Psychoactive Substances and Their Impact on the Human Body

According to statistics, in recent years, 16% of the population aged 15 to 64 has used illegal drugs at least once in their life. Due to their effects on the psyche, people have used psychoactive substances for thousands of years to alter perception, mood, and behavior, as well as for religious practices, healing, and escape from troubles.

Terminology

Addiction is a persistent, compulsive need for a specific substance despite harmful consequences. It results from biochemical changes in the brain following continuous substance use. In Contrast, in Addiction, the Body Adapts to Chronic Use of the Substance. Tolerance Develops, Meaning Increasing Amounts of the Substance are Needed to Achieve the Same Effects, and When Use is Abruptly Stopped, Physical and Psychological Symptoms Arise, Known as Withdrawal Syndrome. Addiction Can Occur with Chronic Use of Many Substances, Even Prescription Medications When Used Properly. The aforementioned concepts are highly intertwined—physical dependence does not necessarily equate to addiction, though it often accompanies it. In Anglo-Saxon literature, the term “addiction” has been abandoned due to its broad trivial use, such as in the context of addiction to sports activities. Due to issues with terminology, international experts have recommended that since 1980, the term “addiction” should be used only for the syndrome, and for physical or physiological dependencies, the term “neuroadaptation” should be used. In the ICD-10 classification, we speak of addiction syndrome in the diagnosis of forms FX.2 (F10.2-F19.2) and harmful use in the diagnosis of FX.1. Harmful use indicates a pattern of psychoactive substance (PAS) use that causes health damage on a physical or psychological level. According to ICD-11, diseases caused by PAS misuse and addiction are included in diagnoses 6C40-6C4G.

Addiction Syndrome

Repeated consumption of PAS leads to behavioral, cognitive, and physiological phenomena. It is important that, along with neurobiological changes in the brain, there is also maladaptive behavior in the individual. For addicts, upon cessation of abstinence, it is also characteristic to experience withdrawal symptoms in a much shorter time than it took for addiction to develop. The criteria for diagnosing PAS addiction syndrome according to the ICD-10 classification state that at least three of six symptoms must be present in the patient over the last 12 months.

• Strong desire or compulsion to use PAS.
• Difficulties in controlling behavior related to PAS use (difficulty controlling the onset and end of use and the amount of PAS consumed).
• Physiological withdrawal state when PAS use is stopped or reduced, manifesting as a characteristic withdrawal syndrome for that PAS; use of the same or similar PAS to relieve or avoid the withdrawal state.
• Development of tolerance—larger doses of PAS are needed to achieve effects initially produced by lower doses.
• Progressive neglect of other pleasures and interests due to PAS use, extending the time needed to achieve, enjoy, and overcome PAS use.
• Continued PAS use despite clear harmful consequences (e.g., liver damage from alcohol consumption, depressive mood after intense PAS use, or cognitive functioning problems related to PAS).

Effects of PAS on the Brain

Essential needs trigger a rewarding or pleasurable effect in people. This pleasure can be amplified by certain non-chemical rewards, such as high social status. When discussing the reward pathway in the brain, we refer to the mesocorticolimbic pathway (from the ventral tegmentum to the nucleus accumbens), which includes the limbic system and the prefrontal cortex. The most critical of these is the limbic system, as it contains the most structures associated with the reward effect. PAS (psychoactive substances) act on these neurochemical pathways in the brain. The primary neurotransmitter involved in the development of addiction is dopamine. Others that also participate in this process include serotonin, norepinephrine, acetylcholine, glutamate, and GABA. Additionally, PAS affect endorphins and endocannabinoids, endogenous substances that influence the reward effect and pain perception. PAS have the most active effect in the mesolimbic part of the reward pathway by increasing the activity of dopamine neurons in the ventral tegmental area (VTA). Dopamine release is most significantly increased in the nucleus accumbens, amygdala, and prefrontal cortex. PAS can affect the mesolimbic pathway either directly or indirectly. When PAS increase the availability of dopamine, they are said to act directly; examples of these PAS include stimulants and cocaine. Other PAS, such as alcohol and nicotine, act indirectly by affecting neurotransmitters to boost dopamine availability. The effect on dopamine release is significantly stronger and faster with PAS compared to natural and endogenous rewards. With prolonged and repeated exposure to PAS, brain structures become more sensitive to cues that predict PAS use. Physiologically, the brain is adapted to only brief and not overly intense dopamine release. The amygdala, which is responsible for emotional processing of fear and pleasure, becomes vigilant to all cues associated with PAS. Thus, increased motivation and craving for PAS can be explained by chemical changes in the brain. Consuming PAS releases two to ten times more dopamine in the brain than natural rewards. In some cases, this effect occurs immediately after administration (smoking, injection of PAS). Additionally, the effect lasts longer than natural reinforcers.

Long-Term Effects of PAS Consumption

The brain must adapt to long-term PAS (psychoactive substance) stimulation to continue performing its functions. This adaptation is known as neuroadaptation, which involves two processes. The first is tolerance, where endogenous dopamine release is reduced, the number of dopamine receptors decreases, and the sensitivity of dopamine receptors diminishes. As a result, the impact of dopamine on the reward effect can become abnormally low, reducing the ability to experience pleasure. Over time, addicts face depressive moods because they can no longer enjoy things that once brought them pleasure. During this phase, they must consume PAS to try to restore dopamine function to normal. They also need to consume increasingly larger doses of PAS to achieve the same effect. The second process of neuroadaptation is sensitization. In sensitization, the number of dopamine receptors increases, making a person more sensitive to dopamine, leading to a strong increase in craving for PAS. Sensitization occurs with repeated consumption of large amounts of PAS with breaks in between. Neuroadaptation is possible due to neuroplasticity, the brain’s ability to form new connections between neurons and change the function of existing neurons. Neuroplasticity also allows for the treatment of addiction when PAS is discontinued. Long-term use also causes other changes in brain pathways. For example, glutamate, which is involved in the reward effect and affects learning ability, is altered with prolonged PAS consumption. The brain attempts to compensate for these changes, which can lead to cognitive function disturbances. The effect of PAS on the prefrontal cortex is also significant, as this area is responsible for behavior planning, good judgment, decision-making ability, and inhibition of unwanted and impulsive behavior. Addicts experience impaired control. When severely damaged, the addict craves PAS and compulsively consumes it. The person loses self-control, and the brain starts sending strong impulses for PAS consumption.

Mental Disorders and ASD

PAS consumption can induce mental disorders and behavioral disturbances. These include acute intoxication, withdrawal, delirium, mood disorders, psychotic disorders, and dementia. Withdrawal syndrome involves various serious symptoms that occur with complete or partial cessation of PAS after a period of continuous substance use. Psychotic disorder is characterized by psychotic phenomena (hallucinations, delusions, psychomotor disturbances) with clear consciousness, occurring during or after PAS use, which cannot be explained solely by acute intoxication and are not part of the withdrawal state. Amnestic syndrome is a condition with significant impairment of long-term and short-term memory, with short-term memory being more affected. Residual or late psychotic disorder occurs after prolonged abstinence or when PAS no longer has a direct effect. These are episodes of re-experiencing hallucinations or mood states that the person experienced while under the influence of PAS. The method of PAS consumption can lead to harmful use and addiction. PAS also have a significant impact in psychiatry, with accompanying mental disorders. Addiction can trigger, cause, or exacerbate other mental disorders, just as other mental disorders can provoke or worsen addiction syndrome.

PAS Groups

Based on their pharmacological characteristics, psychoactive substances (PAS) can be divided into four groups, which will be detailed below.

1. Depressants, which include alcohol, sedatives/hypnotics, and volatile solvents.
2. Stimulants, such as nicotine, cocaine, amphetamines, and ecstasy.
3. Opioids, including morphine and heroin.
4. Hallucinogens, which include phencyclidine (PCP), ketamine, LSD, and cannabis.

These groups differ from one another in terms of their site of action, effects, rate of tolerance development, withdrawal symptoms, and long-term effects.

Depressants

Alcohol

When we talk about alcohol, we are primarily referring to ethanol. Although it is a legal substance, its effects classify it as a drug. It is the only PAS that does not have a specific receptor for binding. Ethanol increases membrane fluidity, enhances the inhibitory effect of GABA, reduces the excitatory effect of glutamate, and increases activity in the mesolimbic dopamine pathway. Acute intoxication manifests as disinhibited behavior, mood instability, impaired attention, and aggression. The effects depend on the concentration of alcohol in the blood. All these mechanisms have long-term effects on altering the function and structure of the entire brain, with a particular emphasis on the prefrontal cortex. There is also a decline in cognitive functions. Many psychiatric disorders are associated with excessive alcohol consumption. These commonly include other PAS dependencies, antisocial personality disorder, mood disorders (depressive disorders with increased suicidality, anxiety disorders), and elevated mood. Due to the effects of alcohol, long-term drinkers experience increased levels of dopamine and serotonin. Immediately after cessation of drinking, levels of both neurotransmitters drop sharply, usually causing a short-term severe form of depression or anxiety, which typically resolves within 2-4 weeks after stopping alcohol consumption. Alcohol disrupts sleep architecture—it facilitates falling asleep but prevents REM sleep. Memory is also impaired, a condition observed even in acute alcoholics, where “blackouts” occur due to reduced glutamate production in the hippocampus, which is responsible for intact memory.
Withdrawal is characterized by central nervous system hyperactivity—tremors (of the tongue, eyeballs, extended hands), sweating, agitation, nausea, vomiting, headache, tachycardia, hypertension, insomnia, physical weakness, epileptic seizures, transient hallucinations (visual, auditory, or tactile). Anxiety is common. Delirium tremens (alcoholic delirium) may also occur.
In psychiatry, alcohol dependence is associated with alcoholic psychoses such as pathological jealousy and alcoholic hallucinosis. Malnutrition may also lead to a deficiency of vitamin B1 (thiamine), described as Wernicke-Korsakoff syndrome. In this syndrome, the first stage is Wernicke’s encephalopathy (cognitive decline, psychomotor retardation, ataxia, nystagmus, peripheral neuropathy). If the first stage is not treated, Korsakoff’s syndrome may develop, including extensive loss of short-term memory and confabulation. Alcohol consumption during pregnancy causes fetal alcohol syndrome, the leading cause of mental retardation in the United States.

Sedatives

In this section, we will focus on anxiolytics and sedative-hypnotics. Among these are benzodiazepines and barbiturates, which can cause dependence.

Benzodiazepines

In clinical practice, benzodiazepines are used as anxiolytics, hypnotics, antiepileptics, and anesthetics. They work through the GABA neurotransmitter, enhancing its effects. Acute intoxication is manifested by euphoria, disinhibition, apathy or sedation, aggression, mood lability, distractibility, anterograde amnesia, and psychomotor disturbances. Similar symptoms occur when benzodiazepines are taken in combination with alcohol. Prolonged use leads to impaired memory. Withdrawal symptoms depend on the average dose and duration of use. Symptoms typically appear on the 2nd or 3rd day of abstinence and include anxiety, dysphoria, intolerance to bright lights and loud noises, nausea, sweating, transient hallucinations (of all types), seizures, and delirium.

Barbiturates

Barbiturates were widely prescribed, even in high doses, before benzodiazepines were introduced. As a result, they were very easily available on the black market. They have a rather narrow therapeutic range, as a dose 10 times higher than the normal recommended dose can be fatal. Barbiturates act through the GABA neurotransmitter. When taken in relatively small doses, it is clinically difficult to distinguish intoxication from acute alcohol intoxication. Symptoms include poor coordination, impaired thinking, slurred speech, and decreased comprehension, erratic judgment, disinhibited sexually aggressive urges, and emotional lability. Neurological effects include nystagmus, diplopia, strabismus, ataxic gait, positive Romberg’s sign, and hypotonia. Users experience various degrees of withdrawal symptoms, including anxiety, weakness, insomnia, increased sweating, as well as seizures, delirium, cardiovascular events, and even death. Most symptoms appear within the first 3 days of abstinence, peaking 2 or 3 days after onset. Psychotic symptoms may also develop.

Inhalants (Volatile Solvents)

Inhalants include volatile hydrocarbons (toluene, n-hexane, methyl butyl ketone, gasoline, etc.). They can be found in various glues, sprays, thinners, and fuels. Inhalant poisoning is mainly seen in children and adolescents who inhale vapors. Due to very rapid absorption through the lungs, they quickly reach the brain, where they act as central nervous system inhibitors. They act similarly to alcohol, benzodiazepines, and barbiturates, most likely through the GABA neurotransmitter. Acute effects include intoxicating delirium, dementia, psychosis, mood disturbances, and, at high doses, quantitative disturbances of consciousness (stupor, coma), with amnesia for the duration of intoxication. In cases of delirium from intoxication, it is important to avoid using benzodiazepines to prevent respiratory depression. Poisonings can be fatal due to arrhythmia, respiratory depression, asphyxiation, and aspiration of vomit. Tolerance usually does not develop, but if it does, there is a higher likelihood of seizures.

Stimulants

Amphetamines

Amphetamines are pharmacologically classified as psychostimulants and sympathomimetics. The most commonly used is methamphetamine (a very potent form of amphetamine), but they also include ephedrine, pseudoephedrine, and phenylpropanolamine (PPA). Methamphetamine is a synthetic drug that users inhale, smoke, and inject. It acts by accelerating the release of dopamine and preventing its reuptake. Acute effects after ingestion include increased productivity and euphoria. High doses can cause acute psychosis or intoxication delirium, with agitation and tactile hallucinations being very common. Withdrawal is characterized by fatigue, nightmares, extreme hunger, sweating, headaches, muscle cramps, abdominal pain, depression, anxiety, and intense craving for the substance. Depression symptoms usually subside within a few weeks. Drowsiness after consumption can last for several weeks. High doses can also lead to cardiovascular events.
Amphetamines also include ecstasy or MDMA (3,4-methylenedioxy-N-methylamphetamine), which is a recreational dance drug. Acute toxic effects can be fatal, as excessive sympathetic activation leads to hyperthermic syndrome.

Caffeine

Caffeine is the most commonly consumed psychoactive substance in the world. Its effect includes vasoconstriction of cerebral blood vessels and a reduction in cerebral blood flow (CBF). Its effects include restlessness, excitement, increased diuresis, insomnia, gastrointestinal issues, tachycardia, and psychomotor agitation. Caffeine poisoning is described when consuming more than 250 mg of caffeine daily (more than 2-3 cups of coffee), leading to anxiety and disturbed sleep patterns. A distinctive feature of caffeine poisoning is that users often lose their desire for the substance after such an event. Withdrawal from caffeine is not clinically significant and manifests as mild headaches, poor mood and concentration, and a strong craving for caffeine. Excessive use is not typically associated with life-threatening conditions.

Nicotine

Nicotine is one of the most commonly used substances and one of the most significant addictions. On its own, it does not cause problematic behavior or personality changes but leads to severe physiological dependence. Nicotine addicts do not necessarily require specific psychiatric help. It works by activating nicotinic acetylcholine receptors and increasing dopamine synthesis and release. Its effects include improved attention, learning, and reduced reaction time. In cases of acute intoxication, strong cravings for tobacco, irritability, weakness, anxiety, depressive mood, insomnia, increased appetite, and concentration difficulties occur. Withdrawal can be recognized by heightened signs of acute intoxication.

Cocaine

Cocaine acts through the dopaminergic system by preventing the reuptake of dopamine, thus prolonging its effects. It has a strong sympathomimetic effect. Acute effects for users are short-lived and occur very rapidly after use. Effects include increased self-confidence, enhanced concentration, a sense of greater mental and physical ability, euphoria, tachycardia and hypertension, anorexia, strong vasoconstriction, disinhibition, and increased libido. Acute intoxication causes tachycardia, rhythm disturbances, hypertension, sweating, chills, nausea, vomiting, dilated pupils, psychomotor agitation, muscle pain, chest pain, and epileptic seizures. Long-term use can lead to euphoria, hyperattention, alertness, grandiose beliefs, aggression, conflicts, mood swings, stereotyped behavior, visual and tactile illusions, and paranoia. Due to the method of use (inhalation), there may be perforation of the nasal septum and various infections. Psychosis is common with intense use, and other mood disorders such as depressive, manic, and hypomanic states can also be associated. Withdrawal symptoms are not typical but may include dysphoria, anhedonia, anxiety, irritability, fatigue, somnolence, and agitation.

Opioids

The primary representatives of opioids are morphine and heroin. Opioids bind to mu (the most clinically significant), delta, and kappa opioid receptors, causing acute apathy and sedation, disinhibition, psychomotor retardation, and attention impairment. Long-term use reduces the ability to experience pleasure, loss of motivation, and increased sensitivity to stress. After cessation, there is a pronounced need and craving for the substance, tearing, nasal discharge, yawning, sweating, restlessness, muscle cramps and myalgia, abdominal pain, cramping, diarrhea, dilated pupils, piloerection, chills, tachycardia, hypertension, and sleep disturbances. Among addicts, the most common opioid is heroin (diacetylmorphine), which can be inhaled, smoked, or injected. Its effects are noticeable within a few minutes, producing a sensation of physical warmth, self-confidence, and complete mastery of the environment. This is followed by a state of delayed relaxation. Some users may also react negatively with anxiety, depressive feelings, and nausea. In cases of overdose, respiratory depression, skin pallor, muscle spasms, coma, and even death can occur.

Hallucinogens

Hallucinogens include various chemical compounds such as phencyclidine (PCP), ketamine, psilocybin (mushrooms), LSD (synthetic), and mescaline. They are also referred to as psychedelic or psychomimetic substances because, in addition to hallucinations, they cause a loss of contact with reality and heightened awareness. They act through different receptors. LSD acts through the serotonin system. Tolerance develops very quickly, within 3 to 4 days of repeated use. It is also reversible and does not cause specific physiological withdrawal or symptoms. Dependence is primarily psychological. The effects of LSD occur 30 to 120 minutes after ingestion and last from 8 to 12 hours, significantly depending on the individual’s set (internal state, i.e., mood, emotional and mental state) and setting (external environment, i.e., surroundings and interactions with present people). Positive, neutral, and negative effects are summarized in the table below.

Positive Effects	Neutral Effects	Negative Effects
Elevated mood, euphoria, well-being, Visual effects, intensified perception of colors, Increased perception of auditory and tactile information, Synesthesia (ability to taste music or hear colors), Greater introspection, associative thinking, and creativity, At higher doses, feelings of unity with creation and ego disintegration, Spiritual experiences	Wandering thoughts and thought loops, Dilated pupils; increased sensitivity to light, Reduced ability to concentrate, Slight increase in body temperature and heart rate, Altered perception of time.	Feeling of tension, Anxiety, restlessness, confusion, paranoia, Psychosis-like state, Insomnia, Weakness, Dizziness, Vasoconstriction (narrowing of blood vessels)

According to some studies, LSD is said to affect the establishment of communication pathways between parts of the brain that do not normally communicate. It is believed to have the potential to treat certain mental disorders with ingrained thought patterns, such as depression, obsessive-compulsive disorder, and addictions. Long-term use can lead to acute and chronic psychotic episodes and flashbacks.

Cannabis

Cannabis is the most commonly used illegal drug in our region. The active substance is THC (delta-9-tetrahydrocannabinol) or its metabolite 11-hydroxy-delta-9-tetrahydrocannabinol. Cannabis can induce schizophrenia in genetically predisposed individuals and can cause a relapse in patients with developed psychosis. It can also induce anxiety states. The active substance THC binds to cannabinoid receptors, which increases dopamine concentration in the mesolimbic pathway. Acute effects of cannabis consumption include euphoria, disinhibition, anxiety, agitation, paranoia, a feeling of time slowing down, impaired judgment and attention, prolonged reaction time, depersonalization and derealization at extremely high doses, illusions, and hallucinations with preserved orientation. Users are generally more sensitive to external stimuli, more perceptive to details, colors become richer and more vibrant, and time seems to pass more slowly. Long-term use increases the risk of developing psychosis and affects cognitive functions. It also leads to decreased productivity. Withdrawal issues are rare and not well-defined. The literature describes phenomena such as anxiety, irritability, sweating, myalgia, and tremors in outstretched hands.

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The article is sourced from Najzdravnik.comhttps://najzdravnik.com/blogs/blog/zastrupitev-s-psihoaktivnimi-substancami