Synthetic Tetrahydracannabinols

These compounds have been produced as the result of the work carried out by Adams and his colleagues in America and of Todd and his colleagues and the Roche Research Department in this country (England.)

Several compounds of this type are known, and one of the most active pharmacologically is the synthetic hexyl analogue called, in America, synhexyl, pyrahexyl, or parahexyl. 

Chemically, it is ;
1-hydroxy-3-n-hexyl-6-6-9-trimethyl-7-8-9-10-tetrahydra-6-dibenzopyran, and has the following structural formula :


                     CH3
                         |    OH
                        /\      \ /\ ___C6  H13
                       |   |___|   |
                        \/        \/
                         \        /
                          C---O
                             /\
                            /  \
                     CH2   CH3

It is synthesized by condensation of ; ethyl-5-methylcyclo-hexanone-carboxylate-2  with  3  5-dihydroxy-n-hexylbenzene, followed by treatment of the condensation product with methyl magnesium iodide.  It is a pale-yellow, translucent, very viscous, odorless resin, soluble in organic solvents but insoluble in water, alkalis, and acids.  The synthetic lower homologue in which n-amyl replaces the n-hexyl radicle is pharmacologically less active.  Its laevorotatory form is several times as active as the dextrorotatory form.
  
Pharmacology of Synhexyl in Man
  
The pharmacological properties of synhexyl are in many respects similar to those of cannabis, but there are several important qualitative differences in the human subject.  The following data were obtained as the result of a series of experiments which I carried out on myself, a group of normal subjects, and a group of 50 depressive patients.  My findings confirm that the drug is a powerful euphoriant with a specific action on the higher centres, particularly the thalamic system and its cortical connections.  Synhexyl is rather more potent weight for weight than natural cannabis, the effective dosage being from 5-15 mg. in normal subjects to 60-90 mg. in depressive patients.  In narcotic drug addicts, doses of 60-240 mg. three times daily may be given without ill effects (Himmelsbach.)  On account of its resinous nature the drug is most active when administered by the oral route, and the preparation I used was in the form of a powder made by absorbing the drug on silicic acid and contained in gelatin capsules , or as compressed tablets after absorption on kieselguhr.
  
The general effects in normal man are as follows :  There is first a latent period of 1 1/2 to 3 hours before any effect is felt, this being about twice the latent period for the same dose of cannabis extract.  The onset of the synhexyl effect is characteristically abrupt, with a sudden and peculiar sensation of lightness and mild intoxication accompanied by acceleration of the pulse and feelings of slight palpitation and oppression in the head and chest.  Transient feelings of anxiety and vertigo may occur at the onset, but these usually pass off in the course of a few minutes to half an hour.  The euphoric effect quickly follows, and consists of a pleasant feeling of happiness and exhilaration with a marked sense of physical well-being and self-confidence ; there is a sense of relief from tension and anxiety, and the threshold for unpleasant effect is markedly raised, while that for pleasant feeling tone is correspondingly lowered.  There is increased enjoyment of normally pleasant impressions, and zest for live and working capacity may actually be increased in the early stages of the intoxication. 

Later this effect gives way to a sense of dreamy apathy and contentment, which with the larger dosages may reach the stage of ecstasy.  There is often increased speed of the stream of thought, with a marked increase in the power of fantasy and vividness of visual imagery.  With the larger dosages there may in the early stages be a tendency to flight of ideas and pressure of activity.  In the sensory sphere there is little or no true analgesic effect of the opiate type.  With the higher doses there may be some degree of blunting of sensation, but the senses of taste and hearing may actually become more acute.  A generalized sensation of pleasant warmth diffused throughout the body is characteristic.
  
Hallucinatory phenomena and distortion of the temperospatial perception sense of cannabis-mescal type are not found, although elementary visual sensations in the form of photopsias and simple coloured patterns may occur when the eyes are closed or the subject is in darkness.  A peculiar visual illusion is sometimes seen in which the colours and outlines of objects appear abnormally vivid and a soft golden radiance seems to be diffused over the whole room.  With larger doses visual illusions of cannabis type may be experienced in which simple patterns appear to acquire complex and fantastic forms, the whole effect being extremely pleasing to the subject.  On the motor side there may be slight restlessness in the early stages, similar to what is found with moderate doses of Benzedrine.  Hyperreflexia is common, but ataxia and motor incoordination are seen only with the largest doses.  Catatonia and rigidity as seen with mescaline are never found.