Time for the return of the Prodigal Child.

For Albert Hofmann, chemistry was his  hobby as well as his  profession. Employee of  the drug company Sandoz, in Basel, Switzerland,  Hofmann's toys were organic molecules. In 1938, while playing with a rather unstable chemical,  lysergic acid,    he made   a series of its derivatives,    with the hope that at least  one among these  might prove to be a potential cardiovascular drug. None proved satisfactory, except that the  25th compound in the series, a colorless tasteless solid,  made the guinea pigs  unusually restless. Hofmann labeled the compound   LSD25 in his notebook and soon forgot about it.  But in 1943, on a hunch  he synthesized the molecule, LSD25,   lysergic acid diethylamide,   again. Here is what happened in his own words 

"I was forced to interrupt my  work in the laboratory in the middle of the afternoon and proceed home being affected by a remarkable restlessness combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated like condition characterized by an extremely stimulated imagination. In a dreamlike state with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After two hours this condition faded away." 
(Albert Hofmann, LSD : My Problem Child)


Hofmann was bothered, he had  to clear the nagging doubt in his mind, so  three days later he carried out a self experiment. The mystic chemist  intentionally dissolved what he then considered a very small  amount,  250 microgram in water and consumed it. A very precise scientist, he wrote down the time and observation:  19th April 1943, 16.20 hrs: "Tasteless". Forty minutes later is the next entry in the note book:   dizziness, anxiety , visual distortions, unable to move limbs and an uncontrollable desire to laugh. He had to be escorted home by his colleague. The news spread like wild fire, and before long  Hofmann realized that his Problem Child was born. Labelled as hallucinogen and psychedelic drug  LSD fell into wrong hands  was misused, abused and  finally   disgraced, denigrated and shunted out of public view. 
                                        
It is now 75 years since LSD was first synthesized. The medical curiosity didn't die down completely. Of late  there is a renewed, though  subdued interest in LSD  as an anxiety alleviator  and some of the credit for this should go to Serotonin, a neurotransmitter. Serotonin is a tiny organic molecule, an amine,  originally isolated from  human  blood serum and hence the name.   Much later serotonin received a more scholarly and chemically precise name, 5-hydroxytryptamine, which soon  became  just 5-HT, short and sweet.  5-HT proved to be  very mischievous and got  implicated in several diverse and contradictory physiological and psychological functions. For example it could induce migraine or a  general sense of well being, it could induce appetite or nausea.  Intrigued, scientists    prodded on; once released what does it do and where  does it go and sit?   It  was soon found out  that there are,   at least 15 sites along the central and peripheral nervous system, where 5-HT can dock.  These docking stations  are referred to as 5-HT receptors. It is now known that LSD has a preference to the receptor 5-HT2A. Detailed structural information about  5-HT2A receptor and   how  LSD binds to it will unravel most of the mysteries.  

Hofmann died at the age of 102,  to the very end he believed in the therapeutic value of LSD. 

Reference 
1.  LSD: My     Problem Child  by Albert Hofmann. 
2. Structural Basis for Molecular recognition of Serotonin receptors 
    Wang et al Science 3rd     May vol. 340, pages 610-614,  2013 
3. Structural features for functional selectivity at serotonin receptors.
    Wacker etal Science 3rd May Vol. 340, pages 615-618.  2013