Drugs and Narcotics – Abuse and Overdoses English

Cannabis

It is estimated that 147 million people worldwide use cannabis. It appears to be most common in New Zealand, Australia, and the USA. Cannabis is also widely used in Europe, where 14.6 million, or 11.2 percent of all young adults (ages 15–34), have used cannabis at some point in the last year.

Cannabis is the most widespread abuse drug in Sweden. It is mainly a youth drug in the age group of 15–25 years, but abuse also occurs at older ages. In Sweden, 50 percent of those seeking help for cannabis addiction are under 20 years old. 80% of all drug seizures within the EU consist of cannabis. Two-thirds of these seizures are made in Spain and England.

Cannabis is usually consumed by smoking, either as hash (cannabis resin) or marijuana. In recent years, the availability of marijuana in the EU and in Sweden has increased markedly.

An acute cannabis intoxication usually does not require care at an emergency medical clinic but can be managed within psychiatry or at an addiction medicine department, as well as withdrawal symptoms and other negative symptoms associated with abuse. Cannabis is commonly involved in poly-drug abuse with medications and other drugs. Cannabis use is also common among heavy users of heroin or amphetamine. Cannabis use is classified as heavy use when it is consumed daily or almost daily (20 days or more per month).

The management of acute cannabis intoxication is guided by the other drugs ingested, but is mainly symptomatic. The most important thing in acute poly-intoxication is close monitoring of consciousness, breathing, mental functions, and circulation, and directing the patient to the appropriate care unit. Many patients with cannabis addiction need medical treatment first and then assessment by psychiatry, referral to an addiction medicine clinic, and further to social services.

The prognosis for acute cannabis intoxication is generally good except in cases of severe poly-intoxications.

CANNABIS SATIVA

Cannabis is harvested from the plant Cannabis Sativa (Indian hemp) or from the plant Cannabis Indica. The cannabis plant is mainly grown in North Africa (Morocco, Algeria), but it can be cultivated in many other countries, even in Sweden (both indoors and outdoors). The market share for domestically produced, potent marijuana has increased in recent years, and data now suggest that even imported hash has become more potent. Cannabis is included in hash, marijuana, and hash oil, all of which are used as intoxicants. Hash has long been the most common cannabis product in Sweden and accounted for about 85% of the market in Sweden in 2011, but marijuana has become more common in recent years. Since 2013, marijuana has been more common than hash in Europe. In Swedish school surveys, the use of marijuana is more common than hash.

Marijuana is produced from dried flowers and top shoots, while hash (cannabis resin) consists of the resin from the stems of the cannabis plant (female plant), pressed together with plant parts. Hash is usually mixed with regular tobacco, while marijuana is often smoked without tobacco. Cannabis is usually smoked in rolled cigarettes (“joints”) or in a pipe, but can also be eaten in cakes or consumed in drinks, such as tea. All cannabis consumption is illegal in Sweden. Common slang names for cannabis include “brown, green, grass, weed, ganja, braja, smoke, joint, goose, spliff, pipe, fatty,” and more. A gram of marijuana on the street costs about 100 kronor, 2.5 grams costs about 300 kronor. In a rolled cigarette (joint), 200-400 mg of cannabis is usually mixed with tobacco and smoked alone or with others. In a pipe, 700 mg is usually mixed at a cost of about 100 kronor. The price of marijuana is roughly the same as for hash. Heavy users of cannabis typically use more than 2 grams per day.

The most psychoactive substance in cannabis is delta-9-tetrahydrocannabinol (THC), which gives a relaxing and euphoric high. Other active cannabinoids include delta-9-tetrahydrocannabivarin, delta-8-tetrahydrocannabinol, cannabigerol, cannabinol, cannabichromene, and cannabidiol. THC is considered psychotomimetic, while cannabidiol is considered antipsychotic. There are many different cannabinoids (at least 60-80), and it is not entirely clear which ones are psychogenically active. The THC content in marijuana is usually lower than in hash, around 5-10% in marijuana compared to 7-14% active substance in hash. A variant of cannabis called “skunk” is stronger and contains 6-15% THC. Skunk is considered extra potent and has been shown to cause damage to the white matter in the brain near the corpus callosum. The concentration of THC has increased in recent years, with preparations containing THC levels as high as 30% being seized, but usually, it is no more than 14%. A variant of the cannabis plant called “sensimilla” contains no seeds and therefore contains extra high levels of THC.

Cannabis, like opium, is a drug that has been used for a long time in certain cultures as a calming, anxiety-relieving, pain-relieving, and mood-enhancing agent. Cannabis use has increased worldwide in recent years. Cannabis is considered moderately addictive. Addiction is considered to exist when the user continues to use the drug regularly despite behavioral, cognitive, perceptual, and emotionally negative symptoms. Of all cannabis users, about 9% develop an addiction. Of those who start using cannabis regularly during high school, about one in six (16.7%) develop an addiction. Of those who are daily users (20 days per month or more) before the age of 17, 50-60% develop an addiction. There is robust scientific evidence that cannabis increases the risk of psychotic illness, but the extent of the risk is disputed. The risk is commonly stated to be “twice as high” as without cannabis use.

SYMPTOMS

Smoking cannabis can give the user a pleasant feeling of relaxation, calm, pain relief, peacefulness, and pleasurable euphoria. In high doses, perception may be enhanced and altered, with increased and changed sensitivity, particularly to sounds and lights. Cannabis also has pain-relieving and, to some extent, antispasmodic properties. In some parts of the world, cannabinoids are used medically (“medical cannabis”) in regulated forms as pain relief, for example, in multiple sclerosis (MS) and chronic disabilities with muscular contractures and spasticity. Medical studies have shown that cannabis does not help against the progression of MS. Research is ongoing in the field, including effects on diabetes. What is meant by medical cannabis varies between countries and even between states in the USA, with several different preparations being defined as medical cannabis.
Examples of symptoms during cannabis influence:

• Intoxication, euphoria
• Giggling, cheerfulness, “spacey and silly,” smiles
• Talkativeness, more socially active
• Adhesive in speech and thought
• Grandiose thoughts
• Red, bloodshot eyes, shiny eyes
• Dilated pupils, drooping eyelids
• Dry feeling in the mouth and throat
• Craving for sweets
• Slow reflexes, slack muscles (low tone)
• Clumsiness
• Slurred speech
• Palpitations (tachycardia)
• Drowsiness, tiredness, lethargy, drowsiness
• Incoherent in speech and thought
• Passivity, introversion
• Anxiety attacks, panic attacks
• Paranoid thoughts
• Delusions, hallucinations

Withdrawal

Cannabis can cause withdrawal symptoms, even long after use:

• Irritability
• Memory lapses
• Concentration difficulties
• Sleep disturbances
• Nightmares
• Feeling of unreality
• Anxiety
• Depression

Hallucinations and psychotic symptoms can occur in severe cases, even full-blown psychoses, especially after intense use or consumption of very strong preparations. Cannabis is usually calming, but aggressive breakthroughs with psychotic symptoms can occur.

Cannabis Abuse

Mental effects

People with cannabis abuse have higher rates of psychiatric comorbidity compared to the general population (higher levels of mental illness). Higher incidences of depression, dysthymia, mania, hypomania, panic attacks, agoraphobia, social phobias, other specific phobias, and generalized anxiety disorder are observed. Concurrent abuse of other substances is common. Cannabis abuse can lead to withdrawal-like symptoms such as anxiety, confusion, delusions, and hallucinations. In high doses and especially after prolonged use, other psychiatric symptoms may develop, such as:

• Depression
• Apathy, lethargy
• Memory problems
• Mood swings, sadness, anxiety
• Amotivational syndrome, lack of energy, lack of initiative
• Personality changes, increased introversion, quietness
• Altered perception of reality
• Cognitive impairment
• Paranoid ideas
• Psychotic symptoms

Personality changes can become permanent if the user continues to smoke cannabis after the primary psychosis develops. Psychotic symptoms can occur rapidly in sensitive individuals after a few weeks of intense abuse or use of stronger preparations – the so-called “acute hash psychosis.” If there is a connection between cannabis use and the first onset of psychosis, it predicts a worse prognosis with more days in the hospital and more hospitalizations. Some users risk developing cognitive impairment over time after months of intense use, with reduced learning ability, short-term memory, executive functions, and multitasking ability. Personality changes along with altered reality perception with “schizophreniform symptoms” can occur. These symptoms typically do not appear until after several years of regular use. An Australian study reported poorer intellectual development in those who used cannabis before the age of 17. A Swedish study showed a 40% increased mortality rate among those who used cannabis in their teens compared to the general population (OR 1.4).

The risk of developing schizophreniform symptoms is significantly higher for those who use the drug daily (double the risk) compared to those who have only smoked a few times. The risk is higher for those who started smoking at a young age compared to those who started later (after age 18). The risks of developing acute psychosis, personality change, and depression follow the same pattern. Girls appear to be more sensitive than boys, but usage is significantly more common among boys.

Differential Diagnosis Between Cannabis-Induced Psychosis (CIP) and Primary Psychosis (PP)

The following factors are more common in cannabis-induced psychosis (CIP) compared to psychosis caused by schizophrenia (primary psychosis – PP): male gender, expansiveness in emotions and ideas, derealization or depersonalization, visual hallucinations, and altered sensorium. The timing of the last drug intake can indicate whether the patient’s psychotic symptoms are due to cannabis intoxication or withdrawal symptoms. Premorbid personality disorder is more common in underlying schizophrenia. Note that 25% prevalence of positive cannabis urine toxicology has been reported in schizophrenia. A thorough history is important. Carefully distinguish between CIP and cannabis intoxication.

Characteristics of cannabis-induced psychosis (CIP):

• Symptoms appear during or after heavy substance abuse or after an increase in the strength of cannabis.
• A positive toxicology screening can establish a clear time correlation.
• Antipsychotic medications do not always improve symptoms.
• Often associated with visual illusions and paranoid ideas.
• The patient is more aware of the symptomatology and has more insight into the illness.
• Thoughts are more organized and sequential compared to PP.
• Heavy cannabis use during the past month is common.
• Symptoms decrease with reduced drug use.
• Sudden onset of mood instability and paranoid symptoms, within one week after use, but as early as 24 hours after use.
• More mood-related symptoms compared to primary psychosis (more anxiety).

Characteristics of primary psychosis (PP):

• Symptoms usually appear before or without heavy substance abuse.
• Antipsychotic medications significantly improve symptoms.
• Associated with delusions, hallucinations, and thought disorders.
• Symptoms persist despite drug abstinence.
• Less insight into the psychotic state.
• Disorganized thinking (e.g., loose associations, disconnected or circumstantial speech).
• More mood stability compared to CIP.

Cannabis Abuse Can Lead To:

• Impulsive acts of violence
• Suicidal actions
• Distorted perception of time
• Impaired ability to understand the external world
• Loneliness, social isolation, introversion
• Personality change, schizophreniform symptoms

Teenagers may experience delayed identity development and delayed personal maturity. Teenage characteristics and rebellion may persist for many years. Psychomotor functions that require multitasking ability may also be impaired. The ability to drive or perform complex tasks is reduced.

Physical effects

Cannabis abusers have a lower degree of glucose metabolism in the brain, especially in the cerebellum. Cannabis smoking increases exposure to tar (50 percent more than in cigarettes), which increases the risk of cough and bronchitis, both acute and chronic, as well as chronic lung disease. There is an increased risk of lung cancer and some other cancers, as well as an increased risk of cardiovascular diseases.

Fertility reduction can occur with cannabis abuse. During pregnancy, there is an increased risk of fetal growth restriction. There is also a potential increased risk of birth defects, damage to the child’s mental functions, and the risk of the child developing acute non-lymphoblastic leukemia.

Cannabis is often detected in various acute drug intoxications. In drug-related deaths, cannabis intoxication is common, but it rarely causes death in itself.

INVESTIGATION

• Drug screening (urine sample, U-tox)
• Frequent urine tests for tetrahydrocannabinol (THC)
• Electrolyte status check
• Temperature control
• Chest x-ray on broad indications
• Routine blood tests
  – Hemoglobin
  – Na, K, Calcium
  – Liver function tests
  – CRP, ESR
  – WBC, platelet count
  – Creatinine
  – PT, aPTT
• Psychological assessment
• Social worker contact
• Possible referral to an addiction clinic
• Assess which form of cannabis was used
• Estimate how many grams are consumed per week
• Estimate how much money is spent on cannabis per week

TREATMENT of Cannabis Abuse

There is no effective pharmacological treatment for cannabis dependence. Rimonabant, a type of antagonist, a competitive cannabinoid receptor agonist (CB-1 receptor), has shown positive results in some studies in reducing acute physiological problems related to cannabis smoking. However, Rimonabant has been deregistered in Sweden and has no place in treatment. Therefore, treatment is mainly symptomatic in combination with psychosocial support therapy. Treatment can usually be managed on an outpatient basis, but inpatient care is required for acute poly-drug intoxications and acute psychoses. The primary goal of treatment is total abstinence from further cannabis use. Cannabis can cause troublesome withdrawal symptoms after intense use, which usually last about a week.
Pharmacological treatment due to anxiety, withdrawal, and agitation needs to continue for a long time after cannabis abuse. Contact with a psychiatrist or psychologist with specific knowledge of the effects of cannabis is essential. Treatment focuses on the negative effects of cannabis use on cognitive function, motivation, and executive functions. Insight into the illness is usually poor, with low motivation for treatment and abstinence. Psychiatric comorbidity is common. The investigation needs to assess whether psychotic symptoms or increased suicidality are present. If depression and psychotic symptoms are present, there is a high risk of suicidal behavior. Outpatient treatment is individualized and based on frequent contact with a psychiatrist or psychologist, as well as regular monitoring of urine samples for THC. Cannabis can trigger depressive reactions and psychosis. The risk of severe depression is three times higher among cannabis users compared to non-users.

Initially, it is common to experience short-term memory impairment, low insight into the illness, and poor motivation to abstain from drug use. Social aspects must also be considered in the patient’s treatment, and a social worker should be involved.

For those with minor issues, psychosocial treatment focuses on short-term interventions (3-6 visits in outpatient care), while patients with more serious problems receive a longer treatment program, at least 14 visits to a psychologist or social worker over a four-month period. In some cases, support measures for family and relatives may also be justified. Cannabis abusers have a higher degree of dependency on social welfare, higher rates of unemployment, and lower levels of academic education compared to the general population.

Pharmacological Treatment

Treatment for acute cannabis intoxication focuses on immediate abstinence from cannabis. If necessary, administer parenteral fluids, as severe dehydration can occur. Also, replace electrolytes. Provide the patient with a quiet, dark room for rest, food, and sleep.

In the initial phase, pharmacological treatment for withdrawal symptoms is often necessary. The pharmacological treatment is gradually tapered over 3-6 months, while supportive therapy continues. Withdrawal treatment can be carried out using an Oxascand regimen (e.g., oxazepam) with gradually reducing doses over 4-7 days. A heavy Oxascand regimen involves 30 mg x 4 on the first day, followed by gradual tapering. A light Oxascand regimen involves 15 mg x 4 on the first day, followed by gradual tapering. The light regimen should generally be followed, but if withdrawal symptoms are pronounced, such as after a long period of heavy abuse, the heavy regimen can be followed. Studies have been conducted using lithium for withdrawal symptoms, as well as acetylcysteine, buspirone, lofexidine (clonidine-like), and cannabinol.

• Insert at least one peripheral venous catheter (PVC). Take Hb, WBC, platelets, and a urine drug screen.
• If necessary, start IV fluids, e.g., Ringer’s acetate or 1000 ml buffered glucose 5% per day.
• Neuroleptics such as T. olanzapine (Zyprexa) 5-10 mg x 1-2 (sedative) may be used, as well as T. risperidone (Risperdal) 1 mg x 2, or T. haloperidol (Haldol) 4 mg x 1.
• Antihistamines as an alternative: T. hydroxyzine (Atarax) 25-50 mg at bedtime.
• T. oxazepam (Oxascand) 15 mg, according to the regimen, “light” or “heavy Oxascand regimen.”
• T. nitrazepam (Nitrazepam) 5-10 mg at bedtime for 3 days.
• T. mirtazapine (Remeron) 30 mg at bedtime.
• Acetylcysteine may be considered. N-acetylcysteine is an antioxidant that is a prodrug of the naturally occurring amino acid cysteine. It is used as an expectorant and is available over-the-counter in many countries, including Sweden. Its mechanism of action in cannabis dependence is unknown.

Support Measures

Identify any cognitive impairment, psychotic symptoms, the presence of schizophreniform symptoms, and depression, and assess suicidality. Offer support measures of various kinds:

• Psychosocial support measures
• Motivational interviews
• Support for drug-related skill deficiencies
• Investigation and support for drug-related memory losses
• Motivate total abstinence

Note that the impairment of cognitive functions can initially be subtle and must be assessed using structured methods. For cannabis abuse or dependence, Contingency Management (CoM), a behavioral therapy method, in addition to Cognitive Behavioral Therapy (CBT) or relapse prevention (RP) and motivational enhancement treatment (MET), yields better results.

• A small effect on cannabis use compared to CBT or RP with MET alone during treatment or at the end of treatment (moderately strong scientific evidence).
• A small effect on cannabis use compared to CBT or RP with MET alone at 6-12 months of follow-up (moderately strong scientific evidence).

ICD-10

Cannabis and its derivatives T40.7
Mental and behavioral disorders due to cannabis use, harmful use F12.1
Mental and behavioral disorders due to cannabis, psychotic disorder F12.5

References

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11. Mass R et al. Relationship between Cannabis use, schizotypal traits, and cognitive function in healthy subjects. Psychopathology 2001;34:209-214. Link
12. Fletcher JM et al. Cognitive correlates of long-term cannabis use in Costa Rican men. Arch Gen Psychiatry 1996;53:1051-7. Link
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16. Gray, KM, Carpenter, MJ, Baker, NL, DeSantis, SM, Kryway, E, Hartwell, KJ, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. The American journal of psychiatry. 2012; 169(8):805-12. Link
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Opioids

Out of approximately 185 million drug users worldwide, it is estimated that 26-36 million use opioids as their main drug. In Europe, it is estimated that 1.3 million people abuse opioids (0.4% of the population). Of all drug users, an estimated 13-26 million use heroin as their main drug.

Opioids include opiates, which are naturally extracted from opium, and synthetic analogs. Abuse has increased in Asia and Africa, while it has been stable or slightly decreased in Europe in recent years. In Europe, the highest abuse rates have been in Scotland, England, and France, usually concentrated in urban areas. The ratio of men to women who regularly use opioids is about 4:1. Approximately 44% of opioid users are intravenous drug users. Nearly half of all people receiving treatment for drug addiction cite heroin as their main drug. Heroin abuse within the EU has been stable and slightly declining in recent years. Deaths related to heroin have generally decreased, but deaths related to synthetic opioids are increasing. Heroin accounts for 4% of all illegal drug seizures, while cannabis accounts for 80%.

Heroin abuse within the EU has been stable and slightly declining in recent years. The number of deaths related to heroin has generally decreased, but deaths related to synthetic opioids are increasing, and in Sweden, these have increased significantly in recent years. According to the National Board of Health and Welfare’s Cause of Death Register, 765 drug-related deaths were registered in 2014, an increase of 30 percent compared to the previous year. The register records deaths where both legal drugs and illegal drugs like heroin, cocaine, and amphetamine were the cause or a contributing cause of death. The so-called Tox Register at the Karolinska Institute only records deaths where one or more narcotic-classified drugs, legal or illegal, are assessed as the primary or contributing cause of death in forensic autopsy reports.

Strong opioids were assessed as the cause or contributing cause of death according to the Tox Register in the following number of cases in 2014 (with figures from 2006 in parentheses): morphine 53 (28), methadone 104 (10), buprenorphine 84 (14), fentanyl 47 (5), and oxycodone 42 (4). In comparison, deaths related to heroin have remained roughly the same in 2014 as in 1994.

The most common illegal substance among opioid users is heroin. It is estimated that there are between 8,000 and 13,000 heroin addicts in Sweden among 29,000 heavy drug users. The number of new addicts in Europe is approximately 41,000 per year.

Opioids are mainly administered intravenously but can also be taken orally, transdermally via patches, or through inhalation (smoked heroin). The drugs that are inhaled include opium and smoked heroin, as well as fentanyl. Smoked heroin is a brownish heroin base, also called “Brown Sugar” (freebase).

Opioids are used as potent pain-relieving medications in healthcare, primarily for the treatment of severe acute pain, but also for chronic pain in serious medical conditions. Among drug-related deaths, opioids are involved in 90% of cases. The medical use of opioids has increased significantly over the past ten years. Opioids are considered to be the most addictive drugs. Among those receiving treatment for drug dependence worldwide, opioid dependence is the most common cause (50-85% of patients). Among drug-related deaths, opioids are involved in 90% of cases.

Some opiates are

• Heroin
• Morphine
• Hydromorphone
• Raw opium
• Codeine
• Ethylmorphine
• Buprenorphine

Some opioids are

• Ketobemidone
• Oxycodone
• Fentanyl
• Pethidine (Meperidine)
• Methadone
• Tramadol
• Dextropropoxyphene

Acute overdose is usually caused by heroin, fentanyl, buprenorphine, or methadone. Severe cases and deaths due to dextropropoxyphene overdose were common in the past but have decreased significantly after several medications were deregistered. A significant abuse of oxycodone has been reported, primarily from the U.S., since the year 2000. In 2010, about 16,000 deaths involving oxycodone were registered! In Sweden, there is significant abuse of tramadol and Subutex. Still, more than 100 people die annually in Sweden due to acute heroin overdose. Of the deaths, 90% are older than 25 years. About 80% of the deaths are among men.

Heroin

Heroin (diacetylmorphine) is the opioid most commonly associated with drug addiction and illegal drug abuse. The brown form of heroin is the most common, typically originating from Afghanistan, while the white form (hydrochloride salt) is less common and usually originates from Southeast Asia. Brown heroin typically costs between 300 and 700 SEK per gram on the street. The purity level ranges from 10-20%.

Heroin has analgesic, sedative, and anxiolytic properties. It is metabolized into morphine in the liver and excreted mainly through urine. The drug can be smoked, sniffed, or injected; injection is the most common (44%). A typical dose of heroin used by addicts ranges from 15-50 mg intravenously. An overdose occurs with intake above 100 mg, and severe intoxication occurs with intake above 300 mg or more. The effects and tolerance vary significantly between individuals. Note that heroin has a relatively short half-life of 2-3 hours, compared to methadone’s 16-60 hours.

Methadone is usually taken in oral solution or tablet form but is also used in injectable form. For the treatment of heroin withdrawal, a typical dose of methadone is 60-130 mg, administered in an oral solution once daily.

A capsule or bag of heroin typically contains 250 mg of 30% pure heroin when purchased on the street (commonly known as a “kabbe”). Heroin is derived from opium, mainly grown in Southeast Asia, especially in Afghanistan. Raw opium is also abused and imported into Sweden. Raw opium is primarily smoked, even in Sweden. An increasing number of users smoke heroin (diacetylmorphine, freebase) instead of injecting, but many smokers eventually switch to injection use.

Heroin is well known for causing rapid and severe dependence, with increased tolerance and moderate to severe withdrawal symptoms upon cessation.

An opioid overdose is characterized by

• Decreased consciousness, somnolence
• Small pupils
• Fatigue
• Slow speech
• Calmness
• Cold sensation
• Anesthesia
• Coma
• Urinary retention
• Respiratory depression, respiratory failure
• Hypoxia, cyanosis, grayish pale skin
• Bradycardia
• Hypotension
• Circulatory collapse

Life-threatening overdose can occur after injection as well as smoking but is much more common after injections. Respiratory depression is the most serious symptom in overdose and can quickly become life-threatening. Alert patients usually do not have respiratory depression, but alertness can fluctuate rapidly.

Withdrawal Symptoms

• Chills
• Tremors (fine tremor)
• Sweating
• Palpitations
• Shaking
• Feeling of discomfort
• Anxiety
• Agitation
• Aggressiveness
• Unstable temperament
• Restlessness
• Violence

Sometimes, withdrawal symptoms are described as flu-like. These symptoms can appear as early as 4-6 hours after the last dose.

Risks

Intravenous heroin abuse is characterized by significant risks of infectious diseases (HIV, hepatitis B and C) and acute overdose. The abuse is associated with significant criminal activity and an antisocial lifestyle. It has been reported that 66% of all heroin addicts have experienced a life-threatening overdose at some point, and 34% have attempted suicide.

In the past decade, white heroin (diacetylmorphine hydrochloride) has become increasingly pure, producing a “better” product worldwide. This indicates more controlled and refined production. In Sweden, white heroin is most common in the Stockholm and Malmö regions. The user is never entirely certain of the concentration of heroin being injected. The concentration and dosage can vary significantly between different preparations of heroin, which is one reason for many overdoses and deaths.

Another cause of overdose is reduced tolerance. Reduced tolerance develops within just a few weeks of abstinence from heroin. The psychological craving for the drug can remain strong, but the amount tolerated is significantly less than before. Many overdoses, therefore, occur among people recently released from prison, where they had been forced to abstain from heroin.

Heroin abuse is a common cause of drug-related deaths, with an estimated 100 to 200 cases occurring annually in Sweden (FHI). Of these, 40-60 cases are estimated to result from acute overdoses. In cases of heroin overdose and abuse, other potentially fatal diseases such as hepatitis C, acute liver failure, pneumonia, acute fasciitis, abscesses, heart failure, myocarditis, DIC, ARDS, etc., are often present. New studies suggest that trauma, often drug-related, is the most common cause of death in this group of users. Overall, the number of drug-related deaths has decreased within the EU, from approximately 7,700 in 2009 to 6,500 in 2011.

Methadone

Methadone is a pure opioid with calming, analgesic, anxiolytic, and sedative properties. Since the 1960s, methadone has been used for the detoxification of heroin addiction, but due to its own opioid properties, it has a strong potential for addiction. About 2,500 patients in Sweden with opioid dependence are part of various substitution programs and are treated with either methadone or Subutex. Methadone is considered to be more effective as a substitution treatment for heavier and more deteriorated heroin addicts compared to buprenorphine (Subutex). The desired effect of methadone is to block the craving for heroin and prevent new heroin use. Methadone treatment has resulted in more patients returning to work or studies and maintaining social structures within family and cohabitation relationships.

Methadone is usually taken as tablets or in oral solution but is also available in injectable form. For the treatment of heroin withdrawal, a normal dose of methadone is 60-130 mg, administered in oral solution once daily. A typical dosage for pain management is 5-10 mg taken 4-6 times daily in tablet form, and the daily dose should not exceed 100 mg. Overdose with methadone can cause nausea, vomiting, severe respiratory depression, and serious cardiac symptoms with dangerous arrhythmias (Torsades de Pointes arrhythmias, prolonged QT interval). Methadone has a significantly longer half-life compared to heroin, 16-60 hours versus 2-3 hours for heroin, which means that its effect lasts significantly longer, covering all hours of the day. Side effects of methadone treatment include weight gain, impotence, and reduced libido. In treatment with the antidote naloxone hydrochloride (Naloxone) after a methadone overdose, there is a significant risk that the effect will be short-lived and temporary. The sedative and respiratory-depressing effects of methadone may return after a period of awakening and cause serious symptoms. The number of deaths after methadone overdose has increased in recent years during the 2000s.

Oxycodone (OxyContin, OxyNorm, Targinic)

Oxycodone shows affinity for kappa, mu, and delta opioid receptors in the brain and spinal cord. It acts on these receptors as an opioid agonist without antagonistic effects. The therapeutic effects are primarily analgesic and sedative. The absolute bioavailability of oxycodone is 60–87% after oral administration, and maximum plasma concentrations are achieved after about 1 to 1.5 hours. In steady-state, the half-life of plasma elimination is about 3 hours. Oxycodone and its metabolites are excreted via urine.

Prescriptions and consumption of oxycodone have increased significantly in recent years, as has addiction. In 2014, about 250,000 prescriptions were issued compared to just under 50,000 in 2006. Oxycodone was cited as the cause or contributing factor in 42 deaths in 2014 compared to only 4 in 2006. Oxycodone is sold as a fast-acting drug (OxyNorm) or as an extended-release drug (OxyContin, Targinic). OxyNorm is available in capsule or injectable solution form. Targinic is a combination drug containing both oxycodone and naloxone in a 2:1 ratio. Oxycodone is also available in injectable form with roughly the same potency as morphine. Oral oxycodone is about twice as potent as oral morphine (higher bioavailability).

Fentanyl (Fentanyl, Durogesic, Matrifen)

Fentanyl is a potent opioid routinely used in surgery and anesthesia. Fentanyl is about 100 times more potent than morphine, but its oral bioavailability is significantly lower (<2%). Fentanyl can be abused by inhaling, swallowing, or injecting it. An increasing problem in recent years has been the abuse of fentanyl from various patches, which are normally used for transdermal pain management.

These patches normally secrete 25, 50, 75, or 100 µg of fentanyl per hour. In cases of abuse, people may scrape off the fentanyl to extract it. The most common method of abuse is to smoke it, for example, in a broken light bulb used as a makeshift pipe.

There have also been seizures of fentanyl in spray form. Fentanyl is easy to overdose on, and several deaths have occurred in Sweden in recent years. In Estonia, fentanyl-related deaths exceed heroin-related deaths. Fentanyl exists in many chemical variants with varying potency. Some potent variants are carfentanil, alfentanil, remifentanil, furanylfentanyl, 4-fluorobutyrfentanyl, 4-methoxybutyrfentanyl (4-MeO-BF), and acetylf entanyl. Most of these are significantly more powerful than morphine, 100-1000 times stronger, which is why fentanyl is usually dosed in micrograms while morphine is dosed in milligrams.

Desomorphine (“Krokodil”)

A simple variant of an opioid is desomorphine, produced by users primarily in Russia under the name “Krokodil.” Desomorphine is synthesized from codeine, which can be purchased over the counter at pharmacies. Desomorphine has sedative and analgesic properties and is more potent than morphine. The production process involves codeine, iodine, and phosphorus, which results in a compound that is heavily contaminated and very impure.

Injections of desomorphine have led to severe skin infections, sores, dermatitis, fasciitis, and necrosis. The abuse has resulted in extensive scarring and the amputation of limbs. Several deaths have occurred, and desomorphine users typically have a short survival rate (<1 year). The slang name “Krokodil” has also been used for the synthetic opioid 3-methylfentanyl, which is also predominantly used in Russia.

SYMPTOMS OF OPIOID ABUSE

Psychological Effects

Opioid intoxication causes drowsiness, relaxation, pain relief, anxiety relief, and mental dullness. Regular use can lead to concentration difficulties and increased risk of traumatic injuries due to decreased alertness. Movements and reflexes become sluggish and slow, as does speech; breathing may also slow down. The voice may be low and drawn out during opioid intoxication. There is a risk of chronic depression due to abuse, and personality may become blunted.

Physiological Effects

• Miosis (small pupils)
• Reduced bowel function (constipation, paralytic ileus)
• Reduced kidney function, urinary retention
• Nausea, vomiting
• Itching (with scratches)
• Neurological damage, loss of sensation, and numbness
• Complications during pregnancy

Heroin abuse can lead to impaired immune function and opportunistic infections. Users have an increased prevalence of infectious diseases, including hepatitis B and C, HIV, wound infections (S. aureus), skin infections, tetanus, botulism, endocarditis, and sepsis. The risk of bronchitis, pneumonia, and other lung diseases is also increased. Note that impaired kidney function (creatinine clearance <60 ml/min) raises plasma concentrations of oxycodone by 50%.

Injection marks on arms and legs, as well as thrombophlebitis, are seen with intravenous abuse. Poor dental status with severe cavities, poor hygiene, loss of appetite, and weight loss are common.

INVESTIGATION

• Drug screening and toxicity tests
• Pupil checks
• Frequent urine tests for opioids (U-tox)
• Electrolyte status check
• Infection parameters check
  – Hepatitis serology
  – HIV test
• Chest X-ray
• Blood, sputum, and urine cultures
• Routine blood tests
  – Hb
  – CRP, ESR, temperature
  – Liver function tests
  – WBC, platelets
  – Creatinine
  – PT, APTT
• Serum ethanol
• Serum myoglobin

Emaciated and debilitated patients should undergo an echocardiogram (UCG) with a focus on heart failure (cardiomyopathy) and valve disease. For patients with poor dental health, a dental referral for sanitation should be made.

The investigation includes a psychological assessment and contact with a social worker and social services. A report to social services must always be filed in the event of a life-threatening overdose or life-threatening addiction.

TREATMENT

Treatment of acute overdose

Implement life-saving measures according to CPR principles in the event of a life-threatening overdose and obtain the antidote naloxone. Acute heroin poisoning often involves polyintoxication with other drugs, alcohol, and/or medications, especially benzodiazepines. Conduct a drug screening on a urine sample. In a Norwegian study, 65% of heroin users had experienced a serious overdose at some point. A respiratory rate of fewer than 10 breaths per minute or saturation below 90% suggests an overdose.

Management depends on which substances were ingested but is primarily symptomatic.

Antidote treatment

Naloxone (naloxone hydrochloride) plays a central role in treatment and should be given both intravenously (0.4 mg) and intramuscularly (0.8 mg). Higher doses may be needed. Note that the antidote has a shorter half-life than ingested heroin. After antidote administration, the patient should be monitored for 2 hours due to the risk of recurrent severe respiratory depression. The necessity of this observation is scientifically controversial. Several recent studies from Norway (F. Heyerdal et al.) have shown that patients discharged directly from the ambulance after life-saving measures do not have higher mortality than those hospitalized. Currently, nasal administration of naloxone by relatives in the event of a life-threatening overdose is being tested.

The most important aspect of treatment is careful monitoring of alertness, breathing (oxygen saturation/respiratory rate), and circulation, and ensuring the patient is transferred to a unit where vital functions can be secured.

• Ensure an open airway, provide assisted breathing, and administer oxygen if needed.
• Monitor the patient in the hospital for at least 2 hours.
• Place at least one IV line. Check Hb, WBC, CRP, platelets, liver function, and perform a drug screen.
• Administer isotonic crystalloid solutions intravenously, such as Ringer’s acetate. Note the risk of pulmonary edema.
• Check ECG.
• In cases of deep unconsciousness, intubation and controlled ventilation are required.
• Perform a chest X-ray with a focus on pulmonary edema (heroin lung) or pulmonary infection based on liberal indications.

Medication Treatment

• Naloxone hydrochloride (Naloxone) 0.4 mg intravenously as an antidote, possibly more. The dose can be repeated every 3-4 minutes until normal breathing occurs, and the patient regains consciousness. Then, administer the double intravenous dose intramuscularly, usually 0.8 mg. The effect of naloxone can be delayed in cases of mixed intoxication, especially with benzodiazepines or if anoxic brain injury has occurred. The intravenous dose takes effect within 30-60 seconds and lasts for 45-60 minutes. The intramuscular dose takes effect after about 10 minutes and lasts for 2-3 hours.
• Flumazenil (Lanexat) 0.1-0.3 mg/min intravenously can be tried in cases of mixed intoxication with opioids and benzodiazepines. Typically, 0.3 mg is given intravenously to adults, with the dose repeated at one-minute intervals until the effect is achieved. Often, 2-3 doses are sufficient, with a total dose of 2 mg. The maximum dose for adults is 2-5 mg. Flumazenil is not a first-line treatment for suspected opioid poisoning.
• Inotropic treatment for circulatory failure: Dopamine (Abbodop) by continuous infusion 2-10 μg/kg/min, or Noradrenaline (Noradrenaline) 0.05-0.15 μg/kg/min.

After treatment with naloxone, there can be a sudden awakening with restlessness, pain, and aggressiveness. It sometimes happens that the patient then discharges themselves and leaves the hospital. Pulmonary edema may also occur after naloxone administration due to sympathetic activation and increased blood pressure, but it can also be a consequence of heroin overdose itself.

Many patients require a psychiatric evaluation after acute treatment, as well as a referral to an addiction medicine clinic and social services. The prognosis for acute heroin poisoning is generally good, provided the patient has not already sustained anoxic brain damage due to oxygen deprivation.

Detoxification

Detoxification from heroin addiction typically requires inpatient treatment at an addiction medicine clinic. Studies on withdrawal treatment show that more patients complete the treatment (retention) when it is done as an inpatient rather than outpatient. Such treatment is usually elective with planned admission according to specific treatment protocols. A care and treatment plan must be established. The patient first receives medical withdrawal treatment followed by medical substitution treatment, along with psychosocial support therapy.

Patients are invited to an information session (assessment interview) before admission for withdrawal treatment. After a period of inpatient care (3-6 months), some patients may continue withdrawal treatment with maintenance therapy as outpatients, but the risk of relapse is significant.

Substitution Treatment

Some addiction clinics substitute heroin with lighter opiates such as codeine, though this is not without challenges. More clinics use pure opiates like methadone (Methadone) in substitution therapy, or partial agonists like buprenorphine (Subutex) or buprenorphine and naloxone (Suboxone). Methadone does not have significantly better effectiveness than buprenorphine.

The introduction of Subutex has allowed more patients to be detoxified compared to Methadone, but both Methadone and Subutex lead to significant dependence. Many patients receive long-term substitution treatment under controlled conditions, initially inpatient and, after a few weeks (months), on an outpatient basis with daily Subutex administration. Lighter and younger users are more often prescribed Subutex, while older and heavier users are more likely to receive Methadone.

A new medication, Suboxone (buprenorphine plus naloxone), has been introduced into treatment with less risk of side-use and intravenous abuse compared to Subutex. Substitution treatment has enabled more patients to function socially, maintain marital relationships, and pursue studies or employment compared to untreated controls. Sympatholytic agents have also been used in opioid withdrawal treatment, such as clonidine (Catapresan) and dexmedetomidine (Dexdor).

Needle Exchange

In some clinics across the country, intravenous drug users can exchange used needles for new, sterile ones as part of a needle exchange program. This program is an attempt to reduce the risk of criminal activity and infectious diseases, as well as to closely monitor the patients (“Harm reduction”). Efforts are also being made to vaccinate against hepatitis. These users should also be introduced to nasal naloxone for use in case of an overdose.

The risk of premature death is significant among intravenous drug users (20-50 times higher than normal). Intravenous heroin users are often far advanced in their addiction, most are between 30 and 40 years old, and they have an extremely low quality of life, marked by significant antisocial behavior and a marginalized existence. Some degree of self-recovery is observed after 10 years or more of addiction.

Psychosocial Treatment

Psychosocial treatment for opioid addiction and dependence has an effect on the extent of the addiction itself.

• The psychosocial treatment should have a clear structure, focus on the addiction, and be long enough to have an impact.
• A care and treatment plan should be in place.
• Psychosocial treatment is usually provided alongside pharmacological treatment.
• No single psychosocial treatment method has been shown to be superior to others.
• Psychotherapy, such as family therapy, dynamic therapy, and cognitive therapy, appears to be effective in keeping patients in treatment programs.

ICD-10

Mental and behavioral disorders due to opioids, acute intoxication F11.0
Mental and behavioral disorders due to opioids, harmful use F11.1
Mental and behavioral disorders due to opioids, dependence syndrome F11.2
Mental and behavioral disorders due to opioids, withdrawal F11.3
Heroin T40.1
Other opiates T40.2
Methadone T40.3
Other synthetic narcotics T40.4

Sick Leave

Links to insurance medical decision support from the Swedish National Board of Health and Welfare:

F11 Mental and behavioral disorders due to opiates

References

1. Drug Development in Sweden 2011, Report No. 130, Central Association for Alcohol and Drug Information, Stockholm 2012.
2. Annual Report EMCDDA Situation on the Drug Scene in Europe 2011.
3. Pre-Hospital Treatment of Acute Poisonings in Oslo: A One-Year Observational Study. F Heyerdahl, KE Hovda, MA Bjornaas, AK Nore, JC Figueiredo, O Ekeberg, D Jacobsen BMC Emergency Medicine 2008, 8:15.
4. Steentoft A, Teige B, Ceder G, Vuori E, Kristinsson J, Simonsen KW, Holmgren P, Wethe G, Kaa E: Fatal poisoning in drug addicts in the Nordic countries. Forensic Sci Int 2001, 123:63-69.
5. Sporer KA: Acute heroin overdose. Ann Intern Med 1999,130:584-590.
6. Boyd JJ, Kuisma MJ, Alaspaa AO, Vuori E, Repo JV, Randell TT: Recurrent opioid toxicity after pre-hospital care of presumed heroin overdose patients. Acta Anaesthesiol Scand 2006,50:1266-1270.
7. Buajordet I, Naess AC, Jacobsen D, Brors O: Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med 2004, 11:19-23.
8. Sporer KA, Dorn E: Heroin-related noncardiogenic pulmonary edema: a case series. Chest 2001, 120:1628-1632.
9. Warner-Smith, M, Darke S, Lynskey M, Hall W. Heroin overdose. Addiction 2001;96(8)1113-1125
10. Bach, Peter B.; Lantos, John. “Methadone dosing, heroin affordability, and the severity of addiction.” American Journal of Public Health. 1999, May. 89(5): 662-665.
11. Cook, Stephane; Moeschler, Olivier; Michaud, Katarzyna; Yersin, Bertrand. “Acute opiate overdose: Characteristics of 190 consecutive cases.” Addiction. 1998. 93(10): 1559-1565.
12. Darke, Shane; Hall, Wayne; Weatherburn, Don; Lind, Bronwyn. “Fluctuations in heroin purity and the incidence of fatal heroin overdose.” Drug and Alcohol Dependence. 1999. 54: 155-161.
13. Fugelstad A; Ågren G; Romelsjö A. “Changes in mortality, arrests, and hospitalizations in non-voluntarily treated heroin addicts in relation to methadone treatment.” Substance Use and Misuse. 1998. 33(14): 2803-2817.

Central Stimulants

Globally, there are approximately 185 million drug users, and around 34 million use amphetamine as their primary drug of abuse. Amphetamine abuse is relatively common in Sweden compared to other European countries. It is estimated that between 10,000 and 25,000 people in Sweden use amphetamines, with about 8,000 using it as their primary drug—around 32% of those with severe drug abuse. Among intravenous drug users in Sweden, the majority, about 60-70%, use amphetamines, while the remainder use heroin. Injection drug use significantly increases the risk of medical complications such as infectious diseases and thromboembolism. The mortality rate among amphetamine users is about 2% annually. Amphetamine users have a higher mortality rate compared to the general population but lower than opiate users and those with polysubstance abuse. Amphetamine is the drug most frequently leading to police interventions in Sweden, with approximately 7,000 seizures annually. The use of central stimulants thus represents a significant medical and social problem.

Amphetamine, dexamphetamine, methamphetamine, and methylphenidate are the primary central stimulant drugs. Many new psychoactive substances (NPS) are amphetamine derivatives with similar stimulant effects. Related substances are classified as phenethylamines or synthetic cathinones. Cocaine and ecstasy are also stimulants but are typically categorized separately from other drugs of abuse.

The harmful effects of amphetamine are relatively common in medical and surgical emergency departments and addiction services, while isolated amphetamine intoxication is less common. These substances are usually classified as narcotics or, in some cases, harmful goods.

Various Stimulant Drugs

• lisdexamfetamine (Elvanse^®, Elvanse Adult^®)
• methylphenidate (Concerta^®, Ritalin^®, Methylphenidate Sandoz^®)
• dexamphetamine sulfate (Metamina^®, Attentin^®) (licensed medication)
• modafinil (Modiodal^®)
• amphetamine (Amfetamin Recip^®, Adderall XR^®)

Other amphetamine-based drugs, such as amphetamine sulfate (Amphetamine), dextroamphetamine (Dexedrine), phenmetrazine (Preludin), and phentermine (Adipex), are available in other countries and are sold illegally or online in Sweden. Among patients in treatment for addiction in Sweden, about half use amphetamines regularly. Most amphetamine users engage in polysubstance abuse, often including cannabis and benzodiazepines. Legal use of stimulant medications has risen sharply in recent years, particularly methylphenidate (Concerta^® and Ritalin^®), as well as lisdexamfetamine (Elvanse^®). These drugs are now commonly prescribed to children, adolescents, and adults. Only Ritalin^® and Elvanse^® are approved for use in adults.

Amphetamine

Amphetamine is a central stimulant that increases energy, activity, endurance, and alertness while reducing appetite. It is the oldest, most well-known, and most abused of all central stimulants. Among Swedish conscripts, approximately 4% report having tried amphetamines at some point.

Amphetamine is chemically produced and typically comes as a white powder, sometimes with a yellow, brown, or gray tint. It is usually injected but can also be swallowed or dissolved in a drink (“bombed”). Between 40 and 80% of users report injecting amphetamines. A typical dose lasts one to two hours, sometimes longer. Common street names for amphetamines include “Tjack,” “Uppers,” “Speed,” “White,” “Dose,” and “Speed.” Powder, capsules, or tablets are sold illegally, and users refer to taking amphetamines as “grogging” or “popping pills.” The typical dose for nasal, oral, or intravenous use is 100-200 mg.

Methamphetamine

Methamphetamine is a variant of amphetamine that has gained popularity as a drug of abuse in recent years. Some slang terms include “Meth,” “Speed,” and “Yaba.” In Sweden, it is called “Metatjack.” The drug is smuggled into Sweden from countries like Thailand and is described as providing a more intense euphoria with stronger perceptual enhancement than regular amphetamine (more psychotropic). Methamphetamine has become more common in Sweden in recent years, now accounting for about 20% of amphetamine use.

Methamphetamine is typically sold as a white powder in capsules but can also appear in crystalline form, commonly called “Ice” because the crystals resemble small ice blocks or coarse salt. Other nicknames include “Los Angeles Glass,” “Glass,” and “Crystal.”

Ice produces a more potent high than regular amphetamine, providing a sense of exhilaration and energy. Methamphetamine has a longer half-life than regular amphetamine, with effects lasting up to 24 hours. With repeated use, the effects can last several days. Methamphetamine abuse is widespread in the U.S., Japan, South Africa, Southeast Asia (Thailand), and Australia. Methamphetamine is also used intravenously. The normal dosage is 10-30 mg, a strong dose is 30-60 mg, and a very strong dose is 40-150 mg.

SYMPTOMS AND CLINICAL EFFECTS

The classic effect of amphetamine is a brief euphoric high characterized by increased alertness, heightened self-confidence, increased energy, hyperactivity, and an elevated mood, followed by a prolonged dysphoric period. During the euphoria, there is increased wakefulness, self-assurance, and a need for self-assertion, leading to expansiveness in speech and thought, which can be perceived as impulsivity or hypomania. There is increased mental and physical energy, flight of ideas, impulsivity, increased appetite, increased sexual desire, elevated mood, improved concentration, and hypomania. Symptoms of amphetamine intoxication may include dilated pupils, a fixed stare, hyperactivity, uninhibited behavior, tics, flushing (blushing, hot flashes), coordination difficulties, formication (skin crawling sensations), itching, monotonous movements, teeth grinding, difficulty sitting still, and intense behavior (being “sped up”).Euphoria arises as a result of increased release of several neurotransmitters (catecholamines) in the central nervous system (CNS), primarily dopamine and norepinephrine. Amphetamine causes a 1000% increase in dopamine in the nucleus accumbens compared to 150% for cannabis in animal studies. Over time, tolerance develops, increasing the risk of hallucinations and delusions. As a result, amphetamines are typically abused at intervals of a few hours over several days or up to a week. After this, the user needs to recover—sleep and rest. The abuse is often periodic and includes the use of other drugs as well.

Common Symptoms After Long-Term Use Include:

• Anxiety
• Irritability, aggression
• Paranoia
• Hallucinations
• Depression
• Paranoid delusions

Paranoia usually disappears after a period of abstinence.

Effects of Abuse

Symptoms of amphetamine abuse include hyperactivity with excitement and motor restlessness. Over time, the affected person may develop a characteristic bouncy walk and experience involuntary, jerky, and exaggerated movements (choreoathetosis). Other symptoms/clinical signs include:

• Large pupils
• Formication (skin crawling sensations)
• Itching
• Repetitive movements
• Teeth grinding
• Tics

Physiological Effects

Heart rate and blood pressure increase, with the rise being dose-dependent, and at high doses, this can lead to severe hypertension and tachycardia. Amphetamine users commonly experience brain hemorrhages, with systolic blood pressures exceeding 250 mmHg. Bleeding in the brain is often diffuse, making it difficult to surgically evacuate the blood. Angiography may fail to reveal a bleeding source. Treatment is usually conservative, involving invasive blood pressure control. There is an increased risk of developing cerebral aneurysms that can rupture, causing serious subarachnoid hemorrhage.

Hematomas eventually resolve, but varying degrees of neurological damage may remain.

Long-term amphetamine abuse can lead to thromboembolic complications, including damage to the heart and blood vessels, increasing the risk of aortic aneurysm, vascular dissection, and heart failure (dilated cardiomyopathy).

Other physiological effects include lowered seizure threshold, weight loss, poor dental health with severe cavities and dry mucous membranes, vitamin deficiency, and compromised immune function. Amphetamine abuse also increases the risk of:

• Birth defects during pregnancy
• Fetal abnormalities with increased perinatal mortality
• Hepatitis B and C, HIV
• Liver cirrhosis
• Stroke
• Heart valve damage (endocarditis)

Psychological Effects

Abuse of central stimulants can lead to psychological effects, including hyperactivity, hypomania, impulsivity, restlessness, anxiety, mood instability, and increased aggression—both outwardly and inwardly directed.

Psychological Effects

Abuse of central stimulants can lead to psychological impacts such as hyperactivity, hypomania, lack of boundaries, restlessness, anxiety, unstable temperament, and increased aggression, both externally and internally.

Other psychological symptoms and effects caused by abuse include:

• Flight of ideas
• Increased impulsivity
• Manic episodes
• Impaired self-control, uninhibited behavior
• Increased appetite, binge eating (but also loss of appetite)
• Panic attacks, phobias
• Obsessive-compulsive behaviors (intrusive thoughts and compulsions)
• Psychotic-like reactions
• Tics
• Skin itching, tactile hallucinations (“Meth Bugs”)
• Depression, sadness, and suicidal behaviors

Acute Overdose

In cases of overdose, the user experiences a significant sympathetic response with hypertension, tachycardia, sweating, rigidity, and hyperthermia. Psychological symptoms, as listed below, are common.
Moderate overdose occurs with intake over 200 mg of amphetamine, severe overdose with more than 500 mg, and life-threatening overdose with over 1,000 mg (lower doses for methamphetamine). Normal intake is 100-200 mg per dose. Intake exceeding 500 mg can lead to:

• Confusion
• Anxiety attacks
• Psychomotor agitation
• Aggressiveness
• Acute psychosis
• Kidney failure
• Liver failure
• Hyperthermia
• Cardiovascular collapse

Hyperthermia can cause rhabdomyolysis and metabolic acidosis with the release of potassium, increasing the risk of heart arrhythmias. Generalized seizures, blood pressure drop, and oxygen deficiency can occur suddenly.

TREATMENT

Amphetamines have a moderately addictive effect. In a study of adolescents, 11% of those who tried amphetamines developed a dependence. Tolerance development has been described, as well as strong psychological dependence. The pathophysiology of addiction seems to involve disturbances in the brain’s dopamine system. In both animal models and human PET studies, decreased mesolimbic dopamine levels have been observed after amphetamine use, changes that have also been linked to the severity of withdrawal symptoms. Treatment of abuse is primarily symptomatic and therapeutic, with efforts aimed at complete abstinence. Attempts have been made with medical substitution therapy.

Regarding pharmacological treatment, there is insufficient scientific evidence to draw definitive conclusions about effective treatment for stimulant dependence. The number of intravenous drug users has decreased with substitution treatment. There is only limited evidence that substitution treatment for amphetamine dependence has positive treatment effects in terms of abuse, withdrawal symptoms, and drug cravings.

• Newer studies suggest that treatment with dextroamphetamine (Dexedrine), methylphenidate (Concerta^®) and disulfiram (Antabuse^®) is effective in stimulant use, especially with cocaine addiction. Lisdexamfetamine appears to have a lower risk of abuse compared to dexamphetamine, but this may only be a matter of dosage. Other studies are underway using opioid antagonists.
• There is uncertainty regarding the effectiveness of treatment with baclofen (Lioresal^®) and naltrexone (Naltrexon Vitaflo^®).
• Treatment with benzodiazepines is the first choice for treating insomnia, anxiety, and restlessness.
• Psychotic symptoms can be treated with, for example, olanzapine (Zyprexa^®), risperidone (Risperdal^®) or zuclopenthixol (Cisordinol^®).
• Caution is recommended with high-dose neuroleptics due to the risk of hemodynamic instability and lowered seizure threshold.

Psychosocial Treatment

Treatment using relearning and behavioral therapeutic methods has shown positive effects in amphetamine abuse, particularly during the first six months of treatment. Psychotherapy alone as a treatment method has resulted in higher retention rates in structured treatment programs compared to other interventions.

Acute Treatment

Management of acute overdose with stimulants depends on the substance used but is primarily symptomatic. It is important to direct the patient to the appropriate level of care to ensure vital functions are stabilized. Many patients, after acute treatment, require psychiatric evaluation and referral to addiction clinics and social services.

During acute management of confused users, regular monitoring of mental status and vital signs such as pulse, blood pressure, and temperature is crucial. The patient should be placed in a quiet, dark room and allowed to eat, sleep, and rest. For severe hypertension (systolic blood pressure above 200 mmHg), invasive blood pressure monitoring via an arterial catheter should be used. Rehydrate with crystalloid fluids and monitor serum electrolytes.

Benzodiazepines should be given to manage anxiety and agitation and to prevent or treat generalized seizures. In cases of oral amphetamine overdose, activated charcoal and gastric lavage should be considered in the same manner as for other poisoning cases, i.e., generally recommended for severe poisoning within one hour of ingestion.

Acidifying the urine increases amphetamine elimination but is not generally recommended as it is unfavorable in the presence of rhabdomyolysis. Be liberal with echocardiograms (UCG) to diagnose potential heart dilation and cardiomyopathy. For neurological symptoms, a CT scan of the brain should be performed, and cerebral angiography should be done if bleeding is detected.

Pharmacological Treatment:

• Diazepam (Stesolid^®) 5-20 mg 3-4 times daily for anxiety/agitation, or oxazepam (Sobril^®) 15-50 mg 4-6 times daily.
• Nitrazepam (Apodorm^®) 5-10 mg at night for sleep.
• Risperidone (Risperdal^®) 1 mg twice daily, or:
• Olanzapine (Zyprexa^®) 10-20 mg x 2, or:
• Haloperidol (Haldol^®) 5 mg 1-2 times daily (avoid high-dose neuroleptics), or oral solution 1-2 mg, up to every 4 hours for psychotic symptoms. If oral treatment is not possible, Haldol can be administered intramuscularly 2.5-5 mg x 4 or zuclopenthixol (Cisordinol-Acutard^®) 100-150 mg intramuscularly.
• Midazolam (Midazolam^®) 2-5 mg intravenously for motor agitation and anxiety.
• Dexmedetomidine (Dexdor^®) in infusion if treatment is provided in an intensive care unit.
• For palpitations and moderate hypertension, use beta-blockers – propranolol (Inderal^®) 40 mg x 3 or metoprolol (Seloken^®) 50 mg x 3.
• Clonidine 150 mcg x 3
• Symptomatic treatment as needed.

Severe Hypertension

For severe hypertension (> 200 mmHg), blood pressure should be monitored invasively.

Treating high blood pressure must be done cautiously. Intravenous beta-blockers have been described as causing paradoxical effects during toxic effects from cocaine and amphetamines. High blood pressure should, therefore, be treated primarily with vasodilators such as nitroglycerin. Magnesium sulfate is a mild vasodilator that works well in the treatment of sympathomimetic conditions and may be tried for amphetamine toxicity.

• Infusion of glyceryl trinitrate (Nitroglycerin^®) 0.2-0.5 μg/kg/min.
• Infusion of magnesium sulfate 20 mmol in 100 ml NaCl over 20 minutes followed by 20 mmol over 20 hours.
• Clonidine (Catapresan^®) can be tried in continuous infusion, 0.25-0.5 mcg/kg/hour or dexmedetomidine (Dexdor^®). Catapresan can also be given orally, 75-150 mcg x 3.
• Caution with intravenous beta-blockers.
• CT brain in case of hypertensive crisis or neurological symptoms.

Hyperthermia

Sedation and cooling are important in cases of hyperthermia. Active treatment may be required. Sedation is primarily done with benzodiazepines, such as midazolam (Midazolam^® 1 mg/ml) or diazepam (Stesolid^® 5 mg/ml), and secondly with propofol (Diprivan^® 20 mg/ml). Active cooling can be achieved by intravenous administration of 1-2 liters of cold saline solution.

Prognosis

The prognosis for acute stimulant poisoning is generally good if the patient has not already developed complications such as cerebral hemorrhage, serotonin syndrome, or cardiovascular collapse. A “sympathomimetic or serotonin syndrome” can develop in cases of amphetamine overdose, leading to multiple organ failure in severe cases. Each year, approximately 100 people die from drug-related deaths caused by amphetamines.

Roughly half of all deaths from amphetamine abuse are due to cardiovascular collapse, while the rest die from other causes such as accidents, trauma, suicide, severe infections, dilated cardiomyopathy, pulmonary embolism, myocardial infarction, and other intoxications.

ICD-10

• F 15.1 Mental and behavioral disorders due to use of other stimulants, including caffeine, harmful use
• T43.6 Psychostimulants with abuse potential  
• X60-X69 Intentional self-harm through poisoning
• Y10-Y19 Poisoning with unclear intent

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14. Pelham WE, et al. Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Pediatrics 2001;107(6):E105
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16. Ellinwood, E.H. Amphetamine Psychosis. I. Description of the individuals and processes. Journal of Nervous and Mental Disease. 1967;144, 273-283
17. Shoptaw SJ, Kao U, Ling WW. Treatment for amphetamine psychosis. Cochrane Database Syst Rev 2008;(4):CD003026
18. N Buxton and N S McConachie. Amphetamine abuse and intracranial hemorrhage. J R Soc Med. 2000;93(9): 472–477
19. Goodman, SJ; Becker, DP. Intracranial hemorrhage associated with amphetamine abuse. JAMA. 1970;212(3):480–480
20. Borbély A A, Baumann I R and Waser P G. Amphetamine and thermoregulation: Studies in the unrestrained and curarized rat. 1974;281(4):327-40
21. Callaway CW, Clark RF. Hyperthermia in psychostimulant overdose. Ann Emerg Med 1994;24(1):68-76
22. Bloniecki Kallio V, Guterstam J, Franck J. Substitution treatment for amphetamine addiction is being trialed. Läkartidningen 2016;113:DSU6.

Cocaine

Cocaine is a mythologized stimulant drug with a strong euphoric effect, often considered highly addictive. Cocaine is derived from the leaves of the coca plant. Cocaine preparations are usually classified as a separate pharmacological group from amphetamines among illegal drugs. Cocaine preparations are categorized into cocaine powder (a hydrochloride salt) which is sniffed (“snorted”) or injected, and crack (freebase), which is smoked. Cocaine is an alkaloid with the chemical name benzoylmethylecgonine. Ecgonine is a type of local anesthetic with strong vasoconstricting effects, which is why cocaine has similar effects and is sometimes used as a local anesthetic in specific medical contexts, such as eye and nasal surgeries.

Cocaine is classified as a narcotic under Schedule II in the Swedish Medical Products Agency’s list of narcotics (LVFS 2011:10). The drug produces a potent euphoric high and is considered highly addictive. In 2014, around 78,000 cocaine seizures were reported in the EU, resulting in the confiscation of 62.6 tons of cocaine. The number of seizures decreased slightly between 2008 and 2013. Cocaine is most common in southern and western Europe.

Nowadays, cocaine is primarily known as a widespread “party drug,” making it relatively common in club and nightlife settings in major cities, especially in the USA, the UK, and southern Europe. 2.4 million people, or 1.9% of all young adults (aged 15-34) in the EU, have used cocaine in the past year. Cocaine accounts for 10% of all drug seizures, with cannabis making up more than 80%. Nineteen EU countries reported cocaine-related deaths in 2013, with over 800 cases in total. Seventy percent of all those receiving treatment for cocaine addiction come from Spain, the UK, and Italy. Cocaine ranks second among confiscated drugs after cannabis. The price of one gram of cocaine typically ranges between 52 and 72 Euros, and the purity level varies between 36% and 50%.

Approximately twice as many men as women use cocaine, and it is most common in the 18-25 age group. However, among women in their 20s, cocaine use is more common, as young women are often offered the drug by male acquaintances. Cocaine use among young people in Sweden is likely more widespread today than in the 1990s, but it is still significantly less common than cannabis and amphetamines. Less than 0.5% of adults report having tried cocaine in the past year.

In the USA, cocaine is far more common than in Sweden. It is estimated that around 50 million Americans have used cocaine at some point, and 6 million use it regularly. Cocaine is the second most commonly used drug after marijuana in the USA and is responsible for the most hospital emergency visits after alcohol and tobacco. Among emergency room patients, 40% reported chest pain caused by heart ischemia.

Cocaine Hydrochloride

Cocaine is extracted from the leaves of the coca plant (Erythroxylum coca). The coca plant grows in South America and is primarily produced in Colombia, Peru, and Bolivia. The leaves are crushed and combined with solvents to create a dried primary product called coca paste. Cocaine hydrochloride is produced from coca paste by adding hydrochloric acid and applying heat.

Chewing coca leaves is a relatively common practice in the Andes, producing a moderate stimulant effect. When chewed, it takes about 30 minutes for the effects to be felt, and after two hours, the maximum stimulating and hunger-suppressing effects are reached. Coca leaves contain about 0.5% cocaine, and chewing them with alkaline ash releases the cocaine in low doses.

Cocaine is typically refined in primitive factories in the jungle and smuggled through countries like Mexico to the USA, Canada, and Europe. It is sold as a white powder in the form of cocaine hydrochloride, which is snorted, smoked, or injected. Mexico has faced significant criminal activity related to the smuggling and trade of cocaine, known as the “cocaine war.” Cocaine use became widespread in the USA in the late 1800s and was completely banned in 1915.

Cocaine is primarily consumed by snorting through a tube or rolled-up bill, but it can also be injected. Cocaine is absorbed through the veins in the nasal mucosa, producing a rapid onset and a relatively short-lasting high. Cocaine hydrochloride is quickly metabolized into an active metabolite called benzoylecgonine. This metabolite has a longer half-life compared to cocaine and is typically detected during testing for cocaine use.

Common slang terms for cocaine among users include Snow Flake, Girl, Lady, Pimp’s Drug, Speed Ball (with heroin), Blow, Nose Candy, Liquid Lady, and others. Swedish slang terms include pudra näsan (“powdering the nose”), näskaffe (“nose coffee”), ladd, tennis, kola, snö, and schmurk.

Crack

By boiling cocaine hydrochloride with bicarbonate, cocaine base is extracted in crystallized freebase form, known as “Crack.” Crack is fat-soluble and is quickly absorbed in lung capillaries when smoked. It appears as grayish-white or yellowish lumps with a porous surface and greasy texture, which can be smoked after heating. Crack is mostly used by marginalized addicts.

Crack is said to provide a very intense but short-lived high. Cocaine base is absorbed through the endothelium of lung capillaries when smoked, producing an effect within 6-8 seconds.

Synthetic Cocaine

Various synthetic online drugs that resemble cocaine have begun to appear on the market in recent years. Some of these include dimethocaine and camfetamine. These drugs have different user or slang names, including “syntekain.” They have also been called “legal cocaine.” Several of these drugs, with names similar to cocaine, have been found to contain other synthetic psychoactive substances besides cocaine. Synthetic cannabinoids have also been detected in some cases.

Symptoms

Effects of Cocaine Abuse

The effect of cocaine is short-lived (20-40 minutes) after snorting, and the drug must be taken repeatedly to maintain the high. The euphoric high occurs 3-5 minutes after sniffing, with peak brain concentrations occurring after about 4 minutes. The euphoria is strongest during the initial phase of the high. The effects occur fastest via inhalation, followed by intravenous administration, nasal administration, and lastly oral administration. Cocaine typically makes users feel alert, happy, energetic, and “up” (euphoric).

Cocaine primarily stimulates dopamine receptors, but also affects norepinephrine and serotonin receptors, leading to increased catecholamine release.

The cocaine high is described as leading to increased:

• Vitality
• Euphoria, pleasure
• Mental clarity
• Energy and stamina

Acute cocaine poisoning is rare in Sweden, and the direct effects of the cocaine high rarely lead to hospital visits. Acute hospital visits are more often the result of complications from abuse, overdose, or mixed poisoning.

Psychological Effects

In addition to the effects mentioned above, hyperactivity and hypomania can occur. Appetite may increase, leading to binge eating, but appetite loss and anorexia are also possible. Other negative effects include insomnia, restlessness, anxiety, irritability, as well as:

• Flight of ideas, unstable temperament
• Decreased self-control, uninhibited behavior
• Increased unrestrained sexual activity
• Psychosis-like reactions
• Self-centered thoughts, paranoid ideas
• Pseudohallucinations (Magan’s sign), auditory hallucinations
• Depression, sadness
• Suicidal actions

Physiological Effects

The sympathetic nervous system activation from cocaine use can lead to hypertension, tachycardia, and palpitations. The drug blocks the rapid sodium channels in the heart’s myocytes, leading to increased intracellular calcium concentration, decreased magnesium concentration, and increased heart stress. Brugada syndrome may appear on an EKG as a J-wave with an elevated early ST segment.

Cocaine has potent vasoconstrictive effects, especially in the nasal mucosa, brain, and heart, which can cause serious complications due to ischemia. Long-term damage to the heart and blood vessels can lead to heart failure, cardiomyopathy, and myocarditis. Prolonged lack of oxygen in the brain can cause memory disturbances, and in rare cases, severe memory impairment resembling Alzheimer’s disease. Cocaine affects the blood components, inducing platelet aggregation. It can also cause thrombocytopenia and increased atherogenesis, leading to severe thromboembolic complications. There is a risk of rhabdomyolysis with kidney failure and, in rare cases, severe liver failure.

Cocaine can also cause ruptures in brain blood vessels due to vasospasm, hypertension, and microinfarcts, leading to brain hemorrhage or stroke. In the USA, strokes due to cocaine use are not uncommon, and aortic dissection has also been reported. Sudden death (mors subita) is not uncommon among cocaine users and is often preceded by Brugada syndrome.

Other physiological effects include:

• Tremor
• Seizures
• Hyperemia and sores in the nasal mucosa
• Suppressed immune system
• Multiple skin ulcers

Cocaine Overdose

A normal dose of cocaine is around 25-100 mg. A moderate overdose occurs with intake over 500 mg, a severe overdose with over 1,000 mg, and a life-threatening overdose with over 3,000 mg. There is no specific antidote for cocaine. The most common symptoms of overdose include palpitations, intense sweating, and seizures.

Life-threatening overdoses are primarily seen among those smuggling cocaine by swallowing packages (“body packers“) or among those who swallow drugs to avoid police detection (“body stuffers“).

In cases of acute overdose, the patient may develop intense sympathetic nervous system activation, with hypertension, tachycardia, cold sweating, rigidity, and hyperthermia (heat stroke). Excitation, psychomotor agitation, restlessness, and psychotic symptoms are common.
Intake over 500 mg can lead to:

• Confusion
• Psychomotor agitation
• Aggression
• Psychosis
• Mania
• Cardiovascular collapse
• Rhabdomyolysis
• Kidney failure
• Liver failure

Hyperthermia can cause rhabdomyolysis and metabolic acidosis, with the release of potassium and the risk of heart arrhythmias (widened QRS complexes on EKG). Generalized seizures, blood pressure drops, and oxygen deprivation can occur suddenly.

Other symptoms of cocaine use include:

• Dilated pupils (mydriasis)
• Hyperactivity, excitation
• Tremor
• Chest pain, EKG changes

Neurological deficits may occur. There is a risk of brain edema, lung edema with respiratory failure, cardiovascular collapse, and coma.

Evaluation

In cases of acute care for confused users, screening for cocaine is necessary, along with monitoring of pulse, blood pressure, EKG, and temperature. Cocaine is included in most rapid drug tests. Cocaine has several active metabolites: norcocaine, benzoylecgonine, and ecgonine methyl ester. If alcohol is also consumed, cocaethylene can form. In testing for cocaine use, benzoylecgonine is the primary metabolite measured.

Cocaine intoxication can be confirmed through HCMS after a simple urine drug screening.

In cases of symptomatic acute intoxication, adequate patient monitoring is essential, particularly for:

• Consciousness
• Respiration
• Circulation
• Mental functions
• Body temperature
• Kidney function

See also “Management” below.

A CT scan of the brain should be performed in cases of blood pressure crisis or neurological symptoms.

Treatment

Cocaine has a significantly addictive effect, with tolerance development described, as well as strong psychological dependence. Treatment for cocaine addiction is primarily symptomatic and therapeutically oriented.

In terms of pharmacological treatment for cocaine addiction, there is insufficient scientific evidence to draw definitive conclusions about its effectiveness.

• Treatment with benzodiazepines is the first-line option for managing insomnia, anxiety, and agitation.
• Treatment with antidepressants appears to have a positive effect on treatment retention compared to placebo.
• Recent studies suggest that treatment with dextroamphetamine (Dexedrin) and disulfiram (Antabus) may slow cocaine addiction. Ongoing studies are exploring the potential of modafinil, a non-amphetamine stimulant, as a treatment option.
• There is uncertainty regarding the efficacy of treatments like baclofen (Lioresal) and naltrexone (Naltrexone). Psychotic symptoms can be treated with haloperidol (Haldol), risperidone (Risperdal), or olanzapine (Zyprexa).
• Caution is recommended with high-dose neuroleptics due to the risk of hemodynamic instability and lowered seizure threshold.

In the area of psychosocial treatment, cognitive and behavioral therapy methods have shown positive effects, particularly during the first six months. Psychotherapy has been shown to increase retention in structured treatment programs compared to other psychosocial interventions.

Management

Polydrug intoxications involving cocaine, alcohol, and medications (especially benzodiazepines) are common. Management is largely symptomatic, depending on the substances ingested. There is no specific antidote for cocaine. Simultaneous alcohol consumption, which is common, can increase toxicity through the formation of ethylbenzoylecgonine, commonly known as cocaethylene.

Careful monitoring of consciousness, respiration, circulation, and mental function is critical to ensure that the patient is managed at the appropriate level of care to maintain vital functions in the acute phase.

For cocaine intake above 3 grams, there is a high risk of life-threatening cardiac arrhythmias, and the patient must be monitored in a unit equipped with cardiac monitoring and emergency interventions for ventricular fibrillation. EKG monitoring should be performed, and attention should be paid to widened QRS complexes or prolonged QT intervals, which increase the risk of ventricular arrhythmias.

After the acute phase, many cases require psychiatric evaluation and referral to addiction medicine services and social services.

The prognosis in acute cocaine poisoning is generally good, provided the patient does not develop ventricular arrhythmias before hospital arrival.

Treatment in Acute Overdose

For oral cocaine intake, activated charcoal and gastric lavage should be considered, similar to other poisoning cases, and is generally recommended in cases of severe poisoning up to one hour after ingestion.

Rehydrate the patient with crystalloid fluids. Regularly monitor pulse, blood pressure, and temperature. Invasive blood pressure monitoring may be necessary in cases of severe hypertension. Check serum electrolytes. Treat metabolic acidosis with sodium bicarbonate until the base excess is positive in blood gas analysis. In cases of ventricular arrhythmias, consider using lidocaine (Xylocard). Magnesium infusion can also be tried.

In mild to moderate intoxication, place the patient in a quiet, dark room and encourage sleep, food, and rest (allow a “sleep-in”). Benzodiazepines are the first-line treatment for anxiety and agitation, as well as for preventing or treating seizures.

• Insert at least one IV line. Take a complete blood count, platelet count, and drug screen.
• If necessary, initiate IV fluids, such as Ringer’s acetate. Rehydrate the patient until adequate urine output is achieved.
• Regularly monitor consciousness, pulse, blood pressure, and temperature.
• Prescribe Diazepam (Stesolid) 5-20 mg, three times daily
  Alternatively oxazepam (Sobril) 15-50 mg, three times daily
• Zopiclone (Imovane 7.5 mg at night) or Nitrazepam (Nitrazepam) 5-10 mg at night for sleep.
• Haloperidol (Haldol) 5 mg, once or twice daily (avoid high-dose neuroleptics) or as an
  
  oral solution 1-2 mg, every 4 hours as needed. If oral administration is not possible, haloperidol can be given intramuscularly at 2.5-5 mg up to 4 times daily.
  Alternatively, zuklopentixol (Cisordinol-Acutard) 100-150 mg intramuscularly (50 mg/ml, 2-3 ml).
• Midazolam (Dormicum) 2-5 mg intravenously or orally for motor agitation and anxiety (1 mg/ml).

High Blood Pressure and Hyperthermia

Treatment of hypertension and tachycardia during cocaine intoxication must be approached with caution. High blood pressure should primarily be treated with vasodilators such as glyceryl trinitrate. Magnesium sulfate is a mild vasodilator and can be considered in cocaine toxicity:

• For severe hypertension (> 200 mmHg) with intravenous blood pressure control
  – Infusion of glyceryl trinitrate (Nitroglycerin) 0.2-0.5 μg/kg/min
  – Infusion of magnesium sulfate 20 mmol in 100 ml NaCl over 20 minutes, followed by 20 mmol over 20 hours
• Avoid intravenous beta-blockers, as they have been described to produce paradoxical and unpredictable effects.

Sedation and cooling are important in managing hyperthermia:

• Administer 1-2 liters of cold saline intravenously.
• Inject diazepam (Stesolid) 5-20 mg intravenously, or alternatively midazolam (Dormicum) 2-5 mg intravenously.

ICD-10

• Mental and behavioral disorders due to cocaine, acute intoxication F14.0
• Mental and behavioral disorders due to cocaine, harmful use F14.1
• Mental and behavioral disorders due to cocaine, dependence syndrome F14.2
• Cocaine T40.5

Ecstasy (MDMA)

There has been a growing interest in hallucinogenic drugs among young people over the past decades, both in Sweden and across Europe. Ecstasy (MDMA) is a euphoric drug that became popular in the 1990s as a dance and party drug. Ecstasy is classified as a narcotic, and its use is illegal. Among new psychoactive substances (NPS), ecstasy (MDMA), phenethylamines, cathinones, synthetic cannabinoids (Spice), tryptamines, and several other new hallucinogens have emerged. These drugs are also known as “Designer Drugs,” “Legal Highs,” and “Smart Drugs.” Ecstasy has long been the most common and can be considered a reference substance. Many of these substances can be classified as substituted amphetamine derivatives. These agents have pharmacological effects similar to amphetamine. Most have been classified as narcotics according to LVFS 2011:10, but some are classified as harmful substances.

Benzylpiperazine (BZP), dextromethorphan (DXM), mephedrone, methedrone, naphyrone, and others can also be included under the designation “New Psychoactive Substances (NPS).” These drugs are all related to amphetamine, with varying degrees of euphoric and hallucinogenic effects.

Acute intoxication with NPS, along with alcohol and various medications, particularly benzodiazepines, is not uncommon among young people engaged in polydrug abuse. Intoxication with hallucinogenic mushrooms and various gases, such as nitrous oxide, is also common among this group of users.

This overview focuses primarily on ecstasy poisoning. Several variants of ecstasy (MDMA, MMDA, MDE, MDA, PFMPP) are sold online as “legal highs.”

ECSTASY

Ecstasy (3,4-methylenedioxymethamphetamine – MDMA) is a stimulant amphetamine-like substance that became a popular party drug in Europe during the 1990s. Ecstasy is classified as a narcotic according to LVFS 2011:10, Schedule I. Ecstasy was first synthesized in 1912 by Merck in Germany. MDMA was first used as a psychotherapeutic aid in the USA during the 1960s due to its “entactogenic” (empathy-enhancing, trust-seeking) properties and later developed into a so-called party drug across Europe, especially in England and Germany at so-called rave parties featuring mainly electronic dance music (“techno, psytrance”).

In Sweden, ecstasy was first encountered in 1986 and was classified as a narcotic the following year. Its use among youth in Sweden increased significantly in the late 1990s but has declined substantially in recent years. The drug is sporadically used by youth aged 15 to 25 in connection with parties and intense dancing. Ecstasy is more commonly used by boys than girls. In the 2014 drug habits survey among Swedish school youth, two percent reported having tried ecstasy in the second year of high school, compared to three percent in 2006. Of those who had tried drugs in the second year, 12 percent reported having tried ecstasy in Gothenburg in 2013. Only a few users seek treatment for ecstasy-related problems. Ecstasy is more common in southern Sweden and in metropolitan areas.

Content and Appearance

Ecstasy is a stimulant with somewhat weaker physiological but more euphoric, hallucinogenic (psychotropic), and entactogenic effects compared to amphetamine. Sensory perception is enhanced. There are several different substituted amphetamines with effects similar to ecstasy, such as:

• MDEA/MDE (methylenedioxyethylamphetamine) “Eve”
• MDA (methylenedioxyamphetamine) ”Sally, SASS, Sassafras”
• TFMPP (trifluoromethylphenylpiperazine) ”Legal X”
• MBDB (methyl-benzodioxol-butylamine) ”Eden, Methyl-J”
• PMA (para-methoxyamphetamine) ”Dr Death”
• PMMA (para-methoxy-methamphetamine) ”Superman”

The drugs have many different slang names among users, such as XTC, Love and kissing pills, Adam, Eve, Eden, E, Mandy, Molly, Superman, and X.

Ecstasy is usually sold as colorful tablets that are taken orally, with varying appearances in doses of 50-100 mg. The content and strength can vary between different tablets and is rarely fully known to the user. Therefore, the effect is unpredictable. The tablets are often stamped with a logo, such as a “Smiley,” the Mitsubishi symbol, the Superman logo, the Mercedes star, or similar. On the illegal market, a tablet costs around 100 kronor. Ecstasy in powder form can also be snorted, inhaled, or dissolved and injected, though this is rare. A tablet costs between 60-225 kr/piece (price data from CAN 2014).

Analyses of the contents of different ecstasy tablets have shown the presence of various chemical substances – MDMA, MDEA, MDA, MDB, etc. This means that users may experience varying effects from different tablets of the same appearance. Party drugs are imported from countries like Russia, Poland, Germany, and the Netherlands.

Most party drugs can be detected in blood and urine during extended analysis in cases of suspected drug influence. Rapid urine tests are available for drug screening but only cover the most common substances like ecstasy. MDMA can usually be detected in urine for up to 2-4 days after ingestion.

Molecular structure

Symptoms of Ecstasy Use

The effects of ecstasy and similar substances are characterized by euphoria, social empathy, openness, and increased mental and physical energy. The sense of well-being increases, and a positive sense of pleasure occurs 1 to 3 hours after ingestion. Self-confidence increases, and there is a perception that all problems disappear. The drugs provide an enhanced sense of communication, understanding, and empathy. Users experience increased trust and intimacy with others. Smell, sight, and sound perceptions are heightened. Pupils dilate (mydriasis).

The central nervous system effects are primarily caused by serotonin release in central parts of the brain, particularly the limbic system and hippocampus. However, after prolonged use, serotonin stores are depleted, and patients develop negative mental symptoms, such as depression and sometimes psychosis.

Examples of negative effects:

• Hyperactivity and hypomania (akathisia)
• Flight of ideas, unstable temperament
• Restlessness, anxiety, irritability
• Decreased self-control, lack of boundaries, unstable behavior
• Unrestrained sexual activity
• Increased appetite, binge eating (but also loss of appetite and anorexia)
• Headache
• Psychosis-like reactions, hallucinations

Over time, with repeated use, the drug user becomes exhausted, irritable, and depressed. The patient’s low mood can be difficult to treat and prolonged. Experimental animal data suggest that damage to dopamine pathways and especially serotonin pathways is morphological and partly irreversible. Generalized seizures also occur.

Symptoms that may appear after a few months of abuse include:

• Fatigue, lack of energy, low mood
• Sleep disturbances
• Stereotypical behavior, tics
• Phantom ringing in the ears
• Depression
• Paranoia
• Anxiety
• Mutism
• Catatonia

Treatment with antidepressant medications (SSRI drugs) for low mood works less effectively than usual after ecstasy abuse. The user experiences a reduced effect from renewed intake of ecstasy. With prolonged abuse, many patients develop cognitive dysfunction – memory and learning ability are significantly impaired.

Symptoms of Acute Overdose

A typical abuse dose is estimated at 100 mg orally, with common variations being 50-250 mg. Mild overdose is 250-500 mg, moderate overdose 500-1000 mg, and severe overdose above 1000 mg. In acute overdose of ecstasy and other stimulant party drugs, symptoms such as large, dilated pupils, hyperactivity, excitement, euphoria, increased sweating, restlessness, and agitation are noted. The patient may appear unnaturally excited and exhibit psychomotor agitation. Tachycardia, palpitations, tremors, hypertension, and chest pain may occur. Aggression, confusion, and hallucinations are also common. In a study of acute intoxications with NPS, psychosis was reported in 6% of the patients. There is a risk that the patient may experience muscle tension, muscle twitches, and seizures, with jaw cramping (trismus) and hyperthermia being common. The risk of hyperthermia is significant and can become very serious and life-threatening. Ecstasy is metabolized in the liver via CYP2D6.

In acute overdose, the patient risks:

• Water intoxication with hyponatremia
• Acute confusion
• Heart arrhythmias
• Myoclonic seizures
• Hyperthermia (fever)
• Serotonin syndrome
• Liver damage
• Kidney failure

Water Intoxication

Can occur after taking a couple of ecstasy tablets and excessive water intake; girls are more sensitive than boys. Water intoxication with pronounced hyponatremia (S-Na < 120 mmol/l) can lead to brain edema, headache, blurred vision, seizures, and coma. A few deaths have been reported in Sweden and several cases in England and Europe.

Heatstroke

Can occur after taking ecstasy and prolonged dancing or staying in a warm environment (nightclub setting). The patient is at risk of developing hyperthermia with muscle rigidity, seizures, and rhabdomyolysis. Poor fluid intake increases the risk of hyperthermia. Hyperthermia is often one of the symptoms of “serotonin syndrome” (see below) and can lead to hyperkalemia, heart problems with arrhythmias, coma, and multiple organ failure. Hyperthermia likely results from serotonin dominance in the hypothalamus and striatum with downregulated dopamine function. Body temperatures above 41 degrees Celsius are dangerous, and above 42 degrees are directly life-threatening, requiring immediate care with active cooling. Hyperthermia can become severe and prolonged, especially after taking PMA or PMMA. Isolated cases of liver and kidney failure have also been described. Kidney failure likely occurs secondarily to rhabdomyolysis and myoglobin precipitation in the kidney glomeruli. Always check serum myoglobin. Brain CT or MRI should be performed if pronounced hyponatremia (S-Na < 120 mmol/L) occurs, to rule out brain edema, or if focal neurological symptoms are present. Morphological damage to serotonergic pathways can be detected with PET scanning (f-MRI).

Other serious symptoms that may develop include impaired coagulation, DIC (disseminated intravascular coagulation), and respiratory failure with the risk of pulmonary edema. Seizures and coma can occur. There is also a risk of brain hemorrhage, pulmonary embolism, and cardiovascular collapse.

Serotonin Syndrome

Serotonin syndrome refers to overactivity of the serotonergic system in the brain. It is a serious condition that can occur with overdoses of various NPS, often in combination with antidepressants or analgesics. In the worst case, it leads to multiple organ failure and death. Serotonin syndrome often presents with fever (hyperthermia), and these cases should be treated in an intensive care unit.

Symptoms of serotonin syndrome include:

• Akathisia (“motor restlessness”)
• Tremors
• Sweating
• Enlarged pupils
• Anxiety
• Agitation
• Confusion
• Diarrhea
• Clonus (easily triggered reflexes), especially in the lower extremities
• Tachycardia
• Rigidity
• Hyperthermia

Treatment

Management

The management of acute overdose with stimulant amphetamine analogs is mainly symptomatic and similar for most substances. Specific antidotes are lacking.

The most important thing is to closely monitor:

• Consciousness
• Breathing
• Circulation
• Temperature
• Mental functions

It is essential to direct the patient to the appropriate medical department so that vital life functions can be secured urgently. Afterward, the drug abuse should be treated; psychiatric assessment and referral to addiction medicine clinics and social services are often required. Reports to social services must always be made in cases of life-threatening abuse.

The prognosis for poisoning with party drugs is generally good unless severe complications have arisen before hospital admission. Screening with a drug test strip may sometimes, but not always, provide information about the substances ingested. Negative screening does not rule out poisoning with party drugs.

Treatment for Acute Overdose

Monitor pulse, blood pressure, temperature, and mental functions regularly. Invasive blood pressure measurement should be performed in cases of severe hypertension during moderate or severe intoxication. Place the patient in a quiet and dark room during mild to moderate poisoning and allow them to eat, sleep, and rest (sleep late). Treat anxiety and agitation. Note the risk of hyperthermia. Rehydrate with crystalloid fluids and check serum electrolytes. Perform drug screening on a urine or plasma sample.

Pharmacological treatment for anxiety or agitation:

• Diazepam (Stesolid^®) 5-20 mg 3 times daily or oxazepam (Sobril^®) 15-50 mg 3 times daily
• Nitrazepam (Nitrazepam^®) 5-10 mg at night for sleep
• Droperidol (Dridol^®) 10 mg IM x 1.
• Olanzapine (Zyprexa^®) 10 mg x 2 or risperidone (Risperdal^®) 1 mg x 2
• Midazolam (Dormicum^®) 2-5 mg IV for motor restlessness and anxiety
• Propofol (Propofol^®) IV for severe anxiety in an intensive care unit
• Dexmedetomidine (Dexdor^®) in continuous infusion for severe anxiety in an intensive care unit
• Symptomatic treatment otherwise
• Caution with beta-blockers

Brain CT during a blood pressure crisis or neurological symptoms, such as brain edema or stroke. Check serum myoglobin to assess for rhabdomyolysis. Possibly forced alkaline diuresis if necessary.

In cases of hyperthermia, active cooling and sedation may be required:

• 1-2 liters of cold saline intravenously
• Diazepam (Stesolid^®) 5-20 mg IV
• External cooling with cooling blanket or similar methods
• In cases of extreme hyperthermia, extracorporeal cooling via ECMO can be considered

In the case of serotonin syndrome, treatment with one of the following medications can be administered:

• Cyproheptadine (Periactin^®) Tablets 8 mg x 3 orally (licensed medication, antihistamine) or
• Olanzapine (Zyprexa^®) 10 mg x 2
• Risperidone (Risperdal^®) 2 mg x 3

For severe hypertension (> 200 mmHg) – invasive blood pressure monitoring with arterial catheter:

• Infusion of glyceryl trinitrate (Nitroglycerin^®) 0.2-0.5 μg/kg/min
• Infusion of magnesium sulfate, 20 mmol in 100 ml NaCl over 20 minutes followed by 20 mmol over 20 hours
• Beta-blockers with caution, such as metoprolol (Seloken^®), labetalol (Trandate^®)
• Alpha-blockers with caution, such as doxazosin (Alfadil^®), labetalol (Trandate^®)

ICD-10

• F16.0 Mental and behavioral disorders due to use of hallucinogens, acute intoxication  
• F16.1 Mental and behavioral disorders due to use of hallucinogens, harmful use
• F14.2 Mental and behavioral disorders due to use of cocaine, dependence syndrome
• T43.6 Psychostimulants with abuse potential
• T40.6 Other and unspecified narcotics
• F15.1 Mental and behavioral disorders due to use of other stimulants, including caffeine, harmful use
• F15.0 Mental and behavioral disorders due to use of other stimulants, including caffeine, acute intoxication

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6. Bankson MG, Cunningham KA. 3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions.J Pharmacol Exp Ther. 2001 Jun;297(3):846-52.
7. Montoya AG et al. Long-term neuropsychiatric consequences of “ecstasy” (MDMA): a review. Harv Rev Psychiatry 2002 10(4):212-20.
8. Karlsen SN, Spigset O, Slördal L. The dark side of ecstasy: neuropsychiatric symptoms after exposure to 3,4-methylenedioxymethamphetamine. Basic Clin Pharmacol Toxicol. 2008;102(1):15-24.
9. Dar KJ, McBrien ME. MDMA induced hyperthermia: report of a fatality and review of current therapy. Intensive Care Med 1996;22(9):995-6.
10. Bråbäck L, Humble M. [Young woman dies of water intoxication after taking one tablet of ecstasy. Today’s drug panorama calls for increased vigilance in health care] Läkartidningen 2001;98(8):817-9.
11. Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav. 2002;71(4):837-44.
12. Stolaroff MJ, Wells CW. Preliminary results with new psychoactive agents 2C-T-2 and 2C-T-7. Yearbook for Ethnomedicine 1993:99-117.
13. Balíková M. Nonfatal and fatal DOB (2,5-dimethoxy-4-bromoamphetamine) overdose. Forensic Sci Int. (2005) 153, 85–91.
14. Bowen JS, Davis GB, Kearney TE, Bardin J. Diffuse vascular spasm associated with 4-bromo-2,5-dimethoxyamphetamine ingestion. JAMA. 1983;249(11):1477-9.
15. Rammer L, Holmgren P, Sandler H. Fatal intoxication by dextromethorphan: A report on two cases. Forensic Sci Int. 1988;37(4):233-6.

New Psychoactive Substances (NPS – “Internet Drugs”)

Interest among young people in drugs purchased online has increased in recent years. Internet drugs refer to new psychoactive substances (NPS) with psychotropic effects that can be purchased via the internet. These internet drugs resemble several established narcotic drugs, usually amphetamine-like or cannabis-like. Several benzodiazepines not registered in Sweden can also be purchased online. Among modern so-called “internet drugs,” there are various groups such as:

• Synthetic cathinones (e.g., mephedrone, methedrone, naphyrone)
• Phenethylamines
• Tryptamines
• Piperazines
• Opioids
• Benzodiazepines
• Several new hallucinogens
• Synthetic cannabinoids (cannabis-like “Spice”)

The drugs are also called “Research Chemicals (RC-drugs), Designer Drugs, Legal Highs, and Smart Drugs”.

Most internet drugs primarily have amphetamine- or cannabis-like effects. Opioid-like and benzodiazepine-like drugs also exist. Many of the substances can be classified as substituted amphetamine derivatives or synthetic cannabinoids (SC). Most are chemically related to phenethylamine, with alpha-methylphenethylamine being best known as amphetamine. Amphetamine analogs give users increased energy and decreased appetite; users usually feel energetic, alert, and more focused. Excessive use, however, results in several negative consequences with an increased risk of psychosis. Some of the cannabis-like drugs are synthetic or plant-based substances, known as synthetic cannabinoids (“Spice”). The effects of these resemble cannabis but tend to cause relatively more hyperactivity and some central stimulant effects.

The purchase of NPS occurs online on various national or international websites or through dealers in the same way as other narcotic drugs. The delivery comes by mail or through a local dealer. Internet drugs have led to many serious intoxication cases requiring intensive care, and fatal cases have been reported.

Most new psychoactive substances are difficult to detect in routine blood tests but can be detected in blood and urine through extended and targeted analysis. Rapid urine tests exist for drug screening, but they often detect only the most common drugs, such as ecstasy, cocaine, cannabis, and amphetamine, and may miss the presence of NPS. Spice and other synthetic cannabinoids are harder to detect, but several new urine test strips are available that can detect Spice and other internet drugs.

This overview covers poisoning with various new psychoactive substances. Currently, about 50 new substances are classified each year in Sweden, and about 100 new substances are identified throughout Europe every year. A peak was noted in 2014 and 2015, after which the number of newly discovered substances has slightly decreased in both Sweden and Europe. The drugs are eventually classified as either narcotics or health hazards. Until such classification, the drugs can be sold legally. In total, more than 700 new substances have been reported, and more than 400 have been discovered in the last 5 years.

Spice (synthetic cannabinoid receptor agonists)

Spice is a mixture of several herbs and spices with added synthetic cannabinoids that produce cannabis-like effects. Spice is mixed with tobacco and smoked using a pipe or cigarettes. The synthetic cannabinoids are often dissolved in acetone before being sprayed over a spice blend, which is then smoked. The substances have psychotropic properties and are called synthetic cannabinoids or, more accurately, cannabinoid receptor agonists. The effect on the central nervous system is mainly exerted via CB1 receptors. Effects and side effects after use are cannabis-like, with a euphoric high.

The most common side effects are:

• Dry mouth
• Nausea, vomiting
• Red, irritated eyes
• Memory disturbances
• Increased heart rate
• Elevated blood pressure
• Panic sensations
• Hunger
• Anxiety
• Hyperactivity
• Psychomotor agitation
• Confusion
• Seizures (especially PB-22)
• Kidney failure (especially XLR-11)

The synthetic cannabinoids have a complicated chemical nomenclature (abbreviation plus order number), and in most cases, the user names are entirely different. Most of the cannabinoids are classified as narcotics, and the list grows longer each year. Among these substances are:

• CP 47,497 in several different subtypes (various cyclohexylphenols – CP)
• JWH-015, -018, -019, -073, -081, -122, -203, -250 (various naphthoylindoles)
• HU-210
• 5F-AKB-48, 5F-PB-22, 5F-UR-144, and some variants of JWH-018 are classified as health hazards.
• Other recently reported substances include SDB-006, 5F-SDB-006, and FUB-PB-22 (as of 2014).
• AB-CHMINACA, MBB-CHMINACA

Cathinones

Cathinones are a group of synthetic substances with mild stimulant effects similar to phenethylamines. Among the cathinones are some newer drugs such as Mephedrone, MDPV, Methylone, Methedrone, and Naphyrone. The substances are available in powder, tablet, and capsule form. Mephedrone is known by user names like “Crab” and “Subcoke.”

Cathinones are chemically synthesized from norephedrine and norpseudoephedrine. The effects resemble those of phenethylamines, i.e., stimulant effects with a strong euphoric high and increased socialization. Side effects may include:

• Headache
• Nausea
• Dizziness
• Tachycardia, palpitations
• Anxiety
• Restlessness
• Slurred speech
• Confusion

Acute poisoning with confusion, cold sweats, fever, tremors, slurred speech, and psychotic symptoms have occurred. A few cases of unconsciousness and death have been reported.

Mephedrone

Mephedrone (4-methylmethcathinone) spread rapidly in Sweden in 2009 and 2010. Mephedrone is highly euphoric, and a quickly developing craving for the drug has been reported.

Symptoms of overdose can include:

• Hyperactivity
• Flight of ideas
• Increased energy
• Mydriasis (dilated pupils)
• Tachycardia
• Hypertension
• Increased risk of seizures

Generalized seizures, respiratory arrest, and occasional fatalities have occurred.

Mephedrone seizures in Sweden have come from China and Austria. The substance has a slight shellfish odor, hence the slang name “Crab.” Mephedrone has been classified as a narcotic since 2009.

MDPV

MDPV stands for 3,4-methylenedioxypyrovalerone. MDPV produces stimulant effects similar to amphetamines but with much more hallucinogenic properties. Like pyrovalerone, MDPV likely works by significantly increasing the availability of various neurotransmitters in the brain, such as dopamine, norepinephrine, and serotonin.

Common user names include “MDPV, MDPK, Sonic, Magic, Monkey Dust, Skutz.”

MDPV belongs to the cathinone group and is similar to pyrovalerone (4-methyl-α-pyrrolidino-valerophenone), which is listed in the 1971 Psychotropic Convention (Schedule IV). The prevalence of MDPV has dramatically increased in Sweden in recent years and appears to be one of the most common internet drugs, primarily in Västmanland and around Västerås, Norrköping, and Eskilstuna. MDPV has caused several deaths, mainly due to drug-related traumas.

MDPV appears in powder, ampoules, and tablets. For a normal to strong dose, the reported effects can last between 5 to 12 hours, and the effects are described by users as highly euphoric. MDPV induces a strong high with unstable moods, and the experience can shift rapidly between pleasure and discomfort. Regular use of MDPV can be addictive and lead to tolerance (i.e., increasing doses are needed to maintain effects). A so-called serotonin syndrome can occur, lasting up to a week. Serotonin syndrome involves an excess of serotonin in the brain, affecting vital functions throughout the body, typically requiring medical intensive care.

A normal dose of MDPV is between five and ten milligrams. Among the negative effects is a high risk of acute psychosis with agitation and confusion. Patients may become violent and aggressive, experiencing powerful hallucinations and delusions. Other described side effects include nausea, vomiting, anxiety, dizziness, double vision, sweating, fever, high pulse, high blood pressure, visual hallucinations, heart effects, and paranoia. Neurological symptoms such as involuntary awkward spastic movements, known as dystonias and akathisias, can occur. Several cases of acute poisoning with violent and disruptive handling have been reported in emergency care and by police. High doses have been reported to cause severe anxiety attacks in inexperienced users, and repeated use can lead to addiction. Side effects include anxiety, panic attacks, self-destructive behaviors, depression, paranoid delusions, and aggression. Several cases of sudden impulsive suicide attempts and completed suicides have been observed. Intoxicated individuals have been reported to throw themselves through glass doors and into traffic in front of cars and buses. Prolonged use has also been reported to cause withdrawal symptoms similar to those of methamphetamine.

5-IT

5-IT (5-(2-Aminopropyl)indole or 2-(1H-indole-5-yl)-1-methyl-ethylamine) is an indole and an isomer of alpha-methyltryptamine (AMT). The compound is chemically related to phenethylamine derivatives such as 5-APB, 6-APB.

5-IT mainly has stimulant rather than psychedelic effects. It has been noted that “at 20 mg orally, the substance causes increased heart rate, anorexia, urination, and some heat stroke for about twelve hours.” In various discussion forums, doses around 100-250 mg are described.

Acute overdose with 5-IT has been reported to cause symptoms similar to intoxication with other stimulants, such as anxiety, agitation, and hyperthermia.

Phenethylamines

Phenethylamines (PEA) are chemical derivatives of amphetamines with similar properties. Phenethylamine is actually the chemical backbone of amphetamine. There are at least fifty different phenethylamines; not all are classified as narcotics. Some are classified as health hazards, meaning possession is prohibited unless professional use can be proven.

When consumed, phenethylamines increase the release of dopamine, serotonin, and norepinephrine to varying degrees. These substances generally have psychotropic, hallucinogenic, and energizing effects. The effects are similar to those of LSD and mescaline. Many of the phenethylamines affect the autonomic nervous system, with a risk of increased blood pressure and peripheral vasoconstriction (amphetamines were originally used for their vasoconstrictor effects in cold medicine, such as Benzedrine).

Some examples of phenethylamines are:

• BDB (benzodioxolylbutanamine)
• 2C-B (bromodimethoxyphenethylamine)
• 2C-T-2 (dimethoxyethylthio-phenethylamine)
• 2C-T-7 (dimethoxypropylthio-phenethylamine)
• DOC (4-chloro-2,5-dimethoxyamphetamine)
• MBDB (methyl-benzodioxolylbutanamine)
• TMA-6 (2,4,6-trimethoxyamphetamine)
• PMA (Para-methoxy-amphetamine)
• PMMA (Para-methoxy-methamphetamine)

2C-B is usually sold in the form of pink tablets. Common slang names include Bromo, Venus, and Eve. 2C-T-2 is similar to 2C-T-7 but is not as toxic.

DOB (Dimethoxybromoamphetamine)

DOB is a substituted amphetamine with stronger psychotropic activity than other phenethylamines. DOB typically appears as a white synthetic powder sold in capsules or tablets. The substance has also been found on blotter paper. DOB can also be snorted.

DOB has a slow onset (about an hour) and induces a long-lasting high. It has a powerful vasoconstrictive effect. A common slang name is “Golden Eagle.”

Bromo-Dragonfly

Bromo-Dragonfly (bromo-benzodifuranyl-isopropylamine) is a synthetic phenethylamine similar to DOB, LSD, and amphetamine. The drug has a pronounced affinity for serotonin receptors. Bromo-Dragonfly comes as a powder, blotters, liquid, or tablets. Typical recreational doses range from 50-800 µg.

Bromo-Dragonfly is hallucinogenic but also has amphetamine-like effects. The drug is strongly vasoconstrictive and has caused pronounced vasoconstriction (pseudoergotism), leading to ischemia and amputation of fingers and toes. Pseudoergotism has also occurred after taking DOI. Fatalities have occurred in Sweden. Common symptoms of overdose include psychomotor agitation and confusion.

MT-45

This substance is actually a piperazine but has opioid-like effects, such as sedation, analgesia, and respiratory depression. In 2013 and 2014, MT-45 was detected in twelve cases of hospitalized poisonings. All cases involved men aged 17-35. In eight out of twelve cases, other drugs were also detected, most of which were new synthetic substances. Cannabis was also detected in three of the cases. In nine out of twelve cases, the patients were unconscious when found, and one person died. In several cases, ototoxicity developed, resulting in hearing loss. MT-45 has also caused depigmentation of hair, eyebrows, and other body hair. It has also led to large, flaring, eczema-like skin changes and cataracts.

MDEA/MDE

Methylenedioxyethylamphetamine is a derivative of phenethylamine with ecstasy-like euphoric and empathogenic (“entactogenic”) properties. The drug increases levels of serotonin, norepinephrine, and dopamine. MDEA is often called “Eve.” Common doses are slightly higher than ecstasy, 100-200 mg for a high.

MDA

Methylenedioxyamphetamine is a derivative of amphetamine with ecstasy-like euphoric, empathogenic, and hallucinogenic properties. MDA is also known as tenamphetamine. It is often called “Sally, SASS, or Sassafras.”

MBDB

Methyl-benzodioxolylbutanamine is a derivative of amphetamine with mild ecstasy-like euphoric and hallucinogenic properties. MBDB is often called “Eden or Methyl-J.” The drug appears to be slightly less potent compared to ecstasy (MDMA).

PMA

Para-methoxy-amphetamine is a derivative of amphetamine with ecstasy-like euphoric and hallucinogenic properties. PMA is also known as 4-methoxy-amphetamine and primarily affects serotonin. PMA has caused several fatalities and is often called “Dr. Death or Death.” The drug can induce severe cardiac arrhythmias and is also a potent MAO inhibitor, which can lead to pronounced serotonin syndrome with severe and difficult-to-treat hyperthermia.

PMMA

Para-methoxy-methamphetamine is a derivative of methamphetamine with ecstasy-like euphoric and hallucinogenic properties. PMMA is also known as methyl-MA or 4-methoxy-methylamphetamine. In 2011, PMMA was detected in 12 deaths in Norway. The drug is often called “Superman or Superman ecstasy.”

Tryptamines

Tryptamines are a group of synthetic drugs with LSD- and mescaline-like effects. Tryptamines are more hallucinogenic than phenethylamines. Tryptamines are structurally similar to serotonin. Among these are:

• DiPT (diisopropyltryptamine)
• 5-MeO-DiPT (5-methoxy-diisopropyltryptamine)
• AMT (alpha-methyl
  
  tryptamine)
• DMT (n,n-dimethyltryptamine)
• 5-MeO-AMT (5-methoxy-alpha-methyltryptamine)
• 5-MeO-DMT (5-methoxy-DMT)
• dimethyl-5-methoxytryptamine
• DPT (dipropyltryptamine)

Tryptamines are usually sold in capsule or tablet form and taken orally. In powder form, the substances can also be snorted or smoked. Psilocin and psilocybin, found in hallucinogenic mushrooms, can be classified as tryptamines.

Intake of tryptamines enhances sensory perception, primarily hearing. An overdose, like other party drugs, can cause symptoms such as:

• Hyperactivity
• Agitation
• Confusion
• Visual hallucinations

There is a risk of psychotic symptoms and generalized seizures. Tryptamines can cause severe hypertension in case of overdose and may also cause dangerous drug interactions.

BENZYLPIPERAZINE (BZP)

Benzylpiperazine is related to amphetamine and has similar effects to other party drugs. Piperazines were used medically in the 1970s as antidepressants due to their serotonin-enhancing effects. However, they showed no positive long-term effects and were removed from the pharmaceutical market. BZP has instead become a party drug and a substance of abuse among youths, particularly in New Zealand and Australia. It is not classified as a narcotic and can be ordered online or bought abroad.

BZP is commonly found in capsule form, taken orally. The high lasts six to eight hours. In cases of overdose, the same symptoms as with other amphetamine analogs can be observed, such as high blood pressure, tachycardia, and psychomotor agitation.

TFMPP (trifluoromethylphenylpiperazine) has effects that users describe as similar to ecstasy. TFMPP is often called “Legal X.”

DEXTROMETHORPHAN (DXM)

Dextromethorphan (DXM) is a cough suppressant and NMDA antagonist that is sold over-the-counter in some countries, including Denmark, Finland, and the USA. DXM has opioid-like effects with sedative and dissociative properties. Increased recreational use of DXM has been reported among younger teenagers in Sweden. In high doses, DXM has hallucinogenic effects. Acute poisonings involving DXM and benzylpiperazine have been relatively rare in Sweden until recently. Two DXM-related deaths were reported in 1988, and additional fatalities were reported in 2008.

Dextromethorphan is now classified as a narcotic but can still be ordered online or bought abroad. DXM is sold internationally under brand names such as Dexofan, Dexalon, Coricidin, Wick’s formula, Neo-Tussan, Resilar, and Robitussin.

Some slang terms for dextromethorphan include “DXM,” “Dex,” “Robo,” “Skittles,” “Syrup,” “Triple-C,” and “Tussin.”

Symptoms of DXM poisoning include:

• Fever (hyperthermia)
• Gastrointestinal symptoms
• Itching
• Drowsiness
• Respiratory failure
• Dreamlike experiences
• Feelings of isolation
• Dissociation
• Disorientation
• Hyperesthesia
• Ataxia

Increased suicidality has also been reported.

Benzodiazepines

Various non-registered benzodiazepine preparations are available on the black market and sold online. Even flunitrazepam, which is registered in Sweden (Flunitrazepam Mylan), is sold illegally online. Previously, Rohypnol (flunitrazepam) was a commonly available drug on the illegal market.

A relatively new benzodiazepine is phenazepam. It is a substance with a very long half-life, up to three days, which can cause prolonged effects in cases of overdose. Memory disturbances, coordination difficulties, and disorientation have been described for up to a week after taking phenazepam. Phenazepam is imported to Sweden, primarily from Russia.

Various non-registered benzodiazepine preparations found online include:

• Adinazolam
• Bromazepam
• Diclazepam
• Desmethylflunitrazepam
• Flubromazepam
• Flubromazolam
• Fludiazepam
• Flurazepam
• Flunitrazolam
• Etizolam
• Phenazepam
• Camazepam
• Clonazolam
• Cloniprazepam
• Chlordiazepoxide
• Loprazolam
• Lorazepam
• Lormetazepam
• Meklonazolam
• Norfludiazepam
• Pyrazolam
• Zapizolam

Symptoms of New Psychoactive Substances (NPS)

The effects of most NPS, such as cathinones, phenethylamines, and various amphetamine analogs, are characterized by euphoria, social empathy, openness, and increased mental and physical energy. Well-being increases, and a sense of positive desire sets in 1-3 hours after intake. Self-confidence rises, and users feel that all problems disappear. These drugs enhance communication, understanding, and empathy with entactogenic or empathogenic effects. Smell, sight, hearing, and perception are intensified, and pupils dilate (mydriasis).

The central nervous effect is mainly caused by serotonin release in the brain’s central areas, especially the limbic system, striatum, and hippocampus. After prolonged use, serotonin reserves become depleted, and users risk developing negative mental symptoms, depression, and psychosis.

Examples of negative effects:

• Hyperactivity and hypomania
• Flight of ideas, unstable temperament
• Anxiety, restlessness, irritability
• Decreased self-control, boundaryless behavior
• Excessive sexual activity
• Increased appetite, binge eating (but also loss of appetite and anorexia)
• Headaches
• Psychosis-like reactions, hallucinations

Over time, the drug user becomes exhausted, irritable, and depressed. The low mood can be difficult to treat and prolonged. Animal data suggest that damage to dopamine pathways and, especially, serotonin pathways is morphological and partly irreversible. Generalized seizures can also occur.

Symptoms that may appear after months of abuse include:

• Fatigue, irritability
• Sleep disorders
• Stereotypical behavior
• Depression, suicidal thoughts, increased suicidality
• Paranoia
• Anxiety
• Mutism
• Catatonia

Symptoms of Acute Overdose

In acute overdose from internet drugs, large, dilated pupils, hyperactivity, excitement, euphoria, restlessness, and agitation are common. The patient may appear unusually excited and exhibit psychomotor agitation. Tachycardia, palpitations, tremor, hypertension, and chest pain can also occur. Confusion and hallucinations may also present. There is a risk of muscle tension, rigidity, muscle twitching, and seizures, with jaw clenching (trismus) being common.

Overdose poses risks for:

• Water intoxication (acute hyponatremia)
• Cerebral edema
• Acute confusion – acute psychosis
• Heart arrhythmias
• Myoclonic seizures
• Hyperthermia (fever)
• Serotonin syndrome
• Liver failure
• Kidney failure

Heatstroke, rhabdomyolysis, and serotonin syndrome are particularly likely to occur after ingesting various synthetic cathinones or phenethylamines combined with prolonged dancing, exposure to hot environments, and poor hydration. Hyperthermia can lead to muscular rigidity, seizures, and rhabdomyolysis. Hyperthermia is often a symptom of “serotonin syndrome” (see below) and can result in hyperkalemia, heart arrhythmias, acidosis, coma, and multiple organ failure. Other serious symptoms that may develop include impaired coagulation – DIC (disseminated intravascular coagulation), respiratory failure with risk of pulmonary edema, and cerebral hemorrhage, along with cardiovascular collapse.

A body temperature over 41 degrees is dangerous, and over 42 degrees is life-threatening – liver and kidney failure have been reported. Kidney failure likely occurs secondary to rhabdomyolysis and myoglobin deposition in the kidney glomeruli. Kidney failure has also been reported after ingesting certain Spice varieties. CT or MRI brain scans should be performed to rule out cerebral edema if pronounced hyponatremia occurs (S-Na < 120 mmol/L), as well as in cases of focal neurological symptoms. Morphological damage to serotonin pathways can be detected with PET imaging or functional MRI.

Treatment

Management of acute overdose with stimulant drugs is primarily symptomatic. No specific antidotes are available.

The most important considerations are careful monitoring of:

• Alertness
• Respiration
• Circulation
• Temperature
• Mental functions

It is important to direct the patient to the appropriate medical department to ensure that vital life functions are stabilized. Afterward, the drug abuse should be treated; psychiatric evaluation and referral to addiction medicine clinics and social services are often necessary. Reporting to social services is mandatory in life-threatening cases of substance abuse.

The prognosis for poisoning with NPS is generally good if severe complications have not developed before arriving at the hospital. Drug testing can sometimes, but not always, provide information about which substances were taken. A negative drug screen does not rule out poisoning with party drugs.

Treatment for Acute Overdose

Regularly check pulse, blood pressure, temperature, and mental functions. Invasive blood pressure monitoring should be performed in cases of severe blood pressure spikes during moderate or severe intoxication. Place the patient in a quiet, dark room for mild to moderate poisoning and allow them to eat, sleep, and rest (late morning recovery). Treat anxiety and agitation (see below). Monitor for hyperthermia.

Rehydrate with crystalloid fluids and check serum electrolytes. Perform drug screening on urine or plasma samples. Request targeted analysis of urine samples for internet drugs.

Pharmacological treatment for anxiety or agitation:

• Diazepam (Stesolid^®) 5-20 mg 3 times daily, or oxazepam (Sobril^®) 15-50 mg 3-4 times daily
• Midazolam (Dormicum^®) 2-5 mg i.v. (1 mg/ml) for motor agitation and anxiety
• Olanzapine (Zyprexa^®) 10 mg x 2, or Risperdal 1 mg x 2
• Droperidol (Dridol^®) 10 mg i.m. x 1
• Haloperidol (Haldol^®) 5 mg 1-2 times daily, or oral solution 1-2 mg, up to every 4 hours. If oral treatment is not possible, haloperidol can be given i.m. 2.5-5 mg x 4. Propofol (Propofol^®) i.v. for severe agitation in an intensive care unit
• Dexmedetomidine (Dexdor^®) in continuous infusion for severe agitation in an intensive care unit
• Symptomatic treatment as needed
• Be cautious with beta-blockers
• Clonidine (Catapresan) 75-150 micrograms x 3

CT brain scan is performed in cases of blood pressure crisis or neurological symptoms, such as brain edema or stroke. Check serum myoglobin to determine if rhabdomyolysis is present. Consider forced alkaline diuresis if necessary.

In cases of hyperthermia, active cooling and sedation may be required:

• 1-2 liters of cold saline intravenously
• Diazepam (Stesolid^®) 5-20 mg intravenously
• External cooling treatment with a cooling blanket or similar
• In cases of extreme hyperthermia, consider extracorporeal cooling through ECMO system or similar

In cases of serotonin syndrome, treatment with one of the following medications may be administered:

• Cyproheptadine (Periactin) – 8 mg x 3 orally (licensed drug, antihistamine)
• Risperidone (Risperdal^®) 2 mg x 3

In cases of severe hypertension (> 200 mmHg) – invasive blood pressure monitoring with arterial catheter:

• Infusion of glyceryl trinitrate (Nitroglycerin^®) 0.2-0.5 μg/kg/min
• Infusion of magnesium sulfate (Addex-Magnesium) 20 mmol in 100 ml NaCl over 20 minutes followed by 20 mmol over 20 hours
• Beta-blockers with caution, e.g., metoprolol (Seloken^®), labetalol (Trandate^®)
• Alpha-blockers with caution, e.g., doxazosin (Alfadil^®), labetalol (Trandate^®)

ICD-10

• Mental and behavioral disorders due to hallucinogens, acute intoxication F16.0
• Mental and behavioral disorders due to hallucinogens, harmful use F16.1
• Mental and behavioral disorders due to cocaine, dependence syndrome F14.2
• Psycho-stimulants with abuse potential T43.6
• T40.6 Other and unspecified narcotic substances
• F15.1 Mental and behavioral disorders due to other stimulants, including caffeine, harmful use
• F15.0 Mental and behavioral disorders due to other stimulants, including caffeine, acute intoxication

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22. Bråbäck L, Humble M. [Young woman dies of water intoxication after taking one tablet of ecstasy. Today’s drug panorama calls for increased vigilance in healthcare] Läkartidningen 2001;98(8):817-9.
23. Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav. 2002;71(4):837-44.
24. Stolaroff MJ, Wells CW. Preliminary results with new psychoactive agents 2C-T-2 and 2C-T-7. Yearbook for Ethnomedicine 1993:99-117.
25. Balíková M. Nonfatal and fatal DOB (2,5-dimethoxy-4-bromoamphetamine) overdose. Forensic Sci Int. (2005) 153, 85–91.
26. Bowen JS, Davis GB, Kearney TE, Bardin J. Diffuse vascular spasm associated with 4-bromo-2,5-dimethoxyamphetamine ingestion. JAMA. 1983;249(11):1477-9.
27. Rammer L, Holmgren P, Sandler H. Fatal intoxication by dextromethorphan: A report on two cases. Forensic Sci Int. 1988;37(4):233-6.

Synthetic Cannabinoids “Spice” Intoxication and Abuse

Interest among young people in the use of cannabis and cannabis-like substances has increased significantly in recent years. Some of the cannabis-like drugs are semi-synthetic plant-based preparations, so-called “Spice”. Spice consists of Indian herbs mixed with various synthetic cannabinoids. The mixture is smoked in a similar way to marijuana, usually in rolled cigarettes, but synthetic cannabinoids can also be ingested in other ways, such as swallowing or injections.

The effects of synthetic cannabinoids are similar to those of cannabis, but these substances often cause more hyperactivity and have more central stimulant effects compared to natural cannabis. Most synthetic cannabinoids are produced in China and then transported to Europe through legitimate transport and distribution networks. In the first half of 2013, eighteen countries reported more than 1800 seizures of synthetic cannabinoids. The largest seizures were reported from Spain (20 kg) and Finland (7 kg). In an English study from 2015 of 179 cases presenting to an emergency department due to drug intoxication, synthetic cannabinoids were detected in 10% of the cases. Of these, only 50% admitted to consuming these substances.

The use of Spice became increasingly common among young people in Sweden until 2015. In 2012 and 2013, inquiries about Spice to the Poison Information Center in Stockholm were the most common cases involving various types of drugs purchased online. Among illegal seizures made by Customs and Police in 2012, Spice accounted for 4%. In late 2014, several youths collapsed after smoking Spice and required intensive care across Sweden. The number of seizures made by the police and customs authorities increased dramatically in late 2014 but has significantly decreased after 2015. The abuse appears to have declined since 2015, although it has not completely disappeared. Several variants of Spice have been classified as narcotics in recent years.

The purchase of Spice usually takes place online via various websites or abroad in so-called “Head Shops”. The delivery arrives by mail, often in small “zip bags”.

Spice has caused many serious cases of intoxication requiring intensive care, and some fatal cases have been described. Several fatal cases have been under forensic investigation, most of these were mixed poisonings, but a few pure fatal Spice intoxications have occurred. Reports of acute renal failure and acute myocardial infarction have been published. The risk of needing acute medical care after consuming synthetic cannabinoids appears to be significantly higher compared to natural cannabis, in one study reported as 30 times higher.

This review addresses poisoning with Spice. Currently, around 15 new substances are classified per year in Sweden, and around 100 new substances are identified throughout Europe each year. The drugs are gradually classified as either narcotics or hazardous substances. Until such classification, the drugs can still be sold legally. Of the 81 new psychoactive substances reported in 2013, 29 were synthetic cannabinoids.

Spice

Spice consists of a mixture of about ten mainly Indian herbs and spices with effects similar to cannabis. These herbs are called “Blue Lotus”, “Lions Tail”, and “Indian Warrior”. The herbs themselves have weak psychotropic properties. The herbs in Spice are mixed with synthetic psychoactive substances that have activity on the brain’s cannabinoid receptors. Spice tends to be addictive, and in recent years, several serious overdoses, including some deaths, have been reported by healthcare professionals.

Some common variants of Spice are called:

• Spice Silver, Spice Gold, Spice Diamond, Black Ice, Spice Arctic Synergy, Spice Tropical Synergy, Spice Egypt, Spice Yukatan Fire, Boom, Double Dutch, Remix, Vegas, Earth Impact, etc.

For oral or injection use, it is usually the raw material, i.e., the synthetic cannabinoids used in powder form. Effects and side effects after ingestion are cannabis-like, with a euphoric, relaxing, and pleasant high. The psychoactive additives in Spice are commonly referred to as cannabinols but are not true cannabinols, so the correct term would be “cannabinoid receptor agonists” or synthetic cannabinoids. Acetone is often used in the preparation of the cannabinoid dry substance, which is why patients sometimes also smell of acetone.

Since the substances bind to the same types of receptors in the brain (CB1 and CB2) as THC, they primarily produce a cannabis-like high that is perceived as euphoric and relaxing. The various cannabinoids are often named after their chemical structure formula, which is a complex combination of letters and numbers, such as CP 47,497. This name can also contain the initials of the chemist who developed the synthesis of the substance, as in the case of different variants of JWH.

Most cannabinoids are fat-soluble, small non-polar molecules with 20-26 carbon atoms. Many are more potent on the CB1 receptor than THC, and the active dose is relatively small, often less than 1 mg. The daily dose for an abuser varies between 1-15 mg of the active substance. Several cannabinoids have been classified as narcotics, such as the substances HU-210, JWH-018, JWH-073, and CP 47,497-C7, and several others are on the way. Most cannabinoids are weaker than THC, but some are stronger and some much stronger, such as JWH-004, JWH-180, JWH-250, and CP 47,497-C6. Chemically, most cannabinoids in Spice belong to five different main groups, with naphthoylindoles being the most common, see Table 1.

Different variants of synthetic cannabinoids

Many of the cannabinoids are classified as narcotics, and the list grows longer every year. Among these substances are:

• CP 47,497 in several different subtypes (various cyclohexylphenols – CP)
• JWH-015, -018, -019, -073, -081, -122, -203, -250 (various naphtoylindoles)
• HU-210
• 5F-AKB-48, 5F-PB-22, 5F-UR-144, and certain variants of JWH-018 are classified as hazardous substances.
• Other newly reported substances include SDB-006, 5F-SDB-006, and FUB-PB-22 (as of 2014).

Spice is difficult to detect in routine blood sampling but can be detected in blood and urine through extended and targeted analysis. Special drug testing kits are available for Spice. Spice and other synthetic cannabinoids can be difficult to detect in drug analyses. Blood samples can detect more variants of Spice than urine samples. The Forensic Chemistry Laboratory in Linköping and the Department of Clinical Pharmacology, Karolinska University Hospital in Solna, can detect several different variants of Spice.

Shortly after the pleasant high, negative symptoms can appear after consuming Spice. The negative symptom profile after Spice intake is characterized by:

• Dry mouth
• Panic feelings
• Hunger pangs
• Anxiety
• Nausea, vomiting
• Tiredness
• Somnolence
• Large pupils, red bloodshot eyes
• Memory disturbances
• Increased heart rate, irregular heart rate, sometimes slow heart rate
• Increased blood pressure

In a clinical study conducted in the USA in 2012, tachycardia was presented in 37.5%, agitation in 21.8%, drowsiness in 17.9%, vomiting in 15.4%, hallucinations in 9.9%, nausea in 9.8%, confusion in 9%, and high blood pressure in 8.5% of cases. Reports have emerged in recent years of more severe side effects such as acute renal failure, acute myocardial infarction (ischemic signs on ECG), and liver damage. Even a few fatal cases and cases with severe neurological deficits have been reported, such as after ingestion of MDMB-CHMICA and ADB-CHIMINACA. In cases of renal failure, the substance 5F-UR-144 (XLR-11) was common. In a German study (abstract EAPCCT Congress, 2016) of 45 patients who presented after ingestion of AB-CHMINACA or MDMB-CHMICA, 29% exhibited generalized seizures, 25% aggressive behavior, 13% psychosis (including self-harming behavior), and 13% syncope. As many as 16% (7 out of 45) were assessed as life-threatening poisonings, emphasizing the severity of Spice intoxications.

SYMPTOMS AND CLINICAL FINDINGS

Acute Spice overdose may exhibit the following symptoms:

• Large, dilated pupils
• Red bloodshot eyes
• Hyperactivity
• Excitation
• Euphoria, restlessness, and agitation. Aggressive behavior
• The patient may appear unnaturally excited and be psychomotorically restless.
• They may suffer from palpitations, tremors, high blood pressure, and chest pain.
• Confusion and hallucinations may occur.
• Syncope
• The patient may experience muscle tension, muscle twitching, and eventually collapse.

Overdose also carries the risk of:

• Somnolence
• Tachycardia
• Disorientation
• Acute confusion – acute psychosis
• Hyperglycemia
• Hypokalemia
• Hypertension
• Nausea, vomiting
• Amnesia, which may be prolonged
• Metabolic acidosis
• Myoclonic generalized seizures, rhabdomyolysis
• Renal failure
• Liver failure
• Intermittent apnea
• Cardiac arrhythmias, ECG changes

There is also a small risk of acute myocardial infarction and cardiovascular collapse.

TREATMENT

The management of acute Spice overdose is mainly symptomatic. There are no specific antidotes. It is important to direct the patient to the hospital if they are too confused to explain their condition or if they have difficulty standing or walking so that vital life functions can be urgently ensured. In the aftermath, drug abuse treatment should be addressed; assessment by a psychiatrist and referral to addiction medicine clinics and social services are often necessary. A report to social services (concern report) should always be made in cases of life-threatening abuse. An urgent LVM (Compulsory Care of Substance Abusers) report may also be considered.

The most important thing is careful monitoring of:

• Alertness
• Breathing
• Circulation
• Temperature (risk of hyperthermia)
• Mental functions

The prognosis for Spice poisoning is generally good unless severe complications have occurred before hospital arrival. Drug screening with a test strip can sometimes, but not always, provide information about which drugs have been taken. Negative screening does not rule out Spice poisoning. It is important to use updated urine test strips for drug screening.

Acute Overdose

In cases of acute overdose, much of the treatment focuses on symptom management and monitoring vital signs.

Therefore, ensure that:

• Regular monitoring of:
  – Pulse
  – Blood pressure
  – Temperature
  – Mental functions
• Place the patient in a quiet and calm room in cases of mild to moderate poisoning, and let them eat, sleep, and rest.
• Treat anxiety and agitation (see below).
• Be aware of the risk of hypokalemia, rhabdomyolysis, and hyperglycemia.
• Rehydrate with crystalloid fluids and check serum electrolytes.
• Perform drug screening on a urine or plasma sample. Request a targeted analysis of the urine sample for Spice.

Pharmacological Treatment for Anxiety or Agitation:

• Oxazepam (Sobril) 15-50 mg 3 times daily, or diazepam (Stesolid) 5-20 mg 3 times daily
• Nitrazepam (Nitrazepam) 5-10 mg at night for sleep
• Olanzapine (Zyprexa) 10 mg twice daily for psychotic symptoms
• Droperidol (Droperidol) 10 mg intramuscularly. It provides good effect after about 20 minutes.
• Haloperidol (Haldol) 5 mg 1-2 times daily (avoid high-dose neuroleptics), alternatively oral solution 1-2 mg, at most every 4 hours. If oral treatment is not possible, haloperidol can be given intramuscularly 2.5-5 mg up to 4 times a day. An alternative to haldol is zuclopenthixol (Cisordinol-Acutard) 100-150 mg intramuscularly.
• Midazolam (Dormicum) 2-5 mg intravenously (1 mg/ml) for motor agitation and anxiety. It can also be given orally (10-15 mg) or intramuscularly 2-5 mg.
• Propofol (Propofol) intravenously in cases of severe agitation in an intensive care setting
• Symptomatic treatment as needed

Prognosis

The prognosis is generally good after a single intake of Spice, provided there are no severe complications such as rhabdomyolysis, hyperthermia, or seizures. Special attention should be given to liver or kidney function and rhabdomyolysis.

ICD-10

• Mental and behavioral disorders due to hallucinogens, acute intoxication F16.0
• Mental and behavioral disorders due to hallucinogens, harmful use F16.1
• Psycho-stimulants with abuse potential T43.6
• Mental and behavioral disorders due to multiple drugs and other psychoactive substances F19

References

1. Drug Development in Sweden 2011, Report no. 130, Central Association for Alcohol and Narcotic Development, Stockholm 2012. Link
2. Drug habits among school students 2013. Knowledge Source 2013, report 2013:1. City of Gothenburg, Social Resource Administration.
3. Annual report EMCDDA Situation on the drug scene in Europe 2012.
4. EMCDDA; Action on new drugs briefing paper: Understanding the “Spice” phenomenon. 2009. Lisbon. Link
5. EMCDDA; Perspectives on drugs: Synthetic cannabinoids in Europe, Lisbon. Link
6. Centers for Disease Control and Prevention (2013), Acute kidney injury associated with synthetic cannabinoid use — multiple States, Morbidity and mortality weekly report 62, pp. 93–8. Link
7. Hurst, D., Loeffler, G., and McLay, R. (2011), Psychosis associated with synthetic cannabinoid agonists: a case series, American Journal of Psychiatry, 168, pp. 1119. Link
8. Hermanns-Clausen, M., Kneisel, S., Szabo, B., and Auwärter, V. (), Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings Addiction, 2013, 108, pp. 534–44. Link
9. Uchiyama, N. et al., Chemical analysis of synthetic cannabinoids as designer drugs in herbal products, Forensic Science International, 2010, 198, pp. 31–8. Link
10. Mixmag ‘The Mixmag/Guardian drug survey’, Mixmag (2012). Link
11. Harris CR, Brown A. Synthetic cannabinoid intoxication: A case series and review. J Emerg Med. 2012;[Epub ahead of print] Link
12. Hermanns-Clausen M, Kneisel S, Szabo B, et al. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: Clinical and laboratory findings. Addiction. 2012;[Epub ahead of print]
13. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327–60. Link

GHB (gamma-hydroxybutyrate)

GHB is a liquid chemical used as an intoxicant by many young people, primarily for its strong alcohol-like effect. GHB abuse has been widespread globally since the 1990s, with sporadic endemic outbreaks in various countries, including the USA, Switzerland, Spain, France, Norway, and Sweden. In 2014, 18 European countries reported GHB or GBL seizures. The 1,243 seizures amounted to 176 kg and 544 liters of the drug, with Belgium (40%) and Norway (34%) accounting for more than a third of the seizures.

GHB was classified as a narcotic in Sweden and has been illegal to use freely since 2000. GHB abuse was intense in certain regions between 2000-2010 but has significantly decreased since then. Some abuse still occurs, although to a lesser extent. Related chemicals also abused as intoxicants include GBL and butanediol.

As an abused drug, GHB is usually consumed as a clear oral solution and is mostly used by men aged 20-30, primarily in West Sweden around Gothenburg.

GHB (gamma-hydroxybutyrate) is an organic acid and a derivative of the carboxylic acid butyric acid. Medically, GHB is used as a treatment for narcolepsy and in some countries for alcohol withdrawal, mainly for its strong sedative properties. GHB is registered as a medicine in Sweden for narcolepsy under the trade name Xyrem (sodium oxybate) 500 mg/ml. As a medicine, GHB is often referred to as “Oxybate” or “Sodium oxybate”. Common preparations include Xyrem, Alcover, Anetamin, Gamanest, Gioron, and Somsanit.

GHB is typically consumed in a clear solution, slightly viscous or oily in consistency. The solution is clear or straw-colored. GHB has a faint solvent-like smell, similar to linoleum, and typically tastes slightly salty.

Ingestion of 0.5-2 centiliters of GHB (20-30% solution) produces a euphoric and relaxing high, similar to a combination of benzodiazepines and alcohol. The drug is mainly consumed in liquid form but is also sold in crystalline form in capsules. The high is amplified by alcohol and sedatives, and it is common to take other illegal drugs alongside GHB. In user circles, GHB goes by many nicknames, including “Gobbe”, “Liquid Ecstasy”, and “Soap”.

Recipes for making GHB are available online, and the drug can be easily produced from chemicals in a regular kitchen. GHB is synthesized by combining GBL (gamma-butyrolactone) with sodium hydroxide (caustic soda, lye). The ready-mixed GHB solution is typically consumed from an empty Sprite or Coca-Cola bottle (PET bottle). The solution is ingested by the capful (“corking”), with a typical dose being one to two capfuls (0.5-2 centiliters, equivalent to approximately 2-4 g [200 mg/ml] GHB). A recreational dose can range from a few grams to up to 18 grams.

In the Gothenburg drug habits survey among school students in 2013, the proportion of young people who had tried GHB decreased in recent years. In 2013, 2% of those who had tried narcotics reported using GHB. In 2014, 0.4% of boys and 0.1% of girls in the second year of high school reported having tried GHB. GHB abuse in Sweden has been concentrated around Gothenburg, Västra Götaland, and the Sundsvall region. The abuse has decreased significantly in recent years. Many cases have presented dramatically and chaotically in emergency rooms, either with deep unconsciousness, seizures, and respiratory arrest, or with marked aggression, general agitation, and psychomotor unrest (“raptus”).

Pharmacology

GHB occurs naturally (endogenously) in the body as a substrate (precursor) for GABA in very small amounts, influencing wakefulness and seizure threshold. GHB quickly crosses the blood-brain barrier and exerts central nervous effects, primarily on monoaminergic synapses, affecting dopamine and specific GHB receptors. GABA functions as a neurotransmitter for about 30% of all cells in the CNS. GABA mainly acts as an inhibitory neurotransmitter and influences other neurotransmitters, including dopamine. GHB binds primarily to specific GHB receptors, which are excitatory, as well as GABA_B receptors. GHB releases both dopamine and glutamate. Therapeutic serum concentrations of GHB are not entirely known, but it is believed that around 100 mg/L induces euphoria, while levels above 500 mg/L can result in life-threatening conditions. Significant inter-individual differences exist.

EFFECTS

The intake of GHB produces clinical effects similar to a combination of alcohol and benzodiazepines. The feeling of intoxication occurs 10-20 minutes after ingestion, with a peak effect at 30-60 minutes, which is significantly slower than alcohol. GHB induces intoxication, drowsiness, and euphoria. In higher doses, unconsciousness can occur, sometimes accompanied by seizures and muscle twitching, such as “muscular jerks”, “petit mal”, and “grand mal”. Anxiety, muscle twitches, involuntary movements, agitation, and aggression are common. Peculiar choreoathetotic movements have been observed and documented.

• In small doses, GHB induces euphoria, increased well-being, and enhanced self-confidence, sexual stimulation, and reinforced male identity (the “macho effect”, “reinforcement”).
• Moderate doses of GHB result in alcohol-like intoxication, which is initially stimulating, relaxing, and then significantly sedating.
• GHB can produce feelings of relaxation, calmness, peacefulness, increased sensuality, mild exhilaration, positive sensations, increased “verbal fluency”, and muscle relaxation.
• Repeated use of GHB over time can quickly lead to tolerance, requiring higher doses.
• The risk of dependence and abuse is significant.
• GHB can cause physical and psychological dependence within 3-6 months.
• It typically does not cause a hangover (in fact, users feel good the day after) and has low organ toxicity.

Side effects of GHB abuse may include sleep difficulties, lethargy, dizziness, memory loss, ataxias, stomach pain, choreoathetoses, mental dulling, nausea, vomiting, abdominal pain, impotence, hypotension, and headaches. Withdrawal symptoms are significant in cases of abuse.

Concentration and Dosing:

• The normal dose is 0.5-4 centiliters (20-30% solution) with significant individual differences and variations in solution strength.
• One capful of GHB induces an intoxication equivalent to approximately two strong beers and lasts for about one hour.
• Two capfuls may lead to sleep within 20-30 minutes.
• Three to four capfuls can cause coma lasting 3-5 hours.
• Five to six capfuls in an inexperienced user can lead to deep coma (RLS 8), respiratory depression, slow heart rate with the risk of seizures and sudden death.
• Boys/men seem to tolerate higher doses compared to girls/women.
• GHB induces significant tolerance development after 1-6 months of use.

The concentration of drinkable GHB varies considerably between different solutions. A common strength is 20-30% GHB in liquid form (source: SKL/NFC). GHB has a narrow dosing range (narrow therapeutic window), produces variable intoxication effects from one occasion to another, and is very easy to overdose. Large individual tolerance differences exist, and the effects described above refer to an inexperienced user. An abuser with tolerance can tolerate much larger amounts for similar symptoms.

Symptoms of Overdose

A large overdose causes:

• Drowsiness
• Intoxication
• Rapid onset of sleepiness
• Fluctuating consciousness (periodically waking/sleeping is a relatively typical phenomenon)
• Absence periods
• Nausea
• Vomiting
• Tremors
• Dizziness
• Muscle cramps
• Ataxia
• Choreoathetosis
• Brief unconsciousness
• Slow pulse
• Motor agitation
• Affect lability, aggression
• Rapid onset of sleepiness
• Fluctuating consciousness
• Unconsciousness, coma
• Small pupils, ophthalmoplegia (strabismus)
• Hypotension
• Bradycardia
• ECG changes, possible AV block I-III or high QRS amplitudes
• Irregular pulse
• Slow and irregular breathing, respiratory depression
• Generalized seizures
• Vomiting
• Risk of aspiration of stomach contents into the lungs
• Hypothermia

ACUTE MANAGEMENT

The treatment of acute overdose is primarily symptomatic, and no antidote exists. Consciousness and breathing can fluctuate. GHB poisoning usually has a markedly dynamic course with rapid fluctuations in alertness. Seizures, nausea, and vomiting are relatively common. Insufficient breathing is supported through endotracheal intubation and respiratory treatment in an intensive care unit.

The most important aspects of treatment are:

• Careful monitoring of consciousness, oxygen saturation, and breathing
• Support breathing and circulation if necessary
• Treat hypoxia with oxygen
• Ensure a clear airway (nasal tube, oral airway, intubation)
• Treat hypotension with intravenous fluids and, if necessary, vasopressors (ephedrine, norepinephrine)
• Provide reasonable sedation if needed
• Treat acute confusion and motor agitation calmly and safely
• Admit the patient to the appropriate level of care
• Follow up with evaluation and treatment of addiction through psychiatry, addiction medicine, and social services

Gastric lavage (stomach pumping) and administration of activated charcoal are of limited value and should be avoided.

Sleeping Patient

If the patient is in a deep sleep and cannot be awakened, they should be monitored in an intensive care unit (ICU) with readiness for intubation. If vital parameters are stable and the patient is breathing calmly and regularly, monitoring may suffice, allowing the patient to sleep off the intoxication. If the patient maintains an open airway while lying on their back and has adequate oxygenation, ICU admission is generally not necessary. However, be aware that consciousness may deteriorate suddenly and dramatically.

Other causes of deep unconsciousness should be ruled out. Check electrolytes and an arterial blood gas. Perform a CT scan of the brain in uncertain cases or if focal neurological symptoms are present.

In cases of GHB intoxication, the patient typically sleeps for 1-5 hours. Unconsciousness lasting longer than 6 hours is usually due to other causes, such as mixed intoxication with other drugs. Awakening is generally calm, and the patient usually feels quickly recovered. The patient can typically be discharged home.

If the patient appears agitated during the waking phase, sedation may be administered to prolong sleep and allow for a calmer awakening. Sedation can be achieved with diazepam or midazolam (Dormicum) 1-2 mg intravenously (1 mg/ml), or propofol (20 mg/ml, 1-10 ml). In some cases, the condition may progress into an acute withdrawal phase, which can be severe and require urgent treatment.

Indications for ICU Admission

• Significant decrease in consciousness
  • RLS 3 or higher
  • GCS less than 10
• Severely agitated or confused patient
• Sudden decrease in consciousness
• Inability to maintain an open airway
• Cardiac arrhythmias
• Hypoxia (< 90%)
• Respiratory rate less than 10 or greater than 30 breaths per minute
• Heart rate below 50 or above 130 beats per minute
• Systolic blood pressure below 90 mmHg despite fluids
• Generalized seizures
• Severe metabolic acidosis

Drug Screening and Testing

Conduct a urine drug screen to detect mixed intoxications and other possible causes of unconsciousness. Send urine samples to a clinical chemistry laboratory for GHB analysis using GC-MS (gas chromatography-mass spectrometry). GHB can also be analyzed with a new immunohistochemical test, which can confirm GHB poisoning on the same day the sample is taken. GHB is included in some rapid test strips for drug screening.

Agitated Patient

If the patient is agitated and restless, they can be sedated with midazolam (Dormicum 2-5 mg i.v.) or propofol i.v., which can be repeated. Sedative antipsychotics have also been used successfully in the acute phase, such as droperidol (Dridol) 10 mg i.m. or haloperidol (Haldol) 2.5-5 mg i.v. or i.m. Heminevrin (clomethiazole) should be avoided entirely.

Note that consciousness fluctuates, and the patient may suddenly become unconscious with inadequate breathing.

If the patient is severely agitated and/or violent, full sedation may be necessary, and they may need to be placed on a ventilator. Start with midazolam (Dormicum) 5 mg i.v. followed by propofol (Diprivan) 50-300 mg i.v. as needed until the patient is lightly sedated. These patients usually require continuous propofol infusion for 5 to 8 hours in an ICU. Administer 100-400 mg per hour and adjust the infusion rate based on the patient’s consciousness level. The patient should be monitored in the ICU, and the airway must be secured through endotracheal intubation and mechanical ventilation. Sedation can then be reduced, and extubation can occur once the patient awakens calmly and peacefully.

Inducing sedation with intravenous propofol should only be performed if the situation is untenable with immediate danger to the patient’s life (self-defense). This generally requires active involvement from an anesthesiologist, with intubation and mechanical ventilation for at least 4-6 hours. Consider using LPT (compulsory care under the Mental Health Act).

If the patient’s fluctuating consciousness, “typical of GHB overdose,” does not improve after 3-5 hours, another diagnosis should be considered. Check other intoxication tests, as well as electrolytes (hyponatremia), blood glucose, and an arterial blood gas. Consider a CT scan of the brain.

Agitated and restless patients should not be discharged from the emergency department while still under the influence of drugs, as they may be violent and uncontrollable toward themselves, family members, or staff.

Withdrawal Phase

If the patient exhibits withdrawal symptoms such as anxiety, hallucinations, tremors, nausea, headaches, or psychotic symptoms, acute detoxification may be necessary. The patient should be admitted, preferably to a psychiatric unit or an addiction center. Severe acute withdrawal may follow directly after an acute overdose.

During the first day, sedation may be required with injections of midazolam (Dormicum) or propofol (Diprivan). Thereafter, oral tablets of diazepam (Stesolid) or lorazepam (Temesta) can be administered. High doses of Stesolid are usually needed during the first days. An appropriate starting dose is 60 mg/day or more (Sic). Treatment with propofol should only be administered in an ICU setting.

Zuklopentixol (Cisordinol) can be administered as Cisordinol-Acutard 50 mg/ml, 1 ml intramuscularly. Alternatively, olanzapine (Zyprexa) 10 mg twice daily or more can be given, or risperidone (Risperdal) 1 mg twice daily if the patient exhibits hallucinations or significant agitation despite Stesolid.

If an immediate effect is required, Haldol (5 mg/ml) 0.5 to 1 ml (2.5-5 mg) can be given intravenously or intramuscularly.

In a later phase, an antidepressant may be added, such as mirtazapine (Remeron) 30 mg once daily or sertraline (Zoloft) 50 mg once daily. Remeron has a relatively strong sedative effect. Sertraline also has a sedative effect, especially at the start of treatment or in high doses. Treatment with an antidepressant can help manage the sleep disturbances common in prolonged GHB abuse. Sleep issues are often the patients’ main concern. Many GHB users develop depression, which may require pharmacological treatment.

Note that caution is required when prescribing large doses of benzodiazepines to GHB users on an outpatient basis, as the combined intake of GHB and benzodiazepines can lead to severe respiratory depression. Flunitrazepam should be completely avoided.

FOLLOW-UP

It is important to have psychiatric and social follow-up for patients with established GHB addiction, as mixed substance abuse with medications, alcohol, and narcotics is common. A care and treatment plan should be established. Follow-up visits to psychiatric addiction care or social services are recommended, and a referral to social services should always be made. Depression with suicidal thoughts and increased suicidality may occur.

Stimulant abuse (amphetamines, cocaine, ecstasy) is common among GHB users, as is general social disorder. Cases involving individuals under 18 years of age should be reported to social services and the child and adolescent psychiatry clinic (BUP). School health services may also need to be involved.

For repeated acute overdoses, immediate reporting to social services should be made, and the consideration of care under LVU or LVM should be considered urgently.

Lasting Effects

A GHB overdose generally does not result in permanent damage, unless serious complications occur, such as airway aspiration, seizures, apnea, or hypoxia. However, if respiratory arrest with hypoxia occurs, severe long-term consequences may result.

Temporary sleep disturbances, with significant sleep difficulties lasting 3-4 weeks, are common. A subsequent depression is also common.

Other reported side effects include abdominal pain and impotence. The addiction may require treatment lasting several months.

ICD-10

• Mental and behavioral disorders due to sedatives and hypnotics, acute intoxication F13.0
• Other psychoactive substances, not classified elsewhere T43.8

Sick Leave

Links to insurance medicine decision support from the National Board of Health and Welfare:

F13 Mental and behavioral disorders due to sedatives and hypnotics

References

1. Persson S-Å, Eriksson A, Hallgren N, Eklund A, Berkowicz A and Druid H. GHB – dangerous, addictive, and difficult to control “party drug”. Läkartidningen No 38, 2001 Vol 98 4026-34.
2. Engelsen J & Rolighed Christensen H; Gammahydroxybutyrate an endogenous substance and a new intoxicant. Ugeskr Laeger 199;161:6903-7.
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Threshold Values for Positive Urine Tests (Drug Test)

Cut Off Values in Urinary Screening Tests