Introduction to Psychopharmacology

Psychopharmacology is the study of the effects of any psychoactive drug that acts upon the mind by affecting brain chemistry. Amanita muscaria (the common Fly Agaric) is often regarded as the first such drug, with modern theories positing the discovery of its psychoactive properties circa 10,000 BCE. Modern psychopharmacology studies a wide range of chemicals with many different types of effect.

History
Psychoactive drug use predates recorded history. Hunter-gatherer societies tended to favor hallucinogenic drugs, and today their use can still be observed in many surviving tribal cultures. The exact drug used depends on what the particular ecosystem a given tribe lives in can support, and are typically found growing wild. Such drugs include various hallucinogenic mushrooms and cacti, along with many other plants. These societies generally attach spiritual significance to drug use, and often incorporate it into their religious practices.

With the dawn of the Neolithic and the proliferation of agriculture, new entheogens came into use as a natural by-product of farming. Among them were opium, cannabis, and alcohol derived from the fermentation of cereals and fruits. Most societies began developing herblores, lists of herbs which were good for treating various physical and mental ailments. For example, St. John's Wort was traditionally prescribed in Europe for depression (in addition to use as a general-purpose good-tasting tea), and Chinese medicine developed elaborate lists of herbs and preparations.

With the scientific revolution in Europe and America, the use of traditional herbal remedies fell out of favor with the mainstream medical establishment, although a few people continued to use and maintain knowledge of traditional European herblore. In the early 20th century, scientists began reassessing this rejection of traditional herbs in medicine. A number of important psychiatric drugs have been developed as a byproduct of the analysis of organic compounds present in traditional herbal remedies. The use of psychiatric drugs to restore mental health, or at least limit aberrant behaviour, has only been part of the European and American medical institution since the 1950s, when a number of new classes of drugs were discovered, notably tranquillizers and antidepressants, and LSD was popularized among many psychiatrists as a mental miracle drug capable of curing all manner of problems.

In the latter half of the 20th century, research into new psychopharmacologic drugs exploded, with many new drugs discovered, created, and tested. Many once-popular drugs are now out of favor, and there are fashions in psychiatric drugs, as with any other kind of drug.

Reduction of anxiety
Barbiturates were used as hypnotics and as anxiolytics, but the development of the safer benzodiazepines (Lowell Randall and Leo Sternbach, 1957) in the 1960s and 1970s led to billions of doses being consumed annually under tradenames like Mogadon, Valium (diazepam, 1963) or Librium (chlordiazepoxide). However, as these drugs became more widely prescribed, the problems of chronic use and dependence led to the development of other drugs, such as the azapirones.

Antipsychotic drugs
Outside of the more popular drugs, there was success in the treatment of some of the symptoms of psychosis and depression. The first antipsychotic compound, for the treatment of the symptoms of schizophrenia, was chlorpromazine (known by tradenames like Largactil or Thorazine) in 1953. Their effects went beyond simple sedation, with patients showing improvements in thinking and emotional behaviour, and over 100 million patients were treated. From chlopromazine, a number of other similar antidopaminergic compounds were developed, such as the phenothiazines. Such drugs had a revolutionary role in transforming mental institutions from an almost purely custodial role.

Enthusiasm for the first generation of anti-psychotic medications peaked in the late 1960s, but the image of the drugs plummeted in the mid-1970s, as studies emerged showing that chronic users of anti-psychotic medication developed high rates of tardive dyskinesia, a typically permanent neurological disorder similar to Parkinson's disease involving involuntary movements. The first generation of antipsychotic drugs are now commonly referred to as typical antipsychotics.

In the 1990s, several atypical antipsychotic drugs were first marketed. Atypical antipsychotics are believed to have a lower incidence of tardive dyskinesia and extrapyramidal side-effects than the first generation typical antipsychotics. The atypical antipsychotics are believed to be better at treating the "negative symptoms" of schizophrenia. They are currently marketed under the names Abilify (aripiprazole) and Risperdal (risperidone), among others.

However, the limited available knowledge of brain chemistry means that even the more modern compounds cause a range of extrapyramidal side-effects. While effective at controlling acute symptoms, antipsychotic drugs are of less value in treating chronic symptoms.

LSD
LSD, a powerful hallucinogen, was developed at the Sandoz Laboratories (now Novartis) in Switzerland from research on chemicals found in the ergot fungus, which had several traditional uses in European herblore. In the 1950s, LSD was manufactured under the trade name Delysid by Sandoz, and widely promoted as a psychiatric cure-all, useful for treating schizophrenia, criminal behavior, sexual deviancy, alcoholism, and a wide variety of other mental ailments. Sandoz suggested in its literature that psychiatrists should take LSD themselves, to gain a better subjective understanding of the schizophrenic experience. Early results seemed very positive, indicating that if LSD was taken under the guidance of a caring professional, dramatic improvement in mental state and behaviour could be induced after just a single "trip", or drug use session. People who had come into contact with LSD in a professional capacity began using the drug recreationally and sharing it with friends and accquaintences.

Many users of LSD report profoundly positive life-transforming experiences, often incorporating mysticism and religious elements, while others have experienced intensely negative "bad trips", and a few have devolved into states of LSD psychosis.

Scientific research into the effects and potential uses of LSD was common in the 1950s, but it gradually declined as LSD became increasingly associated with spiritual experiences, recreational use, and the hippie counterculture during the 1960s. Several researchers, most prominently erstwhile Harvard psychology professor Dr. Timothy Leary, dissociated themselves from the mainstream mental health research establishment as its support for LSD research declined, and transitioned to roles as spiritual gurus. Leary believed that the state of mind LSD induces is that which is described in Buddhism as bodhi, or "enlightenment". He advocated the use of LSD for personal spiritual growth, and as a tool for socially overthrowing "the establishment". LSD was prohibited in the United States in 1967, listed by the DEA as a Schedule I drug with no medical uses and no possibility for safe use in research under medical supervision. Many researchers blame Leary and his anti-establishment proselytizing among the hippies for the prohibition. Systematic research since that time has been uncommon.

LSD was central to experiments conducted as part of the CIA's MKULTRA program, which was focused on finding reproducible methods to program and control human minds. Subjects included military personnel and private citizens, the vast majority of whom had no knowledge of the nature of the experimentation throughout their participation. Most MKULTRA experiments constituted significant breaches of human rights, and have since been openly denounced by the United States government. LSD itself proved ineffective as a means of controlling subjects, but reports indicate that many of the people involved suffered significant psychological trauma as a result. See MKULTRA.

MDMA
MDMA, commonly known as Ecstasy, was popularized as an adjucant to talk therapy in the 1960s and 1970s by Dr. Alexander Shulgin. One primary effect of Ecstasy is diminution of inhibitions, rendering users extremely comfortable talking about themselves and others.

This drug works upon serotonergic synapses by acting upon the SERT-1 transporter (the same target as many SSRIs such as Prozac-- hence MDMA and SSRIs inhibit one another's function). Serotonergic neurons store serotonin (also known as 5HT) near the synapse and it is the role of the SERT-1 transporter to re-uptake 5HT from the synapse. MDMA when bound with SERT-1 causes this transporter to reverse its function and pump 5HT into the synapse. Numerous studies now show that pure MDMA acts only on the serotonergic system.

Potential theraputic uses of MDMA have been overshadowed by its popularity as a recreational drug and negative public perceptions fostered by anti-drug groups. Limited research continues, with University of Manchester researchers determining that MDMA dramatically reduces tremors in patients receiving L-DOPA treatment for Parkinson's Disease. Other researchers have implicated long-term MDMA use as a potential cause of Parkinson's Disease. (Some of this research has been roundly debunked.) The authors of a report showing MDMA to cause Parkinson's Disease retracted their work after it became apparent that they were using MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine), not MDMA, in their work. MPTP is well documented as being highly toxic to dopaminergic neurons, and is in fact used in animal models to induce a Parkinson's Disease.

Much remains unknown about the potential uses and effects of MDMA. The United States DEA's scheduling of MDMA as a Schedule I drug with no legitimate medical uses has severely hampered research, while some experts have recommended it be listed instead on Schedule III, a less severe classification which would allow for the possibility of medical applications. Approval has now (February 2005) been given for Harvard to use MDMA in therapy for people suffering from post-traumatic stress disorder (PTSD).

Antidepressant drugs
Two major classes of drugs combatting depression were developed in the late 1950s, one group based on iproniazid, an MAOI developed at Hoffmann-La Roche in 1956, the other on imipramine, a tricyclic antidepressant developed by R. Kuhn at Geigy Laboratories in 1958. Improvements were made but the results were less marked than with anti-psychotic drugs. This category also includes tetracyclic antidepressants or SSRIs such as Prozac, discovered by D. T. Wong at Eli Lilly and Company in 1974 and approved by the FDA in 1987.

Mood stabilizers
In 1949, the Australian John Cade discovered that lithium salts could control mania, reducing the frequency and severity of manic episodes. It did not take long for others to discover that these drugs also reduced the frequency and severity of depressive episodes. Other mood stabilizers include valproic acid, carbamazepine, lamotrigine, and topiramate.

Treatment of addiction
Research with the drug ibogaine to treat heroin addiction has shown much promise in eliminating physical withdrawal symptoms. The drug is obtained from an African plant and was used as early as the 1960s by Claudio Naranjo.