Addiction

In the United States, the lifetime prevalence of addiction to alcohol and illicit drugs is estimated to be between 12% and 3% respectively; addiction to prescription drugs has been found to occur in 4.7% of the population. Perhaps most concerningly, in 2018, 2-million people misused prescription opioids for the first time, while 47,600 people died from opioid overdose, and a full 2.1 million people qualified for a diagnosis of opioid use disorder. Prognosis across addiction types is poor, and current treatment options for all types of addiction are scant and produce variable results, with relapse rates across substance use disorders estimated to be between 40 and 60%.

In the United States, the lifetime prevalence of addiction to alcohol and illicit drugs is estimated to be between 12% and 3% respectively; addiction to prescription drugs has been found to occur in 4.7% of the population. Perhaps most concerningly, in 2018, 2-million people misused prescription opioids for the first time, while 47,600 people died from opioid overdose, and a full 2.1 million people qualified for a diagnosis of opioid use disorder. Prognosis across addiction types is poor, and current treatment options for all types of addiction are scant and produce variable results, with relapse rates across substance use disorders estimated to be between 40 and 60%.

Of course, not everyone that misuses a substance necessarily suffers from an addiction. For many, the harmful side effects of misuse (i.e. a hangover after excessive alcohol consumption) will deter additional use. Those suffering from addictions, however, may pursue the substance regardless of personal costs. Symptoms of addiction include:

  • Being unable to refrain from seeking drugs
  • Being unable to refrain from harmful habit-forming behaviour
  • Losing interest in activities not related to harmful substance or behaviours
  • Relationship difficulties (e.g. lashing out at those who try to address dependency)
  • Taking risks and engaging in secrecy around behaviour or substance use
  • Continuing substance use or behaviour despite personal, professional, and health costs
  • Profound changes in appearance, including deteriorating hygiene

According to numerous experts, “[d]rug abuse and addiction exact an astoundingly high financial and human toll on society through direct adverse effects, such as lung cancer and hepatic cirrhosis, and indirect adverse effects – for example, accidents and AIDS – on health and productivity.” In the United States, the economic effects of addiction exceed those from all types of cancers and diabetes combined.

Addiction is a complex and multifactorial condition with significant links to numerous psychiatric disorders, including depression and anxiety. Moreover, the causes of addiction are only beginning to be fully understood, with persisting questions around why similar experiences produce addiction in one person but not another. In short, however, the addiction – and by extension dependence – potential of a drug varies from substance to substance, as well as from individual to individual.

It is important to note that physiological dependence is a distinct, albeit related, concept to the behavioural effects of addiction. A 2007 study by Professor David Nutt developed a scale of harm and dependence liability of 20 drugs, using a scoring system that compared pleasure, psychological dependence, and physical dependence to produce a mean score indicating dependence potential. A selection of these is below:

Drug

Mean

Pleasure

Psychological dependence

Physical dependence

Ecstasy

1.13

1.5

1.2

0.7

LSD

1.23

2.2

1.1

0.3

Cannabis

1.51

1.9

1.7

0.8

Ketamine

1.54

1.9

1.7

1

Amphetamine

1.67

2

1.9

1.1

Alcohol

1.93

2.3

1.9

1.6

Barbiturates

2.01

2

2.2

1.8

Tobacco

2.21

2.3

2.6

1.8

Benzodiazepines

2.23

1.7

2.1

2.8

Cocaine

2.39

3

2.8

1.3

Heroin

3

3

3

3

Interestingly, though tobacco was found to have lower dependence potential than either heroin or cocaine, data from the National Institute of Drug Abuse and the UK National Addiction Centre indicate that tobacco’s capture rate (percentage of users who become dependent) was 31.9%, exceeding both heroin (23.1%) and cocaine (16.7%). The capture rate of marijuana users was found to be just 9.1%.

Neurologically speaking, addiction is a disorder of the brain’s reward pathways that typically develops over time from high levels of exposure to addictive stimuli. This can include everything from eating food, the use of cocaine, engagement in sexual activity, participation in high-thrill cultural activities such as gambling. One study reports:

“Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction.”

Dopamine is the most important neurotransmitter in the reward system of the brain, and plays a key role in regulating emotion, cognition, motivation, and feelings of pleasure. Though everyday activities like eating release dopamine, most addictive drugs also affect the brain’s reward system by heightening dopaminergic activity. Excessive intake of certain drugs, as well as overindulgence in high-risk behaviour like gambling or sexual activity, can result in chronically high levels of dopamine in the synaptic cleft, leading to downregulation of mesolimbic dopamine receptors, decreasing natural reward sensitivity and reinforcement. The behavioral aspects of addiction (e.g. compulsive drug seeking) stem from glutamatergic projection from the prefrontal cortex to the nucleus accumbens (a region of the brain that has a significant role in processing motivation); this activity can be interrupted by inhibiting glutamate receptor activity.

Crucially, the subject of addiction seems to matter less than the associated neurological activity, with functional neuroimaging studies in humans showing that gambling, shopping, orgasm, playing video games and the sight of appetizing food activated many of the same brain regions (i.e., the mesocorticolimbic system) as many drugs of abuse.

So how does addiction arise and what are the risk factors?

As with depression and anxiety, addiction arises from an interplay of genetics and environmental factors, which each make up approximately half of an individual’s risk for developing an addiction (the impact of epigenetics is as yet unknown). Regardless of one’s genetic risk for addiction, sufficient exposure to addictive stimuli for extended periods can produce addiction. Age and comorbid mental health disorders also affect the likelihood of developing an addiction.

Although there are numerous environmental and psychosocial factors that have been implicated in addiction, an individual’s exposure to an addictive drug is by far the most significant risk factor. Other factors cited by the National Institute of Drug Abuse include a lack of parental supervision, prevalence of peer substance use, drug availability, and poverty – particularly among children. Indeed, adverse childhood experiences and other forms of maltreatment and household dysfunction have been shown by the Centers for Disease Control and Prevention to have a strong dose–response relationship with numerous health, social, and behavioural problems throughout a person’s lifespan, among them substance abuse and addiction. Children’s neurological development can be permanently disrupted by abuse, physical and emotional neglect, or witnessing a parent suffering from mental illness, leading to deficiencies in the child’s ability to cope with negative or disruptive emotions. One study of 900 court cases found that the vast number of children who experienced abuse went on to suffer from some form of addiction in adolescence or adulthood.

With respect to genetics, epidemiological studies indicate that approximately 40-60% of risk for alcoholism is genetic, with additional studies suggesting similar rates of heritability for other substances. It has been theorized that genes predispose an individual toward addiction in numerous ways, including by changing the structure or functioning of specific brain regions during development, thereby influencing susceptibility to initial and subsequent drug use. Nevertheless, despite consensus that genetics play a key role in addiction, data on individual genes is mixed. This may be due in part to the fact that addiction studies typically focus on common variants with allele frequencies above 5%, which are known to add only minor amounts of additional risk (1.1-1.3%); rarer variants are hypothesized to add a much larger degree of risk.

Importantly, according to the Mayo Clinic, those with comorbid psychiatric disorders (also highly influenced by genetics), particularly depression, anxiety, attention deficit hyperactivity disorder, or post-traumatic stress disorder, are much more likely to develop substance use disorders. One study by the National Bureau of Economic Research found a “definite connection between mental illness and the use of addictive substances”, with those suffering from a psychiatric disorder consuming up to 38% of all alcohol, 44% of all cocaine, and 40% of all tobacco (these numbers are even higher when viewed in terms of lifetime incidence of mental health disorders).

While there is still much to learn about the mechanisms that underlie addiction, it is clear that chronic drug use causes alterations in gene expression in mesocorticolimbic projection. The transcription factor DeltaFosB (ΔFosB) is likely the most significant biomolecular mechanism in addiction and is common to the development of nearly all forms of behavioral and drug addiction.  The overexpression of ΔFosB in the nucleus accumbens is critical to the neurological changes and behavioral effects seen in drug addiction and is frequently used as a biomarker for the condition. ΔFosB expression directly and positively regulates self-administration and reward sensitization in drug use, while decreasing sensitivity to aversion (negative outcomes of behaviour, such as hangover or withdrawal). Importantly, ΔFosB also plays an important role in regulating behavoral responses to natural rewards (e.g. food and sex), and chronic pursuit of these rewards can lead to the same changes in overexpression and pathology as substance addiction. This is important because ΔFosB inhibitors may therefore be an effective treatment for all types of addictions.

Overall, while treatable, prognosis for all types of addiction is poor and relapse rates are consistent with other types of chronic disease. Moreover, treatment options are limited and often come with dangerous side effects or even their own potential for abuse (e.g. methadone or buprenorphine for opioid use disorder / maintenance therapy). But now, evidence is building for a new class of therapeutics: psychedelics. For example, studies examining the potential of psilocybin for smoking cessation and alcohol use disorder have produced encouraging results (additional studies are currently recruiting participants), while ketamine has been found to be effective in curtailing the cravings of cocaine users. But perhaps most compelling is ibogaine, of which the largest observational study to date reported that of 88 subjects interviewed, 80% reported that treatment either reduced or eliminated their withdrawal symptoms.

In summary, addictions are costly, complex and multifactorial conditions that develop due to a combination of genetics and environmental factors. Addiction involves rewiring the reward pathways of the brain through changes in gene expression, leading to alterations in dopamine activity that sensitizes suffers to addictive stimuli while desensitizing them to negative outcomes. Given the complexity of addiction disorders, as well as the lack of effective treatment options, more research in this area is key.

Stay tuned throughout 2020 to learn more about how ATAI Life Sciences is working to serve those suffering from addiction.