age of 18. APHA for many years has sought to draw attention to the need for such controls on exempt narcotics. The abuse of such substances has swelled enormously in the past several years and has been the subject of much discussion by the press and public. Pharmacists are capable of controlling the sales of such preparations and, in our opinion, should be held to this basic professional responsibility. Already, some States have put these substances on a prescription-only basis in the face of their own abuse problem. We are strongly opposed to this approach for several reasons. Legitimate access to these preparations is too severely restricted. Also, the requirement of a prescription order necessarily increases the cost of such preparations by substantial amounts and subjects already overworked physicians to greatly increased prescribing demands. What we have had to say about this bill has been offered with seriously mixed emotions. There is a drug abuse problem in this country, but there is also a health care crisis. We have reached the point where many persons financially able to pay for health care services are unable to obtain them. Legislation enacted to curb drug abuse must not compound the problems of delivering needed health care. For that reason, we have emphasized, and now reemphasize, the necessity for striking a legislative balance between adequate control measures and reasonable access to medically needed drugs. As presently drafted, H.R. 13743 would, in our view, fail in this objective. In this situation, we are left no choice but to oppose this legislation. This is not purely negative opposition, however. Our position is taken in the belief that, through cooperative efforts, sound legislation can be developed which will be welcomed and supported by those concerned with both law enforcement and health care. We stand ready to make the fullest contribution we are able to such cooperative efforts. Thank you, Mr. Chairman. (The material attached to Dr. Apple's statement follows:) CHANGES SUGGESTED IN H.R. 13743, THE CONTROLLED DEPRESSANT AND STIMULANT DRUGS ACT OF 1969 BY THE AMERICAN PHARMACEUTICAL ASSOCIATION Section 102. (b) "'Administer' means to deliver by, or pursuant to the lawful order of a practitioner, a unit dose of a controlled dangerous substance to an ultimate user or research subject by injection, inhalation, ingestion, or by any other immediate means." Section 102. (k) "Dispense' means to deliver one or more doses of a controlled dangerous substance in a suitable container, properly labeled, for subsequent administration to, or use by, an ultimate user or research subject. 'Dispenser' means a person who dispenses." Section 102. (1) "Distribute' means to deliver a controlled dangerous substance other than by the act of administering or dispensing. 'Distributor' means a person who distributes." Comment. The foregoing definitions draw clear lines of demarcation between the three distributive functions in terms understandable to the health care professions. The word "human" has been deleted from the phrase "human research project," in the first two definitions so as to include animals as well as human research subjects. Section 102. (h) "Manufacture' means the production, preparation, propagation, compounding, or processing of a controlled dangerous substance, either directly or indirectly by extraction from substances of natural origin, or independently by means of chemical synthesis or by a combination of extraction and chemical synthesis. 'Manufacturer' includes any person, other than a dispenser who packages, repackages, or labels any container of any controlled dangerous substance." Section 102. (p) "Practitioner' means a physician, dentist, veterinarian, scientific investigator, pharmacist, nurse or other person licensed, registered, or otherwise permitted to distribute, dispense, conduct research with respect to, or administer a controlled dangerous substance in the course of professional practice or research by the United States or the jurisdiction in which he practices or does research." Comment. "Pharmacy" and "hospital" are deleted from this definition and "pharmacist" and "nurse" added, making the definition applicable only to natural persons. For substantive control purposes, covered parties are later enumerated by specific reference [Sec. 302 (a)]. Section 102. (t) "Ultimate User' means a person or animal to whom a controlled dangerous substance may be lawfully administered or dispensed." Comment. This revised definition eliminates the word "administration" which, because it refers to animals, is inconsistent with the present definition of administer in the bill. Further, if the above-suggested definition of "administer" is adopted, the other language stricken becomes surplusage. Section 301. "The Attorney General is authorized to promulgate rules and regulations and to charge reasonable fees relating to the registration of persons engaged in the manufacture, distribution, and dispensing of controlled dangerous substances." Comment. The words "and control" have been deleted to make clear that reasonable fees may be charged only for registration and that other enforcement costs may not be levied against registrants. Section 302. (a) "All manufacturers, distributors, pharmacies, hopsitals, and practitioners (other than pharmacists or nurses unless they are engaged in research involving controlled dangerous substances) shall obtain annually a registration issued by the Attorney General in accordance with rules and regulations promulgated by him. (b) The Attorney General may waive the requirement for registration in particular cases if he finds such waiver consistent with the public health and safety. (c) A registration issued to a pharmacy or hospital shall be issued only in the name of a pharmacist authorized to dispense controlled dangerous substances in the jurisdiction in which the pharmacy or hospital is located. (d) The Attorney General is authorized to inspect the premises of a registrant or applicant for registration in accordance with rules and regulations promulgated by him." Comment." (a)" is revised to tie registration to particular parties, rather than particular functions. The parties specified take into account the expressed intention of BNDD not to register individual pharmacists and nurses other than those who may be engaged in research. Other parties may be specifically enumerated. “(b)” is revised to eliminate the burdensome rulemaking procedures imposed by the Administrative Procedures Act for waiver by regulation. The Attorney General would thus be authorized to grant waivers on an ad hoc basis without delay when appropriate. "(e)" has been revised to eliminate the requirement for multiple registration numbers tied to physical locations. Language is substituted which would require an individual be held responsible for controlled dangerous substances in cases where the registrant is a hospital or pharmacy. "(d)" has been revised to eliminate the commercial tone of "establishment" which is inappropriate to hospitals, research centers, etc., and to substitute, therefore, the more neutral term "premises." Section 304. (d) "The Attorney General may in his discretion, suspend any registration simultaneously with the institution of proceedings under this section, in cases where he finds that there is an imminent danger to the public health or safety. Before taking such action, the Attorney General shall consider its potential effect on the availability to the public of controlled dangerous substances for medicinal purposes. Such suspension shall continue in effect until the conclusion of such proceedings, including judicial review thereof, unless sooner withdrawn by the Attorney General or dissolved by a court of competent jurisdiction. Comment.-Additional language is added specifically to require balancing of health care considerations against law enforcement considerations before immediate suspension is authorized. Section 304. (f) "In the event the Attorney General suspends or revokes a registration granted under Section 303, all controlled dangerous substances owned or possessed by the registrant pursuant to such registration at the time of suspension or the effective date of the revocation order, as the case may be, may, in the discretion of the Attorney General, be placed under seal. Before taking such action, the Attorney General shall consider its potential effect on the availability to the public of controlled dangerous substances for medicinal purposes." No disposition may be made of substances under seal until the time for taking an appeal has elapsed or until all appeals have been concluded unless a court, upon application therefor, orders the sale of perishable substances and upon the deposit of the proceeds of the sale with the court. Upon a revocation order becoming final, all such controlled dangerous substances shall be forfeited to the Government. Section 307. "All registrants shall maintain complete and accurate records of receipts and disposition of all controlled dangerous substances. Records maintained in the ordinary course of business or professional practice shall be deemed adequate for purposes of this section. Such records shall not be required to be maintained so as to be reasonably available for inspection in connection with enforcement of this Act." Comment. This section is revised so as to eliminate the requirement of any inventories, but to insure that inspections and record audits can be made by responsible officials without undue burden on any party. These requirements, combined with the use of the "zero inventory" method of audit, will insure both adequate procedures for enforcement, and reasonable cost to the public. Section 309. (c) "No controlled dangerous substance included in Schedule IV may be dispensed except by a pharmacist or other practictioner licensed to dispense in the jurisdiction in which he practices." Comment. This revised language would incorporate in this statute the basis for regulations concerning distribution of present exempt narcotics. Section 309. (e) "No controlled dangerous substance may be dispensed to or for an ultimate user via the mail." Comment. This language would extend existing prohibitions against mailing of present Class A and B narcotics to all such drugs that would be controlled under this legislation. Such a provision is necessary to control diversion and abuse. Section 502 (a) "It shall be unlawful for any person knowingly or intentionally: (1) who is subject to the requirements of title II of this Act to distribute or dispense a controlled dangerous substance in violation of section 309; (2) who is a registrant to manufacture, distribute, or dispense a controlled dangerous substance not authorized by his registration to another registrant or other authorized person; (3) to bring a controlled dangerous substance classified in schedules I, II, or III into the United States or the special maritime or territorial jurisdiction of the United States for transshipment to another country, or to transfer or transship such a substance from one vessel to another within the United States for immediate exportation or for any other purpose-in violation of Section 404 of this Act; (4) who is a registrant to omit from any container of a controlled dangerous substance the symbol required by Section 305 of this Act; (5) to remove, alter, or obliterate a symbol required by section 305 of this Act; (6) to refuse or fail to make, keep or furnish any record, report, notification, order form, statement, invoice or information required under this Act; or (7) to refuse any entry into any premises or inspection authorized by this Act.” Comment. This section is revised to prohibit the levying of the fine provided for mere inadvertent mistake or unintentional failure to perform. In order to fully understand those problems associated with the control of marihuana, both legal and moral, one must have some knowledge of the plant itself, the chemical constituents in the plant, methods for identifying marihuana samples, the inherent variability in the plant and the type of biological test systems that are used to detect marihuana activity in laboratory animals. If the fact that each of these subject areas involves a major problem can be transmitted, then one can fully appreciate the overall problems of marihuana control. Despite the widespread interest in psychochemistry, it is surprising that progress in the chemical and medical aspects of marihuana has been so slow. History tells us that marihuana has been used for its psychotomimetic effects for at least 5,000 years. The science of phytochemistry, on the other hand, was actually only born in the year 1560 when benzoic acid was first isolated from gum benzoin. It was not until the year 1964 that the active principle of marihuana was discovered and isolated in a pure state. The reasons for this snail's pace are difficult to trace, although undoubtedly the fact that legally speaking marihuana is considered to be a narcotic substance, must be considered as a contributing factor. Also aiding this lack of success is the fact that the active principles of marihuana are quite unstable and this created problems in the experimental phytochemical isolation work. Finally, the lack of a reliable indicator for psychotomimetic (hallucinogenic) activity in laboratory animals is a problem that exists even today. The literature on marihuana is voluminous and often contradictory, especially with regard to some of the earlier chemical studies and all of the clinical experiments that have been reported in the literature must be considered with caution because they were carried out under conditions that were not adequately controlled or were conducted with marihuana of unknown chemical composition. Because many of the chemical problems concerned with this plant have now been solved, because the major active principle is now thought to be known and because this socalled active principle is now available in unquestioned pure form, a parallel advance in the pharmacological and clinical aspects of the study of marihuana can now be expected. As an illicit drug, marihuana and its various preparations are used widely almost all over the world. Marihuana does not cause physiological addiction, although a psychological habituation probably exists. Though legally and through popular misconception it is usually grouped together with the opiates, marihuana is not, as generally believed, used for its narcotic action but mainly for its psychotomimetic effects. It should therefore be considered as a member of the important group of materials which includes, among others, lysergic acid diethylamide-LSD-and mescaline. Marihuana intoxication manifests itself by euphoria, motor excitation and hilarity followed by mental confusion, sometimes accompanied by depersonalization, hallucinations and depression. As with LSD, the effects have a wave-like character. Reports are common of spatial and temporal distortion, increased sensitivity to sound and a feeling of profound understanding of of the meaning of things. Some authorities have concluded that virtually all of the phenomena associated with LSD are, or can, also be produced with marihuana.1 botanical considerations Botanically speaking, marihuana is derived from the plant Cannabis sativa L. The plant genus-i.e., Cannabis-is monotypic, although the Indian variety has often been erroneously referred to as Cannabis indica. It is a tall annual weed sometimes attaining a height of 15 to 18 feet and it will grow in almost any waste or fertile area. It is important to note that the plant is dioeciousi.e., it has plants of separate sexes. The male-staminate plant-usually grows taller than the female-pistillate plant. The staminate flowers are borne in panicles and are axillary. The axillary pistillate flowers are catkins. It is generally acknowledged that the psychotomimetic principles of marihuana are located only in the female plant, and in a sticky resin that is produced by glandular hairs which are particularly abundant on the female flowers and adjacent leaves. There is no good scientific publication in the literature that substantiates these beliefs and it has recently been determined through valid experiments, that the male plant also produces the active psychotomimetic principle A1tetrahydrocannabinol (= A-tetrahydrocannabinol).2 Morphologically, Cannabis sativa is readily identified in the growing state by the character of the leaves, which are large and palmately compoundeach having five to seven linearlanceolate leaflets with serrate (toothed or notched) leaf margins Identification of the plant or parts of this plant in a cigarette suspected to contain marihuana, constitutes special problems-vide infra. Although the layman may not always use the proper terminology in speaking of marihuana or its derivatives, the meaning of certain words associated with the plant is quite clear. Hashish-hash"-and "charas" are terms denoting the unadulterated resin from the flowering tops of cultivated female Cannabis sativa plants. Bhang is prepared from uncultivated female plants. The tops are cut from the plants and a decoction is made in water or milk. The decoction is then either drunk or dried and smoked. Ganjah"ganja" is prepared by harvesting the tops from very carefully cultivated female plants and is used in the same manner as bhang. Ganjah is superior to bhang, but inferior to hashish. Majun is ganjah that has been in corporated into sweetmeats.8 The whole female flowering parts of Cannabis sativa are referred to as "kif" in North Africa, "dagga" in South Africa and "maconha" Brazil'. in Most of these terms are seldom encountered in the United States, with the exception of hashish-a term that is generally used incorrectly-since most of the Cannabis sativa used in this country is in the form of dried flowering tops of the plants-probably a mixture of both male and female plants in most cases. The mixture is admixed with considered leaf material and ordinarily goes more correctly under the names of marihuana, "pot" or "grass." Cigarettes containing marihuana are home made and are referred to as "reefers," mooters," "muggles," "greeters," "gates" or, most frequently as "joints." A large quantity of marihuana that finds its way into the United States is smuggled across the border from Mexico and is often referred to as "Acapulco Gold" by its users. biological evaluation A number of biological detection methods have been applied to marihuana samples-as well as to the pure cannabinoids-but none of these are specific for psychotomimetic substances. Perhaps the most common method for detecting marihuana activity is to administer the sample to a dog and observe for signs of ataxia, a type of muscular incoordination. It is generally recognized that if a suspected marihuana sample induces ataxia in the dog, psychotomimetic effects are being produced." Additional evidence of marihuanalike psychotomimetic effects is obtained if there is abolition of the rabbit blink following administration of this sample to this species. chemical constituents A number of pure cannabinoids have been isolated from Cannabis sativa and their structures elucidated. Some of these have been evaluated for psychotomimetic activity, as well as for other biological effects. The two most important cannabinoidsboth of which produce ataxia in the dog and psychotomimetic effects in man-are A1-transtetrahydrocannabinol (1, see Figure 1)5-8 and 16. transtetrahydrocannabinol (II, see Figure 1).9.0 Tetrahydrocannabinol carboxylic acid (III, see Figure 1) has never been biologically evaluated 10 and the same holds true for the unusual dimeric cannabinoid, cannabidiol carboxylic acid tetrahydrocannabitriol ester (IV, see Figure 1).11 Cannabinol (V, see Figure 1) Norman R. Farnsworth is professor and chairman, department of pharmacognosy, University of Pittsburgh. He received his BS in 1953 from the Massachusetts College of Pharmacy and his MS in 1955 from the same institution. In 1959 he was awarded a PhD from the University of Pittsburgh. His teaching responsibilities at the University of Pittsburgh include courses in pharmacognosy and microbiology. At the research level his major interests are in the isolation, identification and structure elucidation of biologically active entities from plants. He has published numerous articles in this and related areas. is known to be devoid of psychotomimetic effects 12.13 and cannabinolic acid (VI, see Figure 1) has not been tested for biological activity.14 Cannabigerol (VII, see Figure 1)14,15 and cannabigerolic acid (VIII, see Figure 1) have antibiotic activity against gram-positive organisms14. The former is devoid of psychotomimetic activity but the latter has not been evaluated for this type of action. Cannabigerol monomethyl ether (IX, see Figure 1) has not been tested for biological activity. 18 Cannabidiol (X, see Figure 1) has antibiotic activity against gram-positive organisms but is devoid of psychotomimetic effects, 12.17.18.20,21 Cannabidiolic acid (XI, see Figure 1)14.17.19 has no psychotomimetric activity but has sedative activity and is a potent antimicrobial agent against gram-positive organisms. The biological effects of cannabidivarin (XII, see Figure 1)22 are unreported. Cannabichromene (XIII, see Figure 1) 14.28.24 is unusual in that it produces ataxia in the dog but it has no psychotomimetic effects in man. It is a sedative principle. Cannabichromenic acid (XIV, see Figure 1)25 and cannabipinol (XV, see Figure 1) (cannabicyclol) 4.28 biological effects are unreported. In addition to the cannabinoids of known structure, Todd27 has isolated cannabol, C2, H3002 which is uncharacterized and for which no biological activity has been recorded. Also, Covello28 has isolated a crystalline substance, m.p. 129-133°, which has been reported to have inebriating effects in the dog. HO The concentration of these cannabinoids varies considerably in various Cannabis sativa samples examined. A good psychotomimetic sample of marihuana is thought to contain about 1.0 to 1.5 per cent of tetrahydrocannabinol. An example of an analysis of a typical sample of hashish for major cannabinoids iscannabidiol 4 percent, cannabidiolic acid 3.25 percent, cannabinol 1.2 percent, cannabigerolic acid 0.5 percent, A'-tetrahydrocannabinol 0.4 percent, cannabigerol 0.3 percent, cannabinolic acid 0.25 percent and cannabicyclol 0.1 percent.20 Although there are six possible isomers of the tetrahydrocannabinols based on the position of the double bond in ring A, only the A-and the A1(e)-isomers have been isolated from Cannabis sativa (XVI, see below). It is known that there is a difference in the psychotomimetic effects of the two known naturally occuring THC isomers and that the naturally occuring (-)-A-transtetrahydrocannabinol is 11-15 times more potent as a psychotomimetic agent than synthetic (+)-A-transtetrahydrocannabinol. Further, the A' isomer is present in about a 10 to 1 ratio when compared with the A1(8) isomer. Since (-)-A-transtetrahydrocannabinol (synthetic) has only been available for biological evaluation since 1967 and it is presumed that ali studies utilizing "tetrahydrocannabinol" prior to this date were conducted utilizing a mixture of isomers, the majority of literature on the biological effects of tetrahydrocannabinols |