Legal substances and their abuse: Legal highs

Antihistamine

Antihistamines have anticholinergic properties such as tachycardia, hypertension, hyperthermia, dilated pupils, dry skin and mucus membranes and produce euphoria, detachment and hallucinations, and potentiate the effects of other psychoactive substances.(Malcolm and Miller, 1972; Orzechowski et al. 2005). Tripelennamine and other antihistamines are often taken in combination with opiates and opiate-like drugs, including heroin and pentazocine to potentiate opiate effects and reduces histamine mediated itching and rhinitis associated with opiate use. (Showalter, 1980).

Antihistamine intoxication can result in a variety of serious central nervous system and cardiovascular effects, including delirium, psychosis, agitation or sedation, delayed cardiac conduction as manifested by prolonged QRS interval, which may lead to dangerous and lethal cardiac arrhythmias, wide fluctuations in blood pressure, and generalised seizures. (Buckley et al, 1994). Antihistamine withdrawal can present with cholinergic symptoms such as rhinorhea, wheezing nausea and vomiting (Thomas and Nallur et al, 2009).

Caffeine

Caffeine-containing product sold as ‘energy’ drinks and chewing gums, are used for improving alertness, memory and exercise performance (Kendler and Prescott, 1999; Conca and Worthen, 2012). Caffeine abuse and overdose can present with gastrointestinal symptoms such as nausea, vomiting, abdominal pain, diarrhea, tachyarrhythmia, headache, insomnia, agitation, tremor, hyper tonicity, tinnitus, and delirium Caffeine may induce cardiac arrhythmias, and precipitate seizures (Chopra and Morrison 1995; Shum et al, 1997; Kendler and Prescott, 1999).

Although caffeine abuse was not commonly associated with mortality, deaths due to caffeine overdose attributed to non prescription product abuse, with abrupt onset of intractable seizures and electroconvulsive activity, have been reported both in the literature and lay press (Shum et al, 1997; Reuters News, 2012).

Caffeine and taurine found in energy drinks can increase blood pressure and platelet aggregation and reduce endothelial function (Worthley et al. 2010); adults and children with pre-existing cardiac conditions and those who combine alcohol with caffeine containing products may be more susceptible to caffeine induced arrhythmias and sudden cardiac deaths (Mail Online, 2012).

Dextromethorphan

Dextromethorphan, a cough suppressant structurally related to codeine and used in many cough and cold preparations acts as a dissociative hallucinogen in high doses and causes changes in sensations, perception (Miller 2005, Vahid et al, 2005).

Dextromethorphan overdose or abuse can cause nausea, vomiting, somnolence, nystagmus, ataxia, hallucinations, hypertension, and breathing difficulties. Deaths have been reported with intentional dextromethorphan abuse. (Logan et al, 2009). Large doses (>2 mg/ kg) of dextromethorphan produces dissociative effects similar to those of phencyclidine and ketamine. Serotonin syndrome, a potentially lethal condition with a variety of symptoms such as tremors, myoclonus, hyperreflexia, dilated pupils, hypertension, hyperthermia, diaphoresis, impaired coordination, hallucinations and coma, has been associated with dextromethorphan ingestion (Boyer, 2004; Banken and Foster, 2008; Romanelli and Smith, 2009).

Synthetic cannabinoids

Synthetic cannabinoids such as ‘spice gold’, ‘spice silver’, ‘genie’, ‘K2’ and ‘yucatan fire’, produce effects similar to those of marijuana when smoked.

They are incorporated into herbal smoking mixtures and are widely available as incense or potpourri and have been sold virtually everywhere. (Hudson and Ramsey, 2011) The statement, ‘not intended for human consumption,’ is often printed on these products so the products avoid government regulations (Gibbons, 2012). As such, these products are not only found in head shops (selling substances that can be smoked and smoking equipment such as pipes and bongs) and tobacco shops but also in gas stations, convenience stores, and grocery stores.

There is no international control by the United Nations (UN) drug control conventions for any of the synthetic cannabinoids, but several of them scheduled drugs in several countries including UK. However, more and more new versions are created to avoid legislature and synthetic cannabinoids use and abuse continues.

Marijuana’s effects of relaxation, euphoria, anti-nausea and analgesia are produced by its main active ingredient tetrahydrocannabinol, or THC. However, completely opposite effects of anxiety, tachycardia, and nausea are in many first time users. Many of the synthetic cannabinoids produce elevated heart rate, elevated blood pressure, palpitations, diaphoresis, tremulousness, anxiety, and agitation (Vearrierand and Osterhoudt, 2010; Schneir et al. 2011). More serious effects such as seizures, arrhythmias, psychosis and hallucinations can also result with the use of these drugs (Müller et al, 2010; Johnson et al. 2011). Most of these effects appear within 30 minutes, last for within 3–4 hours, and resolve within 6 hours (Quan et al, 2011).

Salvia divinorum

Salvia divinorum (‘seers sage’), is often advertised as a legal alternative to marijuana and is legal in many countries including UK (European Monitoring Centre for Drugs and Drug Addiction, 2012). The effects of salvia are due to salvinorin A, and it has more in common with hallucinogens such as lysergic acid diethylamide (LSD) and mescaline rather than those of marijuana ( Johnson et al. 2011; Gibson, 2012). Salvia can be chewed (though ingestion is ineffective) or inhaled to produce hallucinations, which occur within seconds with both buccal exposure and inhalation, and last for about an hour after buccal exposure and 20–30 minutes after inhalation (Siebert 1994, Babu et al, 2000).

Smoking or vaporizing is the most preferred method (93 %) in may abusers (Baggott et al. 2010) Hallucinations can vary and distortions of visual, body image, or environmental perception; and accentuation of actual sensations, and out of body experiences have been described. (Baggott et al. 2010, Kelly, 2011).

‘Bad trips’ with intense anxiety reactions, confusion with a frightening sense of a ‘fractured reality’ and temporary language impairment have been reported (Lange et al. 2010). Headaches and drowsiness can last for several hours after use and persistent psychosis in a previously well patient has been reported (Przekop and Lee, 2009).

Clinically significant adverse effects are rarely reported with salvia which could be due to several reasons such as a lack of reporting by the patients or recognition by emergency care providers, or masking of symptoms due to coingestions. However, several media reports of salvia associated suicides has implication for monitoring and control of salvia (USA Today, 2006).

Acute salvia intoxications may present with normal vital signs or tachycardia and hypertension. It is more likely that patient presenting to medical care with cardiovascular effects or neuropsychiatric toxicity have used Salvia with other substances or alcohol (Vohr et al, 2011; Rosenbaum et al, 2012).

Synthetic cathinones or ‘bath salts’

Amphetamine-like euphoric effects produced by chewing leaves and twigs of khat plant is due to cathinone and, its metabolite cathine (Catha edulis) (Brenneisen et al, 1990) With the regulation of cathionine by the United Nations and many countries, new synthetic cathinones such as mephedrone (‘Meow Meow’, ‘MCAT’) were produced and marketed as legal alternatives to cathinones (Gibson, 2012). Despite the ban of mephedrone and a few other related compound in UK, cathiones use continues (McElrath and O’Neill, 2011).

Many of these are marketed as ‘legal highs’ or ‘herbal highs’ or are described as bath salts, plant food, insecticides, novelty items, chicken feed additives, or research chemicals and advertise the products with names like ‘energy’, ‘white knight’, ‘ivory wave’, ‘lady bubbles’, ‘drone’ and ‘meow meow’ (Schmidt et al, 2011).

Multiple routes of exposure have been reported. Based on user reports, typical doses of mephedrone and methylone are 100–200 mg orally, with onset of effects around 30–45 min and duration of 2–5 hours (Erowid Vaults 2012, Rosenbaum et al, 2012). Cathionones are reported to produce of euphoria, heightened alertness, increased energy, talkativeness, and increased sexual arousal and many re-dose repeatedly to prolong the effects (Winstock et al, 2011; Erowid Vaults, 2012).

Snorting bath salts have led to be severely aggressive and psychotic behaviour (American Association of Poison Control Centers, 2010). These bizarre behaviours and patients’ unusual physical strength has to be taken into account when treating these patients so that paramedics and other first responders are not injured. Self-mutilation, suicide attempts, and persistent paranoid psychosis are also reported. Cathinone intoxication also produces sympathomimetic toxicity with hypertension, tachycardia, hyperthermia, dehydration, and psychomotor agitation with trismus, bruxism, tremors, insomnia, and paranoia. ( James et al, 2010; Rosenbaum, et al, 2012). There have been case reports of myocardial infarction and mephedrone-related myocarditis. (Nicholson, et al 2010)

Multiple deaths have occurred in the setting of bath salt use, with mephedrone and MDPV identified during post-mortem (Torrance

and Cooper, 2010; UK Home Office, 2010). Like amphetamines, synthetic cathinones are considered to be capable of inducing tolerance and dependence and 30 % of mephedrone users reported symptoms of dependence, such as tolerance, impaired control, and craving ( James, Adams et al, 2010).

Synthetic cathinones are not detected by common drug tests; however, the cathinone derivates may cause a false positive methamphetamine screen (Torrance and Cooper, 2010) Some commercially available kits can detect some of them.

Kratom

Kratom, (mitragyna speciosa korth), is a tropical tree found in many parts of South East Asia and its leaves have been chewed by natives to provide energy and relieve muscle pain. Kratom is an illegal substance in Thailand and Malaysia but is a legal substance in almost all other countries including UK ( Jansen and Prast 1988; Assanangkornchai and Muekthong et al, 2007; US Department of justice, 2012).

Kratom products are available as powder, leaves, and gum and the drug is typically, chewed, smoked or brewed into tea (Rosenbaum and Carreiro et al, 2012). Mitragynine, the most abundant chemical in Kratom, is 13 times more potent than morphine and responsible for its opium-like properties but also has the unusual dual properties that result in both stimulation and analgesia (Vicknasingam et al. 2010). Kratom has been used for centuries as a substitute for opium and to treat opiod withdrawal and is freely available via the internet (Boyer et al. 2007; Boyer et al. 2008). Kratom also causes neuromuscular blockade, which may contribute to the relief of myalgia (Chittrakarn et al. 2010).

Kratom is also called herbal speedball and is advertised as an effective agent to relieve muscle pain, and prolong sexual intercourse. Some of the attributed medicinal effects include analgesic, anti-inflammatory, antipyretic, antitussive, antihypertensive, local anaesthetic, hypoglycaemic, anti- diarrheal, and anti-malarial effects. (Suwanlert, 1975; Jansen and Prast, 1988; Vicknasingam et al. 2010). Kratom’s effects begin within 5–10 minutes of use and last up to an hour (Adkins et al. 2011).

A cocaine-like stimulant effect is seen at low doses, and opiod effects at higher doses (Babu et al. 2008; Gibson, 2012). There are case reports of intractable seizures needing intubation with Kratom use (Roche, 2008; Nelsen et al. 2010).

A withdrawal syndrome consisting of symptoms of hostility, aggression, emotional lability, rhinorhea, diarrhea, achy muscles and bones, and jerky movement of the limbs has been observed. Several cases of kratom psychosis were observed where kratom addicts exhibited psychotic symptoms that included hallucinations, delusion and confusion (Suwanlert, 1975; McWhirter and Morris, 2010).

A dangerous powdered mixture of kratom and O-desmethyl-tramadol (a synthetic product that is the active metabolite of tramadol added to booster opiod effects of kratom) called ‘krypton’ has been responsible for nine deaths in Sweden (Kronstrand et al. 2011). Kratom and its metabolites can be identified in urine, and several tests have been developed to identify Kratom in plant products (Rosenbaum et al, 2012).

Management

No specific antidote is available and management is similar to those patients with ketamine or phencyclidine exposure with supportive care, aggressive sedation with benzodiazepines, anti-emetics, intravenous fluids, and respiratory support as needed.

Piperazine derivatives

The piperazine derivatives such as BZP, MCPP, MDAI, TMFPP are stimulants often described as ‘party pills’ or ‘legal ecstasy’ and sold under several trade names such as ‘benzo fury’, ‘MDAI’, ‘head rush’, and ‘strong as hell’ BZP is a scheduled drug and in a 2010 survey of club goers in the UK, 26 % had used BZP previously (Dick and, Torrance 2010). The other piperazine derivatives are still legal to possess and use.

The piperazine derivatives frequently contain blends of two to four chemicals (Staack, 2007). A typical dose of BZP is 75–150 mg, and the resultant effect lasts from 6–8 hours. The onset of BZP effect may take more than two hours after ingestion and users can take multiple doses before the onset of effect which can lead to significant toxicity (Bye et al. 1973).The effects of the piperazine derivatives may be indistinguishable from those of the amphetamines, with BZP exhibits one-tenth the potency of dextroamphetamine clinically. In low doses, piperazine derivatives cause stimulant effects, while hallucinogenic effects predominate at higher doses (Bye et al. 1973; Campbell et al, 1973). The MDMA-like effect is usually achieved by mixing BZP and TMFPP. In a prospective evaluation of 80 emergency department patient encounters involving piperazine derivatives, the most commonly reported symptoms were palpitations, anxiety, headache, and vomiting. Sinus tachycardia was common, and 32 % of patients had documented QT prolongation. Seizures occurred in 14 patients, with a range of 30 minutes to 8 hours after exposure. One patient was found to have significant hyponatraemia (118 mmol/l) (Gee et al, 2005). The exact incidence of hyponatraemia with abuse of ecstasy or its legal alternatives such as piperazine derivatives is unknown. However, severe hyponatraemia induced seizures is a potential cause of death and should be considered in patients with severe amphetamine toxicity.

BZP and other legal highs derived from piperazines are not included in routine drug screen but can be detected from urine in amphetamines screens (Elliott and Smith, 2008).