By Brent Boyett DMD, DO, DFASAM
Controlled substances as recognized by the US Drug Enforcement Agency all have a one thing in common. They all release dopamine into the synaptic clefts of the brain’s motivational reward centers. This center known as the nucleus accumbens creates the sense of pleasure and motivates us to approach or pursue the behaviors that replicate those rewards. While pleasure compels us to pursue pro-survival circumstance that are essential to support life, pain protect us by compelling us to avoid harm.
There are multiple neurochemical pathways that can produce this sense of pleasure and all are the result in the release of dopamine in the nucleus accumbens. This dopaminergic activation creates a sense of pleasurable reward that moves the needle of hedonic tone away from physical and emotional pain (dysphoria) and toward physical and emotional pleasure (euphoria).
The brain and spinal cord are genetically programed to maintain homeostasis despite an ever-changing environment. Opponent Process Theory first described by Solomon and Corbett in 1974 describes the process this way. “Any stimulus that alters our consciousness will elicit an adaptation by the brain that is exactly the opposite to the effect of the stimulus.”
Opponent Process Theory of Motivation (Richard Solomon and John Corbitt 1974)
The opponent process theory of motivation is a psychological theory that explains how emotions are regulated by pairs of opposing emotional processes. According to this theory, any emotional experience consists of a primary emotion, which is followed by an opposing secondary emotion. For example, joy’s opposite is sadness, and fear’s opposite is relief. The theory suggests that these opponent states explain emotional dynamics like thrill-seeking behaviors and drug addiction12.
The theory was proposed by Richard Solomon and John Corbitt in 1974, based on their studies of the effects of heroin and other drugs on rats. They observed that the initial euphoria induced by heroin was followed by a dysphoric state that lasted longer than the euphoria. They also found that repeated exposure to heroin reduced the intensity of the euphoria and increased the intensity of the dysphoria, leading to a negative emotional balance. They proposed that this was due to the development of tolerance to the primary emotion (A-process) and sensitization to the secondary emotion (B-process)3.
The theory can be applied to understand how drug tolerance, dependence, and opioid-induced hyperalgesia (OIH) are related. Drug tolerance is the phenomenon of needing higher doses of a drug to achieve the same effect. Dependence is the state of physical or psychological reliance on a drug, characterized by withdrawal symptoms when the drug is discontinued. OIH is a paradoxical increase in pain sensitivity that occurs with chronic opioid use. According to the opponent process theory, these phenomena are the result of the imbalance between the A-process and the B-process. As the A-process becomes weaker and the B-process becomes stronger, the drug user experiences less pleasure and more pain from the drug, and needs more of the drug to avoid the negative emotional state. This creates a vicious cycle of escalating drug use and worsening emotional and physical outcomes45.
1: Opponent Process Theory of Emotion and Motivational States 2: Opponent-process theory - Wikipedia 3: What is the Opponent Process Theory of Motivation? 4: Opioid-Induced Tolerance and Hyperalgesia | CNS Drugs - Springer 5: Differential Opioid Tolerance and Opioid-induced Hyperalgesia
Speedballing is the practice of using a mixture of opioids and amphetamines, usually heroin and cocaine. Prescription speeding balling is the practice of prescribing amphetamines such as dextroamphetamine/ amphetamine (Adderall) in combination with an opioid pain reliever. This combination can have harmful effects on the brain’s motivational reward circuits, which are responsible for regulating pleasure, motivation, learning, and memory. Some of the potential harms are:
: Dopamine is a neurotransmitter that mediates the rewarding effects of drugs and natural stimuli. Opioids and amphetamine both increase dopamine levels in the reward circuit, but in different ways. Opioids activate opioid receptors, which inhibit the neurons that normally limit dopamine release. Amphetamine blocks the reuptake of dopamine, which prolongs its action in the synapse. The combined effect of these drugs is a massive surge of dopamine, which can overwhelm the reward circuit and cause tolerance, dependence, and addiction12. This is another example of the harmful effects of opponent process described. As the result of overstimulation, dopamine receptors become desensitized to dopamine and ultimately the receptor density can become significantly reduced. As a result of prescription speedballing, patients develop anhedonia resulting in chronic dysphoria.
• : The reward circuit is also involved in learning and memory formation, especially for stimuli that are associated with rewards or punishments. The excessive dopamine release caused by speedballing can impair the ability of the reward circuit to encode and retrieve information, leading to poor decision-making, impaired judgment, and reduced impulse control2. Speedballing can also damage the hippocampus, a brain region that is essential for memory consolidation and spatial navigation3.
: The reward circuit is connected to other brain regions that regulate mood and emotion, such as the amygdala, the prefrontal cortex, and the insula. Speedballing can disrupt the balance of these regions, causing mood swings, anxiety, depression, and dysphoria. Speedballing can also reduce the sensitivity of the reward circuit to natural rewards, such as food, sex, or social interaction, resulting in anhedonia, or the inability to experience pleasure
1. Hypodopaminergic Anhedonia:
o Chronic cannabis use has been associated with a condition known as hypodopaminergic anhedonia. Anhedonia refers to a reduced ability to experience pleasure or interest in previously enjoyable activities.
o Cannabis exposure can lead to decreased dopamine function in the brain, which affects the reward system. Dopamine is a neurotransmitter involved in feelings of pleasure and motivation.
o Reduced dopamine levels can result in symptoms like depression, cognitive decline, poor memory, inattention, and impaired learning performance.
o The high content of delta-9-tetrahydrocannabinol (THC) in modern cannabis products may exacerbate these effects, especially in young adults who use oral or vaping cannabis products1.
2. Damage to Brain Reward Circuits:
o The combination of cannabis and opioids can impact the brain’s reward circuits.
o Chronic cannabis use, as observed through PET scans, shows reduced brain dopamine synthesis. This reduction in dopamine availability can lead to attenuated reward sensitivity and motivation.
o The brain’s reward system relies on dopamine release to reinforce positive behaviors. When this system is compromised, it can lead to apathy and reduced motivation.
o The interaction between cannabis and opioids may further disrupt this delicate balance, potentially worsening anhedonia and cognitive decline1.
Combining cannabis with opioids can have detrimental effects on the brain’s reward pathways, leading to anhedonia and impairing cognitive function. It’s essential to consider these risks when evaluating the use of these substances together.
1.
Reduced Dopamine Function:
o Polypharmacy involving substances like opioids, cannabis, or stimulants can lead to reduced dopamine availability in the brain.
o Dopamine is crucial for feelings of pleasure, motivation, and reward.
o Diminished dopamine function may result in anhedonia (reduced ability to experience pleasure) and apathy.
2. Attenuated Reward Sensitivity:
o Chronic use of multiple substances can disrupt the brain’s reward system.
o Reduced reward sensitivity may lead to decreased motivation and interest in previously enjoyable activities.
o The delicate balance of dopamine release is affected, impacting overall well-being.
3. Cognitive Impairment:
o Polypharmacy can impair cognitive function, memory, and attention.
o The brain’s ability to learn and adapt may be compromised.
o Long-term use of controlled substances may exacerbate cognitive decline.
4. Interaction Effects:
o Interactions between different substances can be unpredictable.
o Combining opioids, sedatives, or other drugs may amplify negative effects on reward circuits.
o The risk of addiction and dependence increases with polypharmacy.
In recent years molecular biology has explained in detail the mechanisms for opponent process theory. Beta arrestin is a protein that tends to build up on G protein receptors. As beta arrestin builds up on the G protein receptor, signal transmission into the neuron is diminished. As G protein receptors are overstimulated, beta arrestin overwhelms the receptor function resulting in neuronal endocytosis of the G protein. The amino acids used as the building blocks of the receptor are recycled by the ribosome for use in other cell proteins.
Over stimulation of the dopamine receptors in the nucleus accumbens may also result in a feedback inhibition to the neuron nucleus resulting in the double stand of DNA to wrap around histone proteins, this blocks the uncoupling of nitrogenous base pairs of the double stranded helix. This quaternary structural inhibition of protein synthesis blocks the mechanism that replaces old dopamine receptors further resulting is a down regulation in dopamine receptor density in the nucleus accumbens leading to anhedonia, chronic dysphoria, and compulsive craving toward escalating drug use.
In summary, polypharmacy of controlled substances poses significant risks to the brain’s motivational reward circuits, potentially leading to anhedonia and cognitive deficits.
Comments