The response to my talk with the same title after the serotonin club dinner during the 1998 society for neuroscience meeting was very well received, and I was asked to provide a brief summary of the talk for the club newsletter. But, how does one condense a 30-minute talk with nearly as many slides into one or two pages? It's clearly impossible. Yet, I believe my message was important enough that it's worth repeating at least a few of the things I said. Here goes...

Psychedelics (a.k.a. hallucinogens) played a profound role in changing our society, for better or for worse. Referring to a work of art, a picture, or an article of clothing as "psychedelic" brings to mind for almost anyone images of wild colors, a high degree of "bizarreness," or extraordinary properties. Many television and movie images, animations, special effects, clothing styles, as well as commonplace phrases ("what a bummer" "far out" "that's a real trip") clearly had their roots in the psychedelic culture of the sixties. There are no doubt multitudes of ways that psychedelics changed our culture that we could never even begin to identify or measure.

I think today, however, that psychedelic agents have been trivialized, especially if all we can remember of them involves bright colors and acid rock. Jaffe, in the 7th and 8th editions of Goodman and Gilman, defined psychedelics as agents that produce changes in thought and perception normally experienced only during dreaming or at times of religious exultation. All of us should take a few minutes to think about the implications of that definition. In that context, psychedelics take on significance far beyond colors and music. I think one could reasonably argue that a significant percentage of serotonin researchers today were motivated to study serotonin systems as a direct consequence of some aspect of psychedelic drugs. Many older scientists perhaps experimented with these drugs in the 1960s, or were subjects in clinical experiments. Others were intrigued by the rich literature and first person reports by users of drugs like LSD. Perhaps others were curious as to why these drugs were so popular, and entered the field from a drug abuse perspective. From whatever direction, however, interest in psychedelics promoted much serotonin research. Certainly, there can be no doubt whatsoever that the early recognition of the similarity between the molecular structures of LSD and serotonin was a powerful motivation to believe that serotonin was an extremely important neurochemical.

Psychedelics didn't just spring upon us in the 1960s out of nowhere. Their use goes far back into antiquity, and one could easily argue that these were the very first psychoactive drugs, discovered by ancient hunter-gatherer societies, as they searched for edible foodstuffs. We do know that there were more than a thousand hymns in the ancient Vedic literature, written in praise of SOMA a psychedelic drug that gave visions of paradise, whose true identity may be lost in antiquity. We know that for more than 2,000 years, in the village of Eleusis in ancient Greece, any adult who had not been convicted of murder was privileged to participate in a once-a-year ceremony that involved the use of a psychedelic concoction known as kykeon. We know very little about this mysterious ceremony, because to speak of it brought the punishment of death. It was such an important event however, that virtually any important Greek that one could name probably had been a participant. Aristides the Rhetor in the 2nd century A.D. reported, "...of all the divine things that exist among men, it is both the most awesome and the most luminous..." and speaks later about "ineffable visions" that had been seen during the ceremony by many generations.

Somewhat more recently, we find the use of Teonanacatl ("god's flesh") among the Aztecs, which gave visions of paradise and was used by the shaman for healing. In the American southwest, the use of peyotl by the indigenous peoples for centuries has been incorporated as a sacrament into services of the Native American Church. In the Amazon valley of South America, ayahuasca is still used by many of the indigenous peoples, and is considered also as a most holy and religious sacrament.

All of these uses seem to be consistent with Jaffe's definition, and certainly indicate that psychedelic substances can produce profound changes in consciousness. What are the implications for modern man? Do we recognize any other drug class that has such profound effects on consciousness where research on the class is virtually nonexistent? Even heroin and cocaine, two of the worst scourges of the drug abuse scene receive attention in numerous research laboratories.

What has happened to interest in psychedelics? It must be a sociological phenomenon, because from a research point of view it's hard to explain how such incredibly interesting drugs can be so widely neglected. I suppose another possibility is that people have bought into the notion that these drugs have nothing further to tell us. After all, "everyone knows" that psychedelics were found to be completely worthless in any kind of therapeutic context.

Well, that view simply isn't true. Very few people realize that the use of LSD in terminal patients, for reduction of pain and improvement in the quality of life was well documented and statistically proven to be efficacious. The major problem is that most clinical research in the 1950s and 1960s was seriously flawed. To begin with, the paradigm that was ultimately found to be most effective was not employed in most studies. Low doses of psychedelics, employed as adjuncts to psychotherapy, were rarely effective, at least as employed in most early clinical designs. On the other hand, high doses, which often provoked overwhelming experiences akin to what are known today as "near death experiences" often brought dramatic improvement, just as it is recognized today that an actual near death experience often produces dramatic personality change in the person who experiences one.

I do not believe that the evidence shows psychedelics to be useless, rather I believe that the early experimental paradigms were inappropriate, and that there was an inability to separate the signal from the noise. If one reads the first person accounts of people who were healed of various emotional disorders through the use of psychedelics, and whose lives were dramatically improved, it is impossible to believe there is nothing at all important to find.

What are some of the therapeutic possibilities? At least some evidence exists for utility of psychedelics in all of the following conditions: alcohol and substance abuse, obsessive-compulsive disorder, pain and depression in terminal illness, and post traumatic stress disorder. Rehabilitation of social deviants and treatment of violent behavior remain tantalizing possibilities. Imagine the economic benefit to society if truly effective treatments would result for any of these!

In a purely science context, one could envision studies of dreaming, cognitive processes, memory, and personality structure and development, among others. These are all exciting and challenging areas for research, yet they remain unexplored today. What is required is a reinvestigation, using modern methods, and the best experimental paradigms. If only a very small percentage of the anecdotal personal accounts of dramatic healing represents the true potential of psychedelics, then we, the community of scientists, are missing out on something fundamentally very important by continuing to ignore these drugs.

Three families of serotonin receptors (5-HT₄, 5-HT₆ and 5-HT₇) couple to G proteins of the G_s type to activate adenylate cyclase and increase intracellular cAMP. The traditional view has been that cAMP signals the downstream effects of these receptors by activating protein kinase A (PKA). Recent studies, however have uncovered two additional mechanisms by which cAMP can regulate cell function independently of PKA.

Direct regulation of ion channels by cAMP. The first hint that cyclic nucleotides could elicit physiological responses independently of protein kinases came from the study of a class of nonselective cation channels involved in visual and olfactory sensory transduction. Early physiological studies had shown that cyclic nucleotides directly gated the opening of these channels (Fesenko et al., 1985). With the cloning of a family of genes encoding for these proteins, it became evident that they contained an intracellular cyclic nucleotide binding domain that gated the opening of the channels upon binding cAMP or cGMP (reviewed by Zagotta and Seigelbaum, Annu. Rev. Neurosci. 19:235-263, 1996). These channels are now know as CNG (cyclic nucleotide gated) channels. Interestingly, these channels are expressed not only in primary sensory cells but also in some central neurons (reviewed by Zufall et al., Curr. Opinions. in Neurobiol. 7:404-412, 1997). This observation hinted at a possible role for CNG channels in mediating central responses to cAMP and hence Gs coupled receptors.

Parallel work on I_h (aka I_f or I_q), the pacemaker current in the heart, had suggested that this current also was regulated by cAMP through a mechanism independent of PKA (DiFrancesco and Tortora, 1991). This current is also expressed in central neurons where it is an important regulator of membrane excitability. Three recent papers report the cloning of five separate genes coding for the channels responsible for this current (Gauss et al., 1998, Ludwig et al., 1998, Santoro et al., 1998). As anticipated by the physiology, all of these genes code for subunits containing putative cyclic nucleotide binding domains. Interestingly, some (but not all) of these genes code for channels that are highly sensitive to cAMP ( Santoro et al., 1998). These findings might be relevant for understanding serotonin physiology. For example several studies have reported serotonin regulation of I_h mediated by cAMP and involving an as yet unidentified (orphan?) receptor. Thus it is possible that one or more 5-HT receptors might regulate some of these cloned channels.

Direct activation by cAMP of a guanine-nucleotide-exchange factor
Rap1 is a G protein of the Ras family that is activated by cAMP. G proteins of the Ras are activated by guanine nucleotide exchange factors (GEF) that accelerate the formation of the active (GTP bound) form of the of the protein. Rooij et al (1998) recently showed that cAMP activated Rap1 through a mechanism independent of PKA. A database search for proteins homologous to known GEFs and possessing a cyclic nucleotide binding domain led to the cloning of Epac (Exchange protein directly activated by cAMP). Cyclic AMP binds Epac through a motif homologous to that seen in the regulatory subunits of PKA and CNG channels and causes Epac to activate Rap1. Thus Epac represents a new effector for cAMP, one capable of activating downstream small G proteins. Perhaps not surprisingly, Epac seems abundantly expressed in the brain. This elegant study identifies a third target for direct regulation by cAMP.

The results outline above indicate unsuspected complexity in the signaling by cAMP of cellular responses. It will be interesting to discover whether and how different Gs coupled receptors couple to these different signaling cascades and effectors.

Contributed by Rodrigo Andrade, December 1998.