Neurobiology of Psychoactives

Author: Fuzz



          Psychoactive substances are compounds – either natural or manufactured – that affect the balance of one or more neurotransmitters in the brain.

            MDMA: (3,4-methylenedioxy-methamphetamine: ‘Ecstasy’) is a manufactured psychoactive that was first synthesized by the pharmaceutical company Merck in 1912. (1) Merck’s researchers had no idea of MDMA’s psychoactive properties and listed it only as a chemical intermediate “for products of potential pharmaceutical value”. Knowledge of its effects on the mind did not become widespread until the late 1970’s. It was first used by humans outside of the lab in the early 1980’s. It began mass production in 1983 and was available via phone call and even in convenience stores in some locations until the DEA succeeded in having it made schedule I in 1985. (1)

            The substance will be referred to here as MDMA, rather than by its street name. Although the two were originally synonymous, MDMA now only truly refers to one possible ingredient in ‘Ecstasy’ since the production quality has deteriorated so greatly.

            When ingested by humans, MDMA “triggers intense emotional release beyond the bounds of everyday experience”. (1) Users report feeling at peace with themselves and with the world. Anger, fear, and other negative feelings completely disappear. The MDMA experience is possibly the highest known state of mind that human beings are capable of achieving. This wonderful experience is brought about on a chemical level by the compound’s ability to both increase the synaptic release and inhibit the reuptake of serotonin (the neurotransmitter associated with feelings of well-being and satisfaction) in the brain. (1) However, there are many drugs that affect the serotonin balance similarly. Where MDMA differs is in its incredible ability to completely reverse the direction of the body’s serotonin reuptake pumps. The serotonin reuptake centers are normally responsible for capturing and destroying the neurotransmitter after it has circulated through the brain. MDMA modifies the protein responsible for transporting the serotonin into these centers, reversing the direction in which it is carried. (1) This action in combination with the notably increased levels of new serotonin being produced and released into the neural synapses account for the indescribably powerful feelings of peace and well-being that users experience. As a secondary action, MDMA causes an increased release of dopamine (the neurotransmitter associated with feelings of euphoria). This increase certainly does add to the exuberance of the experience, but its effects are not nearly as unique or special as those that result from the unparalleled levels of serotonin already flooding the synapses by the time the dopamine release kicks in. These secondary effects commonly last for ninety minutes to two hours, while the effects of the serotonin increase usually last for three to four hours.

            Animal studies have shown that chronic abuse of MDMA can imbalance serotonin levels, impair memory, and cause brain damage. (2) There are, however, steps that can be taken to drastically reduce these negative side effects in humans. The biggest danger of MDMA use today comes from the fact that its schedule I status has limited its production to underground labs. As a result, the product tends to be inconsistent and is quite often laced with substances that can be harmful or even fatal to the human body. (2) Through testing of many ecstasy tablets recently sold at raves, it was established that only one third of the samples even contained genuine MDMA. (3)

            Although MDMA use, especially regular use over a prolonged period of time, can result in damage to the brain’s serotonin terminals, these negative side-effects can largely be protected against. The MAOI l-deprenyl blocks the increase of harmful malondialdehyde formation in the brain that normally follows MDMA use. L-deprenyl also protects against the reduced levels of tryptophan hydroxylase activity that normally result. (6) In short, the negative long-term effects of MDMA use can largely be avoided by ingesting a small dose of l-deprenyl about half an hour prior to consumption. The downside to co-administration of ‘Ecstasy’ and l-deprenyl stems mainly from the fact that most ‘Ecstasy’ tablets contain liberal amounts of cutting agents such as amphetamine, a substance which should never be combined with MAOIs. An MAOI is a substance that inhibits the production of an enzyme or enzymes that are commonly used in the process of breaking down serotonin in the reuptake centers of the brain. As a result, MAOIs commonly raise the level of neural serotonin by inhibiting its destruction. Even the practice of regularly combining l-deprenyl with large quantities of pure MDMA (the amounts sometimes ingested at raves) could be potentially damaging to some individuals (depending on natural body chemistry) due to the risk of the excess serotonin crossing into the bloodstream, which has many negative long-term effects and can be fatal in serious cases. (1) Although l-deprenyl does not appear to be a perfect long-term solution to the problem presented by the neurotoxicity of MDMA, it certainly does benefit the occasional user.

            Perhaps future research could be targeted at the use of MDMA as an antidepressant, as it certainly exhibits the most profound and altruistic mood-enhancing properties of any known substance. A combination of a small amount of MDMA (perhaps 20MG or less) and an even smaller amount of l-deprenyl (3-5MG or less) could be packaged in a sustained-release form for administration once or twice daily. The significantly smaller than street dosage of MDMA could easily reduce the risks associated with the combined MAO inhibiting properties of the two substances into a viably safe range. The sustained release mechanism would in theory provide for a full-time elevation in the user’s mood, and subsequently a heightened quality of life. The mixture could also potentially be augmented with a bit of 5-hydroxy-triptophan (the direct metabolic precursor of serotonin) to assist in preventing serotonin depletion, as it can be used for after coming down from an ‘Ecstasy’ high. Such an addition would also have the potential to be dangerous for regular use, as it could add to the risk of excess serotonin crossing into the bloodstream. Whether or not the 5HTP addition would be beneficial is not clear. In any case, some tweaking of the proportions between substances would undoubtedly be required. Such research could only add to the already established list of medical uses for MDMA, which includes the unparalleled results it rendered when used in therapy (1) before it was made Schedule I. This contrasts sharply with the government’s classification of MDMA as a substance that is highly dangerous and holds no possible legitimate medical value.

            MDMA does have legitimate uses in certain situations. It can induce an unparalleled state of magically beautiful consciousness, which alone is evidence that it is not a useless and dangerous substance as the US government would have us believe. Still, it is far from an ideal long-term solution for life-enhancement because of its neurotoxic properties, tolerance effect, and the rebound effect that commonly makes MDMA users feel low (1) a few days after their magical experience.

            A safe and sustainable compound with effects similar to MDMA would prove to be the holy grail of empathogen research. However, a compound structurally similar to MDMA engineered to achieve effects through similar neurological stimulation is not likely to provide safe and sustainable effects. Prolonged stimulation of the receptors through which MDMA’s magical effects are generated typically results in desensitization of the receptors and down-regulation of the neurotransmitters that allow us to feel happy. Only a homeostatic approach consisting of re-regulating the central nervous system to significantly raise the emotional baseline without over stimulating any part of the brain or body could prove to be effective in the long-term. (1) Such a solution will not come about through means similar to MDMA’s reversal of the serotonin reuptake pump.

            Antidepressants: Today’s most common antidepressants are of the SSRI (selective serotonin reuptake inhibitor) and MAOI (monoamine oxidase inhibitor) families. Although these compounds are commonly thought of as modern medicine, only a small portion of their users find them to be satisfactorily effective. (4)

Opioids: The most powerful antidepressants in existence today may still be of the opioid family. Opioids have a history of use dating back almost as far as the history of Man. Fossilized remains suggest that the opium poppy was used by Neanderthal Man over thirty thousand years ago. (9) Opium has been touted as God’s divine gift to Man, with such opinions being commonly expressed in historically significant literature including Homer’s “The Odyssey”. (9) Although the use of opium and more recently the use of opium derivatives have been common and, in many cases, indisputably beneficial throughout recorded history, habitual opioid use has been conditioned by current-day society to bring about mental images of “stupor and mindless oblivion”. Such an opinion seems at least somewhat backwards since the word intensify was first coined to describe the effects of opium on consciousness. (9)

Although such use is officially taboo in today’s medical field, opioids have a unique and powerful efficacy in banishing psychological pain. (4) Their capacity for almost instant relief from mental distress contrasts greatly with the weak and painfully delayed improvements in mood that are sometimes achieved through use of today’s legal antidepressants. However, that leads directly to the down side of opioid use. Along with their illegal status, even today’s more advanced opioids (such as hydrocodone) have two primary flaws. If used regularly for any extended period of time, they are highly addictive. Also, there is the issue of the tolerance effect that chronic users experience. As with many drugs, the efficacy of opioids tends to fade as a result of prolonged use.

            Although today’s opioids are generally not considered an adequate long term remedy for depression, the future may hold the development of highly selective designer opioids intended to correct the genetic imperfections and dysfunctions of our natural opioid regulation systems. (4) Such an endeavor would be far more worthwhile and responsible than focusing our society’s energy on persecuting users of today’s flawed narcotics. “For if there were nothing fundamentally wrong with our default-state of consciousness, then we wouldn't now try so hard to change it.” (4)

            GHB: Another arguably promising compound is GHB (gamma-hydroxybutyrate). Like MDMA, GHB has been demonized by the American mass-media and made Schedule I by the DEA. GHB is remarkable in that can effectively suppress depressive and suicidal thoughts, often in less than 30 minutes. (7) Most compounds commonly thought of as antidepressants by modern medicine are really thymoanaesthetics, compounds that blunt our feelings like an anesthetic for the mind. These compounds blunt rewarding positive emotions as well as depressing negative ones. GHB is the first molecule ever discovered that truly stimulates sociability, which is valuable since depression is largely a defect in sociability. (7) One may feel intense dysphoria and suicidal ideation, thinking that a cure for such feelings is not possible until ingesting GHB. Afterwards, one will realize how beautiful life is and that it deserves to be lived and enjoyed. GHB strongly stimulates the desire to remain alive despite unfavorable circumstances, a property not directly exhibited by any modern conventional antidepressants. It is the fastest acting antidepressant known and despite the enhanced mood it quickly renders, is not addictive physically or psychologically. It is a self-limiting medication since users will feel compelled to discontinue use once they feel emotionally satisfied. (7) This self-limiting mechanism likely comes about directly or indirectly through GHB’s ability to satisfyingly stimulate oxytocin neurotransmission in the brain.

            An overdose of GHB will promptly put the user into a long and deep trance-like sleep. This property along with the side effects of fatigue and anxiety that can result from longer-than-necessary use has contributed to this molecule’s demonization in the American culture. GHB commonly makes users feel very good, which seems to be an automatic red flag to prohibitionist America. The same ability for mood-enhancement contributes to the view of GHB as a valuable medicine by the more open-minded and probably more intelligent science of Europe.

            Although there are many psychoactive substances available that alter one’s state of mind, none appear to be perfect or ideal. MDMA is promising with its ability to induce a loving, empathic, and satisfactory mental state, although its neurotoxicity makes it imperfect. Opioids like hydrocodone and codeine banish psychological pain and worries, leaving the user in a blissful state of consciousness, but regular use is made imperfect because of the tolerance an individual will build up, along with the fact that opioids become addictive if used in such a manner. GHB is not addictive and functions marvelously as an antidepressant. However, it is still not a perfect solution for dealing with the pain of existence, if only due to its illegal status. GHB, along with all other promising drugs discussed here, is listed by the US DEA as a controlled substance. GHB and MDMA are Schedule I drugs, making them illegal to possess in any amounts or forms (this also technically makes it a felony to posses beef since it contains GHB). Hydrocodone and codeine are Schedule II drugs, which are also illegal to possess in any amounts or forms, with the exception of prescriptions.

Psychoactive substances may be imperfect, but so is our default state of consciousness. Development of better substances or methods to aid the human organism in attaining a more pleasant mood would be far more productive than taking up a prohibitionist attitude as a society, demonizing any chemical that makes us feel good. Whether or not the “war on drugs” is a responsible endeavor on which to spend our tax dollars, our society has evolved for us a state of being that is much less pleasant than we deserve. With such a large portion of the American population using one illegal drug or another to alter consciousness, it seems apparent that something is horribly inadequate in the way we live. Just because so many people have the desire to use a psychoactive substance for something other than pure curiosity-driven experimentation or exploration, it is obvious that something is wrong, something that the “war on drugs” is doing nothing to alleviate.