Psychedelic Therapy in the Treatment of Addiction: The Future

Thanks to advances in imaging tools, we are better equipped to measure what happens in the brain after ingesting psychedelics. This allows us to test hypotheses such as:

1. Can psychedelics “fix” hijacked reward networks in the brain, rewiring the parts responsible for reward processing, impulsivity, and inhibitory control?

2. Can psychedelics restore neurotransmitter deficits and address dysfunction in systems related to addiction, such as the opioid, dopamine, and serotonin systems?

3. Can psychedelics restore deficits in cortical neuroplasticity?

Let’s touch on some of these techniques:

Functional Magnetic Resonance Imaging (fMRI)

Functional magnetic resonance imaging (fMRI) provides an indirect measure of brain activity while at rest or performing neurocognitive tasks. fMRI can assess brain activity in areas related to reward processing, memory, cognition, and emotions, among others – making it extremely valuable to investigations of what happens in the brain during states of addiction and relapse, and the actions psychedelics take within the brain to correct these pathways.

For example: fMRI has been used to demonstrate decreased functioning in brain areas related to reward processing (such as “it’s worth not taking this action because the long-term benefits outweigh short-term rewards”) in individuals with addictions compared to those without.

Relevancy: A recent study (Glazer et al., 2023) examined how two single, low-dose applications of LSD affected reward processing compared to placebo. The study provided the first published evidence that low-dose LSD can improve brain activity in areas responsible for reward processing, suggesting a potential therapeutic mechanism for psychedelics in treating addiction.

We can also use fMRI to measure cue reactivity. Cue reactivity refers to our response to video and photo “cues” that can trigger certain behaviors, urges, impulses, etc. Persons with addiction exhibit cravings and stronger responses to “cues” that are related to their addiction. For example – an ad for a gambling service may be a “cue” that triggers certain behaviors in a person with a gambling addiction. As noted in the article:

”…aberrant fMRI cue-reactivity has also been demonstrated in individuals with gambling disorders (GDs) when compared with matched controls, showing greater gamblers to have greater reactivity to gambling cues in the left insula and the anterior cingulate cortex (ACC) and with craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum.”

fMRI also allows us to measure emotional and social processing. In response to perceived threats, some individuals with addiction adopt avoidant behaviors – such as using a drug to get “high” – in an effort to reduce stress and dissociate from a painful reality. Alterations in certain brain regions, including the amygdala and frontal cortex, are thought to drive these responses. 

FMRI has been used to detect dysfunctional amygdala reactivity in response to perceived threats in individuals with addiction. fMRI has also shown that psilocybin decreases connectivity between the amygdala and other brain regions during threat/fear processing – suggesting psilocybin and other psychedelics may allow individuals with addiction to process threats in a healthier manner by actively engaging with their emotions in the present moment rather than engaging in avoidant behaviors.

The research team behind today’s article suggests using fMRI in several ways to enhance studies into the efficacy of psychedelics for treating addiction, primarily:

1. Use fMRI to measure immediate neuropsychopharmacological effects on brain regions limited to reward processing and cue-reactivity

2. Use fMRI to measure changes in brain function pre- and post-psychedelic treatment using tasks that measure functions such as impulse control, inhibitory control, and cognitive flexibility.

Molecular In Vivo Human Neuroimaging

Positron emission tomography (PET) and Single Photon Emission Computed Tomography (SPECT) allow us to “see” a living human brain in action – well, sort of. We can’t see all of everything going on upstairs, but it’s a start.

With PET, we measure gamma rays emitted from a radioactive source attached to a compound which can bind to a known molecular target in the brain. So far, this is the only direct way to quantify the different neurotransmitters (of which there are over 100 known, and likely more we have yet to discover). This method has, among other advances, allowed us to try and establish a neurochemical basis for addiction – in simpler words, what changes happen in brain signaling that are responsible for causing addiction?

By advancing our knowledge of molecular dysfunctions that occur in addition, we can make better, more educated attempts at treating the condition. You can’t “fix the roads” without making a detailed map showing which ones have potholes, which need to be repainted, and so on. Trying to fix our brain infrastructure isn’t different.

Molecular neuroimaging has identified different molecular biomarkers for addiction, and also plays a role in identifying how these biomarkers respond to treatment with psychedelics. These biomarkers include:

Dopamine

The “feel-good” neurotransmitter has been studied thoroughly with respect to its role in addiction. Studies have found decreased availability of some dopamine receptors in alcohol and stimulant use disorders – but no significant changes were found in those with opioid, cannabis, or tobacco use disorder, or in those with a gambling addiction.

Molecular neuroimaging has been used to identify an increase in dopamine D3 receptors (DRD₃) in the hypothalamus and substantia nigra in persons with alcohol use disorder or stimulant use disorder – leading to studies of DRD3 antagonists as possible drug candidates for treating these conditions.

Gamma-Aminobutyric Acid (GABA)

GABA is the primary “inhibitory” neurotransmitter in humans. Studies have found lower GABA binding in certain brain regions in persons with alcohol or heroin addiction. GABA receptor dysregulation has also been identified in persons with a gambling disorder.

Opiod Receptors

An upregulation (increase in numbers) of the opioid receptor system has been shown in persons with cocaine, alcohol, and opioid use disorders. Recent research has also identified targeting opioid receptors as a mechanism for treating gambling disorders.

Neurotransmitter Release Capacity

In addition to changes in receptors, neurotransmitter availability and transmissions may be affected in addiction disorders. This makes sense if we view addiction through the “reward deficient state” lens – which, essentially, posits that deficiencies in how the brain’s reward system functions leads to deficient “reward” signaling – which is compensated for by substance use that delivers said reward through, for example, feeling “high”.

You may be able to guess where this is going – by studying neurotransmitter release patterns across people with and without addiction disorders, we can:

1. Try and discover differences in neurotransmitter release – such as neurotransmitter release capacity – in persons with addiction, and

2. Measure whether psychedelic treatment acts at a molecular level to address these findings

For example, research has discovered persons with cocaine, opioid, or alcohol use disorder exhibit blunted dopamine release – but this has not been demonstrated in cannabis use disorder. Blunted dopamine release may be a sign of increased impulsivity and dysfunctional cost/benefit analysis witnessed in addictive disorders. 

Blunted dopamine transmission may be a way to detect persons who are at higher risk for not only addictive disorders, but resistance to treatment as well. Some research has shown that 5-HT2AR agonism (a hallmark action of psilocybin and other psychedelics) may trigger dopamine release – and may even be necessary along with dopamine release in order for the brain’s reward circuitry to activate appropriately.

Conclusion