body except bone and fatty tissue [some will enter fat cells but not easily]. Ethanol will interact with every other cell i.e., every organ, gland, nerve, muscle etc.

7. Ethanol will affect and compromise protein synthesis inside muscle tissue. Therefore, if you have been training at the gym, running, swimming etc., your muscles will not effectively be able to repair.

8. Once ethanol has reached the brain, it will cross the blood-brain barrier and begin to affect chemical messengers [neurotransmitters] in the grey matter of the brain. It affects serotonin, dopamine, gamma-amino-butyric-acid (aka GABA), glutamate, endorphins etc. The person will experience pleasure, euphoria, lowered inhibitions [related to dopamine], lowered cognitive ability (e.g., decision making/problem solving, emotion regulation) and lowered coordination and reflexes.

The more ethanol ingested, the more dopamine is secreted and communicated between neurons (i.e., nerve cells). One of dopamine’s functions is to make you feel pleasure or ‘rewarded’ for doing things that are good for humans, hence, from an evolutionary perspective, we are likely to do them again to help us thrive in our environment and social world. Dopamine is secreted when we:

• eat healthy foods (but also recently developed processed foods that are high in sugar and salt)
• exercise
• achieve goals
• be productive (e.g., finish a task like cleaning, cooking, work-related tasks)
• master new skills (e.g., learning an instrument or a new talent), and
• have positive and stimulating social interactions

Ethanol influences so much dopamine secretion and communication that the brain becomes unable to make responsible decisions cognitively. The simultaneous experience of euphoria and lowered cognitive ability means we are more likely to be “happy” about making irresponsible decisions.

Increased dopamine is how drinking alcohol “blocks” unpleasant emotions like fear, stress, anxiety, and insecurity. When we don’t feel these unpleasant, yet necessary, emotions we will behave in ways that are dangerous, abnormal, potentially embarrassing, and generally problematic.

Another significant brain region affected by ethanol is the hypothalamus and the pituitary glad [together known as the hypothalamic-pituitary axis]. These structures control the entire hormonal system. The hypothalamus monitors the body, and it will send instructions to the pituitary gland based on information it receives from the hypothalamus. The hypothalamus is aware that ethanol is flooding the brain and it starts adjusting the secretion of hormones via the pituitary gland.

One of the instructions it gives the pituitary gland is to start modulating the adrenal glands to secrete cortisol (i.e., stress hormone) and epinephrine and norepinephrine (i.e., adrenaline).

Now, our cognitive capacity is diminished, inhibitions are lowered, and we will experience a rush of stress hormones and adrenaline coursing through the body. Cortisol and adrenaline will provide a boost of energy. It will increase the heart rate, blood pressure, body sweat, sugar levels in the bloodstream, and enhances the brain’s ability to use glucose. Glucose is a “fuel” source for brain functioning, including the generation of neurotransmitters. Behaviourally, we can see this in children when we say they are “hyperactive” because they’ve ingested too much sugar.

The pituitary gland will also slow the secretion of anti-diuretic hormone (aka. vasopressin). A diuretic is something that makes us urinate. If the anti-diuretic hormone (also called vasopressin) slows down, then we won’t be “holding on” to water as effectively, hence we begin to urinate more. People call this “breaking the seal”.

9. South of the body, blood is pumped into the kidneys via the renal artery which spreads through the renal cortex. The blood is then filtered into urine and expelled from the body. The lowered anti-diuretic hormone will dilate (become wider/bigger or more open) blood vessels in the kidneys which means more blood gets passed through and filtered, but it also means we lose a lot more body water which leads to dehydration. Vasopressin is essential in the control of osmotic balance, blood pressure regulations, and kidney function, therefore, when vasopressin is lowered, we are losing essential water and minerals/electrolytes. Electrolytes are involved in urination because the kidneys need them to make the process of filtering blood more efficient.

The loss of water and electrolytes will contribute to a hangover. Electrolytes play a role in cellular water absorption so if we are losing more water than we are bringing in, and we are losing the electrolytes that support the absorption of water, we become dehydrated very quickly.

10. The Hangover

Symptoms: nausea, fatigue, diarrhoea, vomiting, paranoia, anxiety, anorexia (i.e., loss of appetite), increased thirst, muscle weakness, irritability, sweating, increased blood pressure, and headache.

The exact cause of a “hangover” is not yet known however variables affecting the hangover are:

• individual differences such as sex, size, body fat, genetics etc
• lack of sleep
• general health
• drinking behaviour e.g., frequency, duration, quantity
• food intake before and during
• water intake before and after
• your body’s ability to metabolise alcohol i.e., excessive amounts of acetaldehyde due to fewer enzymes to metabolise alcohol in the liver before entering the bloodstream
• general behaviour while drinking e.g., poly-substance use, dancing, sexual activity, risk-taking behaviours etc.

Strategies for Controlled Drinking

• Setting personal drinking limits and sticking to it
• Alternating alcoholic drinks with soft drinks i.e., one alcoholic drink then a water, soft drink, or juice
• Have a meal before drinking
• Switching to low alcohol drinks
• Having regular alcohol-free days/weeks/months
• Identifying high risk situations for heavy drinking and creating a management plan

Engaging in alternative activities to drinking

Stephen Porges, psychiatry professor and researcher, on the polyvagal theory he developed to understand our reactions to trauma:

[Paraphrased] Polyvagal theory articulates three branches of the autonomic nervous system (ANS) that evolved from primitive vertebrates to mammals. First, there is a system known as ‘freeze’, which involves death feigning or immobilisation. Second, the ANS has a ‘fight or flight’ system, which is a mobilisation system. And third, with mammals, there is what Porges calls, a social engagement system (SES), which can detect features of safety, and actually communicate them to another. The SES may also be referred to by some as ‘rest and digest’, which Porges theory suggests is a function of the Vagus Nerve – the tenth cranial nerve, a very long and wandering nerve that begins at the medulla oblongata. When an individual experiences feelings of safety (within an SES state), the autonomic nervous system can support health restoration. In terms of dealing with a life threat, an ordinary person will most likely go into a feigning death, dissociative state of ‘freeze’.

Polyvagal theory in psychotherapy offers emotional co-regulation as an interactive process between therapist and client which engages the social engagement system of both therapist and client. Social engagement provides experiences of safety, trust, mutuality and reciprocity in which we are open to receiving another person, just as they are.

The following extract has been retrived from https://www.theguardian.com/society/2019/jun/02/stephen-porges-interview-survivors-are-blamed-polyvagal-theory-fight-flight-psychiatry-ace

Polyvagal theory has made inroads into medical and psycho-therapeutic treatment, but how should it inform how people treat each other?

“When we become a polyvagal-informed society, we’re functionally capable of listening to and witnessing other people’s experiences, we don’t evaluate them. Listening is part of co-regulation: we become connected to others and this is what I call our biological imperative. So when you become polyvagal-informed you have a better understanding of your evolutionary heritage as a mammal. We become aware of how our physiological state is manifested, in people’s voices and in their facial expression, posture and basic muscle tone. If there’s exuberance coming from the upper part of a person’s face, and their voice has intonation modulation or what’s called prosody, we become attracted to the person. We like to talk to them – it’s part of our co-regulation.

So when we become polyvagal-informed, we start understanding not only the other person’s response but also our responsibility to smile and have inflection in our voice, to help the person we’re talking to help their body feel safe.”

Clink on the link below to hear Dr. Bessel van der Kolk, one of the world’s leading experts on developmental trauma, explain how our long-term health and happiness can be compromised by prior exposure to violence, emotional abuse, and other forms of traumatic stress.

https://youtu.be/53RX2ESIqsM