FUTURE OF STIMULANTS
As large an area of drug abuse reality and drug abuse potential, is the category that can be called the drugs
of stimulation. This is a most delicate classification, as, although there are a large number of recognized
stimulants (pharmacologically, sympathomimetic agents), all of the pharmaceutical houses have found a
number of alternate and less suggestive classifications for their products. These are drugs that can "clear
the nasal passages, suppress the appetite, or alleviate depression" but that are not in themselves
"stimulants." In truth, all of the chemicals to be considered here can be used and have been used to better
cope with social pressures and can thus be grouped together under the relatively unbiased term
"analeptics."
The best defined and most extensively studied examples of this form of central stimulants are chemicals
commonly referred to as amphetamines. The use of the plural term "amphetamines" is widespread, but it
is ambiguous. The term "amphetamine" is a single specific compound, 1-phenyl-2-aminopropane (12) and
the most restricted use of the term "amphetamines" applies to this chemical, either of its optical isomers,
and generally the N-methyl homolog methamphetamine (13) and its isomers. A more general use has come
into both legal and medical literature that considers that larger family that shares the common chemical
carbon skeleton of the amphetamine molecule and that can in the pharmacologic sense serve as a
substitute. A third usage, found in phrases such as "hallucinogenic amphetamines," refers to compounds
exhibiting the basic carbon skeleton of the amphetamine molecule, but that are so separate in their
pharmacologic expression that they can in no way be considered stimulants. They are discussed in the
Hallucinogen section below.
Amphetamine, as the racemate and as its optical isomers, and the monomethyl homolog
methamphetamine, are, without question, the most widely prescribed, used, and abused stimulants within
this family. The awareness of this abuse is tacitly recognized by the transfer of all forms of these two
chemicals from Schedule III to Schedule II in 1971 41. The extent of this abuse potential is apparent from the
letter sent at that time42 to the registered pharmacists in the country, that listed by name (in an admittedly
incomplete compilation) some 102 commercial forms of prescribable drugs containing only amphetamine
or methamphetamine, and 291 additional drug forms that contain one or the other of these in combination
with additional active ingredients. At least 393 separate brand names were at that time being produced by
at least 204 independent manufacturers. There is no question that abuse of these two fundamental
compounds will persist well into the future. They are easily synthesized, as attested to by their costs as
chemicals (d-amphetamine, $25.35/100 gm, and d-methamphetamine as desoxyephedrine hydrochloride,
$13.65/100 gm)43. This documents a foundation cost of perhaps 2 cents per dosage unit and would seem to
assure the continued availability of the drugs, at least through illicit sources. The widely recognized
precursor to both drugs is phenylacetone, which although being noted at all supply sources as a chemical
potentially employed in the synthesis of controlled substances, is itself quite inexpensive (less than
$10.00/lb) and is not by law a controlled chemical.
The broader use of the term "amphetamines," as defined above, embraces a large number of prescription
stimulants, which have been justified by their manufacturers as being valuable for a broad range of
deficiencies. The two general categories of action include use as antidepressants that brighten the mood
and improve performance, and use as anorexogenics in case of obesity. It has been said that the effects of
the appetite suppressants are actually "Those of central stimulation which may distract the patient from
eating and encouraging dietary cooperation" 44. Therefore, these two latter pharmacologic families actually
become one. Additional clinical applications of these materials, such as the treatment of narcolepsy, the
counteraction of other medications producing drowsiness, even the paradoxical employment in
preadolescent behavior problems, apparently all depend principally upon their actions as a central
stimulant. It is just this activity that provides their abuse reality and potential.
The future of drug abuse in the amphetamine-like stimulant group, and the drugs to be abused in the
future, can be projected with some confidence from the development of the present problem. The earlier
discussions of the narcotic analgesics indicate that there has been a major synthetic and clinical effort made
to develop drugs that would maintain virtue (analgesia) while minimizing undesirable side effects
(euphoria, physiologic dependence liability). An added impetus to this diversity has been the economic
requirements associated with patents and proprietory rights of the developing research laboratories. The
same arguments apply to the stimulants. The search continues for products that fill clinical needs (anorexia,
antidepression), minimize the potential for abuse (excitability, psychologic dependence liability), and are
proprietary. It seems axiomatic that the hoped-for properties are always accompanied by the hoped-
against properties. The degree to which a compound can provide relief from depression through
stimulation is the degree to which the compound can be abused either through overuse or through chronic
use.
The original amphetamine stimulants, amphetamine and methamphetamine, have been displaced by a
number of chemically related drugs that have the phenylisopropylamine skeleton and that appear to
varying extents to duplicate the action of amphetamine. Rather than establishing a class regulation (as has
been done in Great Britain with the Drugs Act, 1964 45), the procedure followed has been to treat each drug
individually and to move it from uncontrolled, to prescriptional availability, to appropriate scheduling in the
Controlled Drugs structure as abuse reality became apparent. Thus amphetamine, used clinically since
193546, and methamphetamine received extraordinarily broad abuse both in the United States and abroad
after World War II; they are now Schedule II drugs. Of the many substitutes for amphetamine that were
prepared and evaluated in the post-war era, both methylphenidate [Ritalin, 14] and phenmetrazine
[Preludin, 15] have been documented with sufficient misuse to warrant scheduling (to Schedule II,
November 1971). As was mentioned in the substituted piperidine portion in the narcotics section, the
concept of the reversed ester (the replacement of a [-COOR] group with the isometric [-OCOR] group with a
retention of pharmacologic style of activity) also applies to the Ritalin molecule.
The reversed ester of 14 is levophacetoperane, which is similar in action to Attalin (stimulant and
antidepressant) and only slightly less potent in humans 47. This latter variant is relatively unexplored and of
course legally unrecognized.
There are many additional amphetamine analogs that are commercially available upon prescription as
antidepressants or anorexogenics, and that might well have the capability of being abused in the same
manner as have been the others, but for which there have been as yet no indications of abuse. These
include, among others, benzphetamine, phenteramine, phendimetrazine, diethylpropion, and a host of
others still in the investigational stages. In the future, it is axiomatic that some of these will be misused, and
so might become our future drugs of abuse.
A point of metabolic interest may be mentioned here, as it may serve as a clue to another class of
potentially abusable stimulants. A frequently asked question is: How can one determine the extent of
abuse of a specific drug? In cases of rampant and conspicuous abuse, there are many indications such as
the sources of the drug, the overwriting of prescriptions, the thefts from druggists' suppliers, and the
broadcast availability of illegally purchasable supplies on the street. But this would imply an already
established abuse. To anticipate an abuse problem, it is necessary to anticipate these signs. And one of the
potentially powerful tools for such previews is the unusual fact that, in humans, both amphetamine and the
homolog methamphetamine are excreted in the urine to a large measure unmetabolized. This has been
used as a device for screening the population for indications of the extent of amphetamine abuse.
However, there are two completely unrelated classes of stimulants that are only superficially related to
amphetamine chemically, but that are unusual in that they are cleaved through their normal metabolism
into either amphetamine or methamphetamine. These are easily synthesized families and they appear to
serve as substitutes for amphetamine in the call for stimulatory properties, and yet their abuse, as noted by
the development of recognizable urinary metabolites, would be assigned to amphetamine.
The first of these is illustrated by fenethylline [Captagon, 16], which was first prepared some 10 years ago,
and is now easily available in Europe as a nonprescription analeptic agent. It is apparently cleaved
metabolically in humans into theophylline (a weak stimulant closely related to caffeine) and amphetamine,
and it has been shown that the action of the parent drug may be correlated to the production of
amphetamine in vivo48. If this form of metabolic cleavage proves to be general, then any of a large number
of stimulants can masquerade as covalently complexed materials that are physiologically available only
through metabolic conversion.
A second type of abuse drug is suggested by the structure of the material Aponeuron [AN-1, 17], which is
prepared by the coalescence of amphetamine, benezaldehyde, and cyanide, and which apparently releases
the contained amphetamine following introduction into the body 49,50. These chemical extensions are
probably documentable in their abuse only through the appearance of amphetamine in analyzed urine
samples. It will be of scientific as well as social interest to see if similar chemical manipulations (the
conversion of a recognized and scheduled drug into a legally innocuous analog which will regenerate the
original drug in vivo) might be extended to include the many structurally similar stimulants and
hallucinogens.
Close relatives to these centrally active, sympathomimetic, amphetamine-like compounds are a growing
number of simple bases employed as decongestants and agents of relief in asthma conditions. These are
chemicals pharmacologically related to ephedrine (18) and largely imitate it in their capability in dilating the
bronchi, but all have shown some degree of potential for central stimulation.
Ephedrine itself is a drug of antiquity, being the active ingredient of plant extracts of Catha Edulis51. In
recent years a number of synthetic analogs have been introduced into clinical practice with the hopes that
the index between decongestion and stimulation would be improved to minimize abuse potential. A
number of these are currently employed as vasoconstrictors and pressor agents [Neosynephrine
(phenylephrine); metaraminol; Propadrine (phenylpropanolamine); mephentermine (Wyamine)].
Documentation for the abuse potential within this family is provided by a report of mephentermine-
induced psychoses52 that were clinically identical to examples seen in cases of amphetamine misuse.
Hydrogenation of the aromatic ring to produce the totally aliphatic analogs, both alicyclic and open chain,
of amphetamine and methamphetamine has been a device used to exclude central action while
maintaining only the desired bronchial and vascular effects of ephedrine. However, there, have been
reports of misuse and abuse, leading to druginduced psychotic states involving these materials [ 53]. Dozens
of pharmacologically related sympathomimetics are currently being investigated clinically, and there is little
question that many of them will have the potential for stimulatory abuse.
Another class of mild central stimulants that are reportedly without tolerance-building capabilities or
antidepressant properties are compounds based upon the structure of Pipradrol (diphenyl-2-
piperadylcarbinol, 19).
There seems to be a valid generalization that if the piperidine ring is alpha-attached to the benzylic carbon
(with or without the benzylic hydroxyl group) the compound has sympathomimetic properties. It is, under
these circumstances, a substituted ephedrine or amphetamine. Some of the clinically explored analogs are
highly potent as stimulants. An analog studied by the Schering group (Sch-5472, 20) is effective in
counteracting fatigue in humans at submilligram levels 54. If the piperidine ring (often as a piperazine ring) is
attached through the nitrogen atom, the resulting compounds appear to be effective agents in relieving
motion sickness (vide cyclizine, Meclizine), although example of this positional isomer are known to be
stimulants (see Su-19789B, 2-[p-methoxy-alpha-(1-piperidyl)-benzyl]-cyclohexanol55). Reports of abuse of
such antihistamine motion-sickness drugs have been reported 56,57 in intentional attempts to produce drug-
induced sensory changes. If the attachment is at the gamma-position of the piperidine ring, one can find
antagonist actions to these stimulants. It is only with this first, the alpha-substituted piperidine group, that
structural manipulation seems likely to lead to new and more potent drugs.
A recently developed and commercially successful class of psychotropic drugs are the tricyclic
antidepressants related to imipramine. This varied group of drugs seem to be stimulants in cases of
pathologic depression (as in the depressed phase of manic depressives) but appear to have little effect in
normals. However, their potential for abuse is well established, since they have clearly defined stimulatory
action in cases of chronic usage 58 and have been encountered increasingly frequently in post-mortem
examinations of accidental deaths due to possible drug overdosages 59. This class of drugs is currently
available only by prescription. They are reasonably sophisticated in their syntheses, and should provide
little incentive to the illicit chemist.
This is not true in the case of another well-known stimulant, cocaine (21). There appears to be a recent
increase in popularity and usage of the drug, although much of that which is claimed to be cocaine is
extensively diluted with procaine 60 and methedrine61. Classically the drug has been obtained from the Coca
tree, which is native to South America. However, the growing popularity of the drug and the extremely high
price demanded in illicit trade have attracted the attention of the underground synthetic chemists, and
there is indeed evidence that the drug is currently being synthesized 62. It is true that cocaine of legitimate
commerce is already semisynthetic. The crude coca alkaloids are saponified to the compound ecgonine,
which can be easily reconstituted to pure cocaine by benzoylation and esterification with methyl alcohol.
The total synthesis of ecgonine (and thus of cocaine) is more tedious. However, the procedures have been
in the chemical literature for decades63 and employ easily available starting materials.
It seems reasonable to anticipate that as more synthetic attention is directed toward this family of
stimulants, more easily prepared analogs will be seriously investigated as cocaine substitutes. In the case of
cocaine itself, it is known that variations of the carbomethoxy group leads to no dimunition of either
anaesthetic or stimulant properties, although most substitution changes on the benzoic acid moiety lessen
activity. A similar but chemically more easily accessable molecule is represented by benzoyl-pseudotropine
(22), also a component of Erythroxylon coca64 and also known to be centrally active. Care must be shown in
classifying these compounds. The pseudotropeines are esters with configuration shown for 22. These only
are the stimulants and anaesthetics. The reversed stereoconfiguration of the eater group (the OCOR on the
side of the piperidine ring opposite the N-CHa rather than on the same side) leads to the normal tropine
series as found in the natural alkaloid atropine and in several clinically valuable synthetic drugs such as
benztropin. This latter family is largely parasympatholytic rather than sympathomimetic, and its future
abuse potential is discussed in the section on hallucinogens.
Another, yet simpler, series of potential cocaine substitutes might be found in the open-chain piperidine
analogs such as 23. A number of these extremely easily synthesized esters have been employed in imitation
of cocaine as contact anaesthetic agents, or in imitation of atropine as mydriatic agents, but there is little
information at hand concerning their abuse potential using the parenteral routes employed with cocaine.
Stimulants: 2050
Stimulants are presumably the most dangerous classification of drugs. Drugs belonging to this group include
cocaine, crack (a stronger, smoke able variety of cocaine), ecstasy, amphetamines, and methamphetamines. This
classification of drug is most likely the most dangerous form as it causes severe mental impairment among many
other horrible after effects.
Methamphetamines (commonly known on the street as meth, crystal meth, ice, crank, crypto, or glass; ice being
the most dangerous and smokeable form) are extremely threatening and cause a plethora of unwanted emotions
and harm to one's body. Unwanted side effects of meth are extremely dangerous for the user's health and can
cause serious life-threatening problems with the lungs, heart, brain, and basically any other vital organs.
Nocturnotine: 2075
Nocturnotine, otherwise commonly known as zenith, BS (Blissful Suicide), 122 (chemical element number 122,
though it is not actually an element), snowy owl, frost, night vision, and nocturnal, is arguably the most dangerous
drug known to exist. In the year 2059, approximately a dozen or so scientists grouped together and artificially
constructed a chemical known as neuronocturnamine. They did not happen upon its drug-like effects until several
years thereafter in 2063; however, once they did so, they experimented with it and days later, three of the
scientists died, earning nocturnotine the rightful name of The BS Drug (Blissful Suicide). Since then, nocturnotine
has been used by suicidally depressed teenagers to earn a seventy-two to eighty-four hour "high" before they fall
into an infinite coma.
Processing The Drug
In order for the stimulating ingredient of nocturnotine to enter the bloodstream and brain, the plant must first be
dried and then crushed into microscopic particles. After this, the powder can be snorted or dissovled in water and
injected; however, for the most peaceful effects before the user's suicide, the powder must be compacted into a
single snow-white pill and swallowed.
The High Of Nocturnotine
Though nocturnotine is the most dangerous drug known to exist, it is said to be the most peaceful and exhilarating
high. It is said to have a complete weightless feeling, possibly even antigravity-like weigtlessness; all pain is
relieved from your body. Additionally, the user will experience slight paralysis in the fingers and arms and obtain
numerous out-of-body experiences. Peaceful deja vu will suffocate the user and all senses (except for visionary)
will be blocked from the mind as nocturnotine's active ingredient floods the neurotransmitters in the brain. After
this has concluded, the user's vision will slowly fade to black over the next hour, at which point, the user has
drifted into death.
Though the main effect of nocturnotine is death, one might have a less blissful experience. If the user is worried
(which most are), the drug will react entirely different. Within eighty-four hours of consumption, the user's ocular
blood vessels will constrict so heavily that they burst (causing red out), their stomach lining will dissintegrate
leaving the abdominal acid to leak over the rest of the body (causing excrutiating pain), and numerous aneurisms
in the brain will almost instantly kill them. All the while, the user feels no euphoria to counteract the extreme pain.
