Samstag, 26. Oktober 2013

Antidepressants - from angel dust to ketamine

'But it was all too much sprinkling angel dust to AT and T, who did not wish you well, oh oh oh, you keep hangin' round'.
Lou Reed sang these lines six years before the National Institute on Drug Abuse decided to hold a conference on the abuse of phencyclidine in February 1978 in Pacific Grove, California.

Phencyclidine, or angel dust, as it was called by the street name, had been traded since the mid-60s on the streets (at first it was reported in the Haight-Ashbury district in San Francisco in 1967) and had a very bad reputation. No one would have ever thought then that it would develop to a drug of choice only 10 years later. 
Within a year, between 1976 and 1977, the consumption doubled in the 12 to 17-year-old. And between 1974 and 1976, the number of emergency assignments had also doubled. A similar trend could be seen in the number of deaths due to PCP overdose. Interestingly, cases of drowning occurred most frequently. 
Phencyclidine had a lot of street names: from angel dust to crystal, horse tranquilizer, killer weed, super weed or rocket fuel. Often, consumers were not aware of the active chemical ingredients (often they mistook it for a more potent sort of marijuana) and therefore used it together with barbiturates, heroin or cocaine, but also with LSD, mescaline or amphetamine. 
Rather rarely Phencyclidine (PCP) was injected intravenously. More often it was smoked as a 'joint' or a menthol cigarette was dipped into the liquid substance before smoking it (,superkools'). The term 'superpot' should obviously suggest that the effect was stronger than marijuana and more comparable to LSD. Oral ingestion or pernasal use was also possible ('snorting'). 
Phencyclidine produces different physiological actions. The stimulating, depressant, hallucinogenic and analgetic properties are dose dependent. A proposal for a classification was as a 'dissociative anesthetic'. The central nervous system effects manifest themselves in a sort of drunken state at low dosages. In medium doses analgesia and anesthesia is produced. A mental state, which is similar to a sensory isolation can be obtained. Also cataleptiform motor responses appear sporadically. In high doses it comes to cramps. In addition, there are sympathomimetic effects with increase of heart rate and blood pressure increase. 
Phencyclidine can be produced quite easily. The starting materials are readily available and are subject to only minor checks.
Ronald K. Siegel, whom Oliver Sacks estimated as a relevant expert in the field of  hallucinogens (,There is no one around who knows more about hallucinations than Ronald K. Siegel '), examined a group of 319 subjects, alltogether PCP users, in his study. He was interested, why PCP was so often and repeatedly used despite its known adverse effects (eg schizophrenomimetic effects such as prolonged psychosis). Thus were his findings: 94% reported increased sensitivity to external stimuli, 92% described a stimulating effect, 88% reported dissociative phenomena and no less than 61% reported mood elevating effects. 

Since then countless chemically related analogues  of phencyclidine have been synthesized over the years, which were also common in street trading. 1976 the movie 'Family Plot' by Alfred Hitchcock showed a scene with a kidnapping victim, which was sedated with a then little-known drug called ketamine. 
Parke Davis and Company had developed ketamine as an anesthetic after PCP had not achieved the desired effects in anesthesia in surgical procedures. Ketamine had then been enthusiastically praised as a non-barbiturate anesthetic with a rapid effect, deep analgesia, almost normal pharyngolaryngeal reflexes and muscle tone, cardiovascular and respiratory stimulation, and only occasional respiratory depression. Doenicke and coworkers found analgesic effects as well as depersonalization and derealization phenomena as well as changes in body image, nausea, dizziness, hallucinations and dreams in their patients and volunteers. Most of them described their dreams and hallucinations as pleasant. In the reports of Rumpf and colleagues the hallucinations were 'fantastic', described as 'utopian', 'unreal' or 'mysterious'. In a study by Collier (1972) most of ketamine dreams or hallucinations were also rated as pleasant and as intense. In one dream a patient ascended to heaven, even saw God and was eventually reincarnated in Italy. Green color, luminosity, a peaceful atmosphere and euphoria were the most remarkable features of the dream sequence. Apparently, the vivid memory of the dream in this patient was lasting permanently. 

John Krystal, psychiatry professor at Yale, was the first to demonstrate the significant antidepressant effect of intravenous ketamine infusions in 2000. This discovery set a number of other studies on the antidepressant effects of ketamine in motion. Throughout a rapid antidepressant onset of action has been detected. One reason for the reluctance of psychiatry to put this procedure into clinical use is the risk and fear of widespread misuse. 
Moreover, a new antidepressant mechanism of action with the NMDA (N-methyl-D-aspartate) receptor antagonism was postulated and thus brought further research efforts to study this mechanism on the way. For the first time in many years, a viable alternative to the so-called amine hypothesis was being proposed. The latter was the foundation for the development of a variety of antidepressants in the past years, including the so called tricyclics and also for the newer SSRIs and SNRIs which, regretfully also lead to a psychopharmacological deadlock in recent years, since a further development of this class of drugs under today's conditions seems most unlikely. 

Now new hope has emerged with the ketamine avenue being explored for a more effective treatment of depression and possibly other mental illnesses.

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