Dimethocaine, also known as DMC or larocaine, is a compound with a stimulatory effect. This effect resembles that of

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

, although dimethocaine appears to be less potent. Just like cocaine, dimethocaine is addictive due to its stimulation of the reward pathway in the brain. However, dimethocaine is a legal cocaine replacement in some countries and is even listed by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) under the category “synthetic cocaine derivatives”. The structure of dimethocaine, being a

4-aminobenzoic acid 4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA i ...

ester, resembles that of

procaine Procaine is a local anesthetic drug of the amino ester group. It is most commonly used in dental procedures to numb the area around a tooth and is also used to reduce the pain of intramuscular injection of penicillin. Owing to the ubiquity ...

. It is found as a white powder at room temperature. When a product sold online in the UK in June 2010, advertised as dimethocaine was tested, it was found to be a mixture of

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine to ...

and lidocaine, and the lack of any dopaminergic stimulant ingredient in such mixes may explain the limited recreational effects reported by many users. Other samples tested have however been shown to contain genuine dimethocaine, and one branded "bath salt" product containing primarily dimethocaine as the active ingredient, was noted to have been particularly subject to abuse by intravenous drug users in Ireland.

History

Dimethocaine was originally synthesized by the Hoffmann-La Roche company in 1930. It was sold under the market name larocaine. During the 1930s dimethocaine gained popularity in the US as a local anesthetic. Just like cocaine and procaine, it was used during surgery, primarily in dentistry,

ophthalmology Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders. An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...

and

otolaryngology Otorhinolaryngology ( , abbreviated ORL and also known as otolaryngology, otolaryngology–head and neck surgery (ORL–H&N or OHNS), or ear, nose, and throat (ENT)) is a surgical subspeciality within medicine that deals with the surgical a ...

. However, in the 1940s, it was removed from the market because of its psychoactive effects and risk of addiction. Nowadays dimethocaine is abused for these psychoactive effects. It is sold as a cocaine surrogate to circumvent legislation issues.

Pharmacology

Pharmacodynamics

Dimethocaine and structurally related local anesthetics such as cocaine and procaine inhibit the uptake of dopamine (DA) by blocking

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dop ...

s (DAT). The dopamine transporter controls the dynamics of the neurotransmitter dopamine. This neurotransmitter controls many functions including movement, cognition and mood. Drugs such as cocaine and dimethocaine induce dopamine overflow by inhibiting dopamine transporters and thus creating a euphoric effect. In addition to inhibiting dopamine uptake, dimethocaine was also shown to inhibit the binding of CFT, a different dopamine uptake inhibitor. These inhibitory properties are responsible for the stimulatory effects of dimethocaine on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. Both ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' and ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' measurements of dopamine transporter activity showed that dimethocaine is a potent and efficacious dopaminergic reuptake inhibitor (also called a dopamine indirect agonist). These effects were mainly observed in the

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...

, a region in the

basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal b ...

. Comparison of the pharmacological potencies of different local anesthetics revealed the following potency order: cocaine > dimethocaine >

tetracaine Tetracaine, also known as amethocaine, is an ester local anesthetic used to numb the eyes, nose, or throat. It may also be applied to the skin before starting an intravenous (injection) to decrease pain from the procedure. Typically it is applied ...

> procaine >

chloroprocaine Chloroprocaine (trade name Nesacaine, Nesacaine-MPF) (often in the hydrochloride salt form as the aforementioned trade names) is a local anesthetic given by injection during surgical procedures and labor and delivery. Chloroprocaine vasodilates ...

Furthermore, the administration of dimethocaine has been shown to lead to antinociceptive responses at nontoxic doses in mice. These responses are suggested to be at least partially caused by the effects of dimethocaine on the central nervous system. A memory impairing effect observed in mice after administration of dimethocaine has been proposed to be a result of a non-anesthetic mechanism of action.

Pharmacokinetics

When inhaled, dimethocaine starts working in 10–30 minutes, with highest effects at 60–120 minutes and until 4–6 hours there is a period of action with the ‘after-effects’. The after effects include fatigue and slight mental impairment.

Metabolism

The exact metabolic pathways of dimethocaine have not been researched, but the different metabolites have been examined in Wistar rats. After administration of dimethocaine, different metabolites have been found and identified in their urine. Due to these metabolites, different metabolic pathways could have been postulated. The main phase I reactions are

ester hydrolysis In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are fa ...

, deethylation, hydroxylation of the aromatic system, or a combination of these three. The main phase II reactions are N-acetylation,

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

and a combination of both. Different

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

s are involved in the initial steps of human metabolism. The N-acetylation is catalyzed by the NAT2 isozyme.

Efficacy and side effects

Just like cocaine, dimethocaine inhibits the uptake of dopamine in the brain by interfering with the dopamine transporters. The potency of these drugs is linked to their affinity for the dopamine transporters, and their potency to inhibit dopamine uptake. In studies with

rhesus monkeys The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...

the affinity of dimethocaine for dopamine transporters is smaller than that of cocaine, whereas dimethocaine's potency to inhibit dopamine uptake is similar. This means that more of dimethocaine is needed to reach a similar response. The peak effects occurred within 10 to 20 minutes after the injection and decreased to baseline levels within an hour. Dimethocaine is often abused as a legal substitute for cocaine. The drug is administered

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

or nasally, because ingestion would lead to rapid

hydrolyzation Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

. Its positive effects are euphoria, stimulation, increased talkativeness and mood lift. However, because the drug acts similar as cocaine, it has comparable negative side effects. These side effects include:

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

, difficulty with breathing, pain on the chest,

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy co ...

and anxiety. Dimethocaine probably poses larger health issues than cocaine. This is due to the fact that more dimethocaine must be administered to produce the same euphoric feeling, resulting in larger risk for the negative effects.

Toxicity

Humans

Cocaine and other local anesthetics are known to produce cardiotoxicity by blocking sodium channels. However, no reports have been published of these same effects of cardiotoxicity associated with dimethocaine. There has been little research about toxicity of dimethocaine in humans, and therefore the exact lethal or pharmacological doses are unknown.

Animals

For mice, the dose at which acute toxicity occurs for intravenous administration is 40 mg/kg and for subcutaneous injection (injection in the layer of skin directly below the dermis and epidermis) this is 380 mg/kg. The lethal dose of dimethocaine for a mouse is 0.3 g per kilogram body weight. An abdominal constriction test was performed in mice, using doses of 5, 10, and 20 mg/kg of dimethocaine which were administered subcutaneously. This test showed induced dose-dependent antinociceptive responses, which are processes that block detection of a painful or injurious stimulus by sensory neurons. Impairment of memory processes was found to be a toxic effect in the elevated plus-maze test in mice.

Legal status

Sweden's public health agency suggested classifying Dimethocaine as a hazardous substance, on September 25, 2019.

References

{{Monoamine reuptake inhibitors Stimulants Local anesthetics 4-Aminobenzoate esters Anilines Designer drugs Diethylamino compounds