Dimethylheptylpyran
Encyclopedia
Dimethylheptylpyran is a synthetic analogue of THC
, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, the active component of cannabis
. DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.
effects, but is considerably more potent, especially having much stronger analgesic
and anticonvulsant
effects than THC, although comparatively weaker psychological effects. It is thought to act as a CB1
agonist
, in a similar manner to other similar cannabinoid derivatives.
ester
were extensively investigated by the US military chemical weapons program in the Edgewood Arsenal experiments
, as possible non-lethal incapacitating agents.
DMHP has three stereocenter
s and consequently has eight possible stereoisomers, which differ considerably in potency. The racemic
mix of all eight isomers of the O-acetyl ester was given the code number EA-2233, with the eight individual isomers numbered EA-2233-1 through EA-2233-8. The most potent isomer was EA-2233-2, with an active dose range in humans of 0.5-2.8 μg/kg (i.e. ~35-200 μg for a 70 kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1–2 mg, all volunteers were considered to be incapable of performing military duties, with the effects lasting as long as 2–3 days.
DMHP is metabolised in a similar manner to THC, producing the active metabolite 11-hydroxy-DMHP, but the lipophilicity of DMHP is even higher than that of THC itself, giving it a long duration of action and an extended half-life in the body of between 20–39 hours, with the half-life of the 11-hydroxy-DMHP metabolite being longer than 48 hours.
Cannabinoids as a class are generally safe compounds with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating agents. DMHP and its esters produce sedation
and mild hallucinogenic effects similar to large doses of THC
, but in addition to this they also cause pronounced hypotension
(low blood pressure) which occurs at doses well below the hallucinogenic dose, and can lead to severe dizziness
, fainting, ataxia
and muscle weakness
, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity. The acute toxicity of DMHP was found to be low in both human and animal studies, with the ratio of ED50 to LD50
in animals being around 2000x, with death ultimately resulting from a combination of hypotension and hypothermia
and preventable with supportive treatment.
The combination of strong incapacitating effects and a favourable safety margin led the Edgewood Arsenal team to conclude that DMHP and its derivatives, especially the O-acetyl ester of the most active isomer, EA-2233-2, were among the more promising non-lethal incapacitating agents to come out of their research program. However they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as effective as the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate
which had also already been weaponised. Funding for continued development was ultimately not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, the active component of cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
. DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.
Effects
DMHP is similar in structure to THC, differing only in the position of one double bond, and the replacement of the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain. It produces similar activity to THC, such as sedativeSedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
effects, but is considerably more potent, especially having much stronger analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
effects than THC, although comparatively weaker psychological effects. It is thought to act as a CB1
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
, in a similar manner to other similar cannabinoid derivatives.
Investigation as non-lethal incapacitating agent
DMHP and its O-acetateAcetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
were extensively investigated by the US military chemical weapons program in the Edgewood Arsenal experiments
Edgewood Arsenal experiments
The Edgewood Arsenal experiments are said to be related to or part of CIA mind-control programs after World War II, such as MKULTRA. Journalist Linda Hunt, citing records from the U.S...
, as possible non-lethal incapacitating agents.
DMHP has three stereocenter
Stereocenter
A stereocenter or stereogenic center is an atom, bearing groups such that an interchanging of any two groups leads to a stereoisomer.A chirality center is a stereocenter consisting of an atom holding a set of ligands in a spatial arrangement which is not superposable on its mirror image...
s and consequently has eight possible stereoisomers, which differ considerably in potency. The racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mix of all eight isomers of the O-acetyl ester was given the code number EA-2233, with the eight individual isomers numbered EA-2233-1 through EA-2233-8. The most potent isomer was EA-2233-2, with an active dose range in humans of 0.5-2.8 μg/kg (i.e. ~35-200 μg for a 70 kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1–2 mg, all volunteers were considered to be incapable of performing military duties, with the effects lasting as long as 2–3 days.
DMHP is metabolised in a similar manner to THC, producing the active metabolite 11-hydroxy-DMHP, but the lipophilicity of DMHP is even higher than that of THC itself, giving it a long duration of action and an extended half-life in the body of between 20–39 hours, with the half-life of the 11-hydroxy-DMHP metabolite being longer than 48 hours.
Cannabinoids as a class are generally safe compounds with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating agents. DMHP and its esters produce sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
and mild hallucinogenic effects similar to large doses of THC
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
, but in addition to this they also cause pronounced hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(low blood pressure) which occurs at doses well below the hallucinogenic dose, and can lead to severe dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, fainting, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and muscle weakness
Muscle weakness
Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity. The acute toxicity of DMHP was found to be low in both human and animal studies, with the ratio of ED50 to LD50
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
in animals being around 2000x, with death ultimately resulting from a combination of hypotension and hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
and preventable with supportive treatment.
The combination of strong incapacitating effects and a favourable safety margin led the Edgewood Arsenal team to conclude that DMHP and its derivatives, especially the O-acetyl ester of the most active isomer, EA-2233-2, were among the more promising non-lethal incapacitating agents to come out of their research program. However they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as effective as the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate
3-Quinuclidinyl benzilate
3-quinuclidinyl benzilate , IUPAC name 1-azabicyclo[2.2.2]Oct-3-yl α-hydroxy-α-phenylbenzeneacetate, is an odorless military incapacitating agent. Its NATO code is BZ...
which had also already been weaponised. Funding for continued development was ultimately not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.