[Sunshine Daydream]

Morning all,

I came across a very interesting (and long) scholarly journal article on hallucinogens. It is quite comprehensive and informitive, and I really enjoyed reading it. So, I figured some of you might enjoy it too.

Here's a link to the article:

http://www.sciencedirect.com/science...62579&ref=full

Here's a list of excerpts that I found particularly interesting (long). If you don't have time to read all of the article, feel free to skim over some of these.

we shall review those substances that principally exert their central nervous system (CNS) effects by an agonist (or partial agonist) action at serotonin (5-HT)2A receptors

Many different names have been proposed over the years for this drug class. The famous German toxicologist Louis Lewin used the name phantastica earlier in this century [Lewin, 1964], and as we shall see later, such a descriptor is not so farfetched. The most popular names, hallucinogen, psychotomimetic, and psychedelic (“mind manifesting”; [Osmond, 1957]), have often been used interchangeably.

There is only a meager amount of factual information about hallucinogenic drugs among the general public today. Furthermore, in the scientific and medical communities, where one expects to find expertise on drugs, there is now a whole generation who knows almost nothing about hallucinogens other than the fact that they are subject to the strictest legal controls applied to any class of pharmacological agents

Despite their high degree of physiological safety and lack of dependence liability, hallucinogens have been branded by law enforcement officials as among the most dangerous drugs that exist, being placed into Schedule I of the Controlled Substances Act. Depending on the locale, especially in the United States, punishments for using or distributing drugs like LSD are often more draconian than if the user had committed a violent crime. Although there is a common perception that Schedule I drugs are particularly dangerous, the 3-pronged test for placement of a drug into schedule I requires only that (1) the drug has no currently accepted medical use in the United States, (2) there is a lack of safety for use of the drug under medical supervision, and (3) the substance has a high “potential for abuse.”

What is it, exactly, that makes these pharmacological curiosities so fearsome? The answer lies, in large measure, beyond hard science and within a complex sociological and political agenda that surround psychedelics, which is well outside the scope of this review. Nevertheless, a very brief discussion of the history and background of these unique substances is warranted to provide a little insight into how this situation arose.

Naturally occurring hallucinogenic drugs played a significant role in the development of philosophy and religious thought in many earlier cultures. One can argue persuasively that hallucinogenic drugs might have been catalysts for the development of humankind's earliest philosophies and theologies. How many Neolithic hunters, one might wonder, eking out an existence in the wild, were likely to sit before the fire at night contemplating the nature of man and the meaning of life? By contrast, if the same group had discovered and ingested some hallucinogenic mushrooms, they would be compelled to confront and would surely have discussed and attempted to understand the nature of their otherworldly mushroom-induced encounters. Assuming that their neurochemistry was not so different from ours today, those occurrences would have been well beyond the bounds of their everyday experiences and vocabulary. They could easily have concluded that these plants were “the residences of divinities or other spiritual forces” [Schultes & Hofmann, 1979].

The late Daniel X. Freedman, one of the great pioneers of LSD research, made comments consistent with that assessment, stating, “…one basic dimension of behavior…compellingly revealed in LSD states is “portentousness”—the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and “boundaryless” events, from the banal to the profound.” [Freedman, 1968]. It might be noted in this context that one doctoral dissertation has even provided evidence that psilocybin-induced mystical-religious experiences could not be distinguished, by objective criteria, from spontaneously occurring ones [Pahnke, 1963].

It should be apparent from the foregoing discussion that hallucinogens have a unique and powerful ability to affect the human psyche. They may alter one's concepts of reality, may change one's views on life and death, and can provoke and challenge one's most cherished beliefs. Therein, this writer believes, lay the roots of much of the fear and hysteria that these substances have fostered in our society.

Hallucinogens are generally considered to be physiologically safe molecules whose principal effects are on consciousness. That is, hallucinogens are powerful in producing altered states of consciousness (ASC), but they do so at doses that are not toxic to mammalian organ systems. There is no evidence that any of the hallucinogens, even the very powerful semisynthetic LSD, causes damage to any human body organ. [Cohen, 1967] has stated, “Death directly caused by the toxicity of LSD is unknown.” This statement was reiterated 20 years later by [Jaffe, 1985], “In man, deaths attributable to direct effects of LSD are unknown.” This observation still remains true today. Hallucinogens do not cause life-threatening changes in cardiovascular, renal, or hepatic function because they have little or no affinity for the biological receptors and targets that mediate vital vegetative functions.

In contrast to many other abused drugs, hallucinogens do not engender drug dependence or addiction and are not considered to be reinforcing substances [O'Brien, 2001]. It is generally believed that most if not all drugs that possess dependence liability have the ability to affect dopaminergic (DA) transmission, particularly in mesolimbic areas of the brain. The behavioral correlate of this effect is increased mood and often euphoria. By contrast, nearly all hallucinogens lack affinity either for DA receptors or for the DA uptake transporter and therefore do not directly affect DA neurotransmission. In an article reviewing drugs of abuse that activate brain reward pathways, drugs identified with this action included opiates, nicotine, cannabis, phencyclidine (PCP), cocaine, amphetamine, alcohol, benzodiazepines, barbiturates, and even caffeine, but there was no mention of hallucinogens [Wise, 1998].

There are no literature reports of successful attempts to train animals to self-administer classical hallucinogens, an animal model predictive of abuse liability, indicating that these substances do not possess the necessary pharmacology to either initiate or maintain dependence.

[Strassman, 1984] and [Halpern & Pope, 1999] have analyzed the published reports on adverse reactions and negative long-term sequelae following hallucinogen use. Halpern and Pope reached a conclusion similar to Strassman's earlier analysis that concerning repeated use of psychedelic drugs the results were controversial, but if any long-term adverse effect did occur it was “subtle or nonsignificant.” It should be noted, however, that in both studies their conclusions were specifically developed based on reviews of supervised clinical research with hallucinogens.

One adverse consequence of hallucinogen use is known as “flashbacks.” Flashbacks were widely discussed in the press, particularly in earlier decades, as one of the most common adverse effects of hallucinogens; their occurrence was emphasized as a deterrent to recreational use.

there appears to be no relationship between frequency of hallucinogen use and rate of occurrence.

There are, however, real and significant dangers that can accompany recreational use of these substances. Although LSD or other classical hallucinogens have not directly caused overdose death, fatal accidents during LSD intoxication have occurred [Jaffe, 1985]. This danger is significant, particularly when these drugs are used recreationally in unsupervised settings.

Less serious but still very substantial injuries can occur in unusual ways. For example, severe and irreversible ocular damage has resulted from prolonged staring at the sun by individuals under the influence of LSD [Schatz & Mendelblatt, 1973 and Fuller, 1976].

The most significant dangers of psychedelics, however, appear to lie principally in their psychological effects. LSD can induce disturbances of experience, otherwise observed only in psychoses, such as alteration of cognitive functions, and depersonalization. Hallucinogens can catalyze the onset of psychosis or depression, which has sometimes led to suicide, and [Cohen, 1960] has estimated the incidence of LSD-related psychosis to be about 8 per 10,000 subjects. In another study, one case of psychosis was reported in a survey of 247 LSD users [McGlothlin & Arnold, 1971]. Fortunately, however, these drugs do not appear to produce illness de novo in otherwise emotionally healthy persons, but these problems seem to be precipitated in predisposed individuals.

Bad trips can usually be treated successfully by “talk-down” therapy and administration of benzodiazepines.

A somewhat later study by [Vardy & Kay, 1983] compared patients hospitalized for LSD psychosis with first-break schizophrenics. In most respects, the LSD psychotics were fundamentally similar to schizophrenics in genealogy, phenomenology, and course of illness. Their findings support a model of LSD psychosis as a drug-induced schizophreniform reaction in persons vulnerable to both substance abuse and psychosis.

Although these studies demonstrate a significant danger of LSD use, the number of such reports is very small relative to the numbers of persons who are believed to have self-administered LSD in recreational settings. A search of Medline in early 2003 for case reports of LSD-induced psychosis found only three reports in the previous 20 years.

The chemical structures of hallucinogens can be classified into two broad categories: (1) the tryptamines and (2) the phenethylamines. Within the tryptamines, however, one should probably include two subsets, the simple tryptamines such as DMT, 5-methoxy-DMT (5-MeO-DMT), and psilocybin, which possess considerable conformational flexibility, and the ergolines, relatively rigid analogues including LSD and a few very closely related compounds.

Our modern awareness of hallucinogens began on Friday, April 16, 1943, when Albert Hofmann, a natural products chemist with Sandoz Pharmaceuticals in Basel, Switzerland, experienced unusual mental effects following work with LSD-25, the diethylamide of lysergic acid [Hofmann, 1979 and Hofmann, 1994]. His suspicion that the effects he had experienced on the previous Friday were due to accidental exposure to a tiny unknown amount of LSD were confirmed three days later on April 19 by his deliberate oral ingestion of a solution containing 0.25 mg of LSD tartrate, a relatively large dose of this substance. On that occasion, the effects were very profound and left no doubt that the unusual intoxication of the previous Friday had been due to ingestion of LSD. No drug had been discovered up to that time that possessed such high potency, so the research management at Sandoz was initially skeptical of Dr. Hofmann's report.

Dosage forms available on the illicit market today are typically 0.04–0.06 mg, whereas in past years they were more often in the 0.10–0.20 mg range; in the late 1960s, tablets were often found that contained 0.25 mg or more.

In contrast to virtually every other class of CNS drug, where the action is usually predictable, the effects of hallucinogens are heavily dependent on the expectations of the user (“set”) and the environment (“setting”) in which the use takes place. Indeed, no clinician experienced with these substances would fail to consider set and setting as primary determinants of the experience. Thus, expectations and environments that would foster religious or spiritual experiences increase the probability of the drug producing such an effect. Conversely, use in a nonstructured, unwise, or recreational way can have unpredictable and even disastrous psychological consequences. Early clinical research, where LSD was expected to produce a model psychosis (recall the term “psychotomimetic”), was not designed to discover positive effects of these substances. Subjects given LSD in a clinical ward and counseled that they might experience schizophrenia-like symptoms indeed often did suffer panic, anxiety, negative effects, and feelings of insanity.

Dr. Stanislov Grof, who supervised more clinical LSD sessions than any other individual, wrote, “I consider LSD to be a powerful unspecific amplifier or catalyst of biochemical and physiological processes in the brain” [Grof, 1975]. These thoughts were echoed by [Barr et al., 1972] who stated, “…the phenomena induced by LSD (and probably by any similar drug) cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.”

This psychological state has often been referred to in the popular press as a “peak experience,” “transcendent,” or “mystical” experience and is a profoundly ASC. The user may feel transported to an alternate time or place, another dimension, or another plane of existence that may seem completely real. It is this experience that has been described as having parallels to the near death experience (NDE; [Grof & Grof, 1980]) and appears to have the most profound and long-lasting effects on the user. This state is of particular relevance to the definition of psychedelic and is emphasized in the term entheogen as noted earlier. Although this effect more often is achieved with high doses of hallucinogens, it can occur unpredictably and independently of the dose.

Surveys have shown that hallucinogen use is most likely to occur in the late teens and into the early 20s but does not usually continue after users reach their late 20s [Chilcoat & Schutz, 1996]. Chronic use of hallucinogens is unusual [Henderson, 1994 and Chilcoat & Schutz, 1996]. This use pattern is in distinct contrast to the compulsive abuse that is often seen with rewarding drugs such as amphetamines, cocaine, or the opiates, which produce craving.

When asked why they use hallucinogens, individuals who take doses with significant psychological effects often say that they use them for personal or spiritual development and increased understanding and self-discovery, that their use seems important to them, and that often they feel they gain important personal, religious, or philosophical insights. These sorts of perceptions might arise as a consequence of markedly affecting cognitive processing in the frontal cortex, the area of the brain where executive decisions and the assessment of significance occurs [Goldberg, 2001]. This reasoning may explain why humans take psychedelics, although they do not have rewarding effects in animal models: the nature of the reinforcement in humans is primarily cognitive, from perceptions of greater awareness, increased understanding, or profound insights that would have no counterpart in lower species with a less developed frontal cortex.

Following the isolation and identification of 5-HT, interest in its role as a neurotransmitter and its possible relevance to behavior was greatly stimulated by the virtually contemporaneous discovery of LSD and recognition that this potent psychoactive substance had the ability to interact with 5-HT systems.

Although at first it may be difficult to understand how the reversible acute receptor effects of hallucinogens could precipitate mental illness, there may be a small population of individuals particularly sensitive to gene expression changes in which the alterations could tip the balance toward the development of long-lasting psychiatric disorders. Persistent alterations in gene expression might also be important as an underlying component of HPPD (discussed earlier).

The clinical studies of DMT were also prompted by the fact that this substance is found naturally in mammalian brain and it might therefore be an endogenous psychotogen or psychosis-producing substance.

Of all the proposed medical indications for hallucinogens, one of the more interesting and well-documented uses, particularly for LSD, was in the treatment of terminal patients. [Kast & Collins, 1964] originally reported that LSD had an analgesic effect in dying patients that far outlasted its acute psychological effects. Their initial observation was that patients for whom this effect occurred seemed to have changed their attitudes toward death. Later studies led [Kast, 1966 and Kast, 1970] to the conclusion that LSD treatment resulted in improved psychological adjustment in dying patients, made them more responsive to their families and environments, and enhanced their ability to enjoy everyday life.

The original motivation for using a hallucinogen in the treatment of alcoholism was based on speculation that the effects of LSD might be similar to delirium tremens, the negative consequences of which might help to deter alcohol use. Unfortunately, the question of whether LSD treatment is effective for alcoholism was never convincingly answered.

Additional recent anecdotal studies have provided further evidence that use of hallucinogens may alleviate symptoms of OCD [Moreno & Delgado, 1997 and Delgado & Moreno, 1998].

In a third set of experiments, these investigators studied the ability of DMT to produce tolerance, a phenomenon that occurs with the hallucinogens LSD, mescaline, and psilocybin and discussed earlier in this review. Obviously, tolerance could not be produced by an endogenous hallucinogen because psychosis is a chronic and ongoing process. Four sequential doses of 0.3 mg/kg i.v. DMT fumarate were administered, separated at half-hour intervals. There was no evidence of tolerance to the effects of DMT and the authors note that this finding would be consistent with hypotheses that DMT could occur as an endogenous psychotogen [Strassman et al., 1996].

Although psilocybin had no effect on direct semantic priming, it did increase indirect semantic priming. Their data suggest that psilocybin leads to increased availability of remote associations, thereby bringing cognitive contents to mind that would normally remain inactivated.

The field of cognitive neuroscience has addressed the challenge of attempting to understand consciousness and how it arises in the brain. Surely, the most potent drugs known that alter consciousness, the hallucinogens, should play a role in that investigation.

It is now understood that there is no “seat” of consciousness and that consciousness is not a property of a single brain location but more likely arises as the result of dynamic interactions among widely distributed groups of neurons that integrate a very large number of sensory inputs and motor responses occurring in parallel. [Edelman, 1989] has emphasized that consciousness concerns the rapid integration of signals from a great variety of modalities and submodalities to create a unified, coherent scene or idea. He suggests that the number of possible conscious states is enormous.

The philosopher in each of us yearns for greater understanding of who we are and why we are here. Irrational fear of inquiries into the nature of consciousness and conscious experience must be put aside, and hallucinogens should be recognized for what they are: tools that will ultimately help us to understand ourselves. The answers lie in further research for somewhere in the complexity of the brain exists the source of answers to all questions about ourselves. In the coming years, we may look forward to substantial progress in understanding how hallucinogens affect brain function, how those changes alter perception and cognition, and ultimately whether these ancient healing substances have medical value and wisdom to impart to our modern age.

Enjoy