The list of Schedule III Anabolic Steroids is about to get longers and DEA wants to add Superdrol and Prostanozol to the list of controlled substances.
Proposed Rules - 2011 - Classification of Two Steroids, Prostanozol and Methasterone, as Schedule III Anabolic Steroids Under the Controlled Substances Act
Proposed Rules - 2011 - Classification of Two Steroids, Prostanozol and Methasterone, as Schedule III Anabolic Steroids Under the Controlled Substances Act
[Federal Register Volume 76, Number 226 (Wednesday, November 23, 2011)]
[Proposed Rules]
[Pages 72355-72362]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-30081]
[Proposed Rules]
[Pages 72355-72362]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-30081]
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
[Docket No. DEA-341P]
RIN 1117-AB31
Classification of Two Steroids, Prostanozol and Methasterone, as Schedule III Anabolic Steroids Under the Controlled Substances Act
AGENCY: Drug Enforcement Administration (DEA), Department of Justice.
ACTION: Notice of proposed rulemaking.
SUMMARY: This Notice of Proposed Rulemaking (NPRM) proposes to classify the following two steroids as "anabolic steroids" under the Controlled Substances Act (CSA): prostanozol (17[beta]-hydroxy- 5[alpha]-androstano[3,2-c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]-ol-3-one). The Drug Enforcement Administration (DEA) believes that this action is necessary to prevent the abuse and trafficking of
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these steroids. If the regulations are amended, these steroids will be listed as Schedule III controlled substances subject to the regulatory control provisions of the CSA.
DATES: Electronic comments must be submitted and written comments must be postmarked on or before January 23, 2012. Commenters should be aware that the electronic Federal Docket Management System will not accept comments after midnight Eastern Time on the last day of the comment period.
ADDRESSES: To ensure proper handling of comments, please reference "Docket No. DEA-341" on all electronic and written correspondence. DEA encourages all comments be submitted electronically through Regulations.gov using the electronic comment form provided on that site. An electronic copy of this document and supplemental information to this proposed rule are also available at the Regulations.gov Web site for easy reference. Paper comments that duplicate the electronic submission are not necessary as all comments submitted to Regulations.gov will be posted for public review and are part of the official docket record. Should you, however, wish to submit written comments via regular or express mail, they should be sent to the Drug Enforcement Administration, Attention: DEA Federal Register Representative/OD, 8701 Morrissette Drive, Springfield, Virginia 22152.
FOR FURTHER INFORMATION CONTACT: Rhea D. Moore, Office of Diversion Control, Drug Enforcement Administration, 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone (202) 307-7165.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments: Please note that all comments received are considered part of the public record and made available for public inspection online at Regulations.gov and in the DEA's public docket. Such information includes personal identifying information (such as your name, address, etc.) voluntarily submitted by the commenter.
If you want to submit personal identifying information (such as your name, address, etc.) as part of your comment, but do not want it to be posted online or made available in the public docket, you must include the phrase "PERSONAL IDENTIFYING INFORMATION" in the first paragraph of your comment. You must also place all the personal identifying information you do not want posted online or made available in the public docket in the first paragraph of your comment and identify what information you want redacted.
If you want to submit confidential business information as part of your comment, but do not want it to be posted online or made available in the public docket, you must include the phrase "CONFIDENTIAL BUSINESS INFORMATION" in the first paragraph of your comment. You must also prominently identify confidential business information to be redacted within the comment. If a comment has so much confidential business information that it cannot be effectively redacted, all or part of that comment may not be posted online or made available in the public docket.
Personal identifying information and confidential business information identified and located as set forth above will be redacted, and the comment, in redacted form, will be posted online and placed in the DEA's public docket file. Please note that the Freedom of Information Act applies to all comments received. If you wish to inspect the agency's public docket file in person by appointment, please see the "For Further Information" paragraph.
Background Information
On November 29, 1990, the President signed into law the Anabolic Steroids Control Act of 1990 (Title XIX of Pub. L. 101-647), which became effective February 27, 1991. This law established and regulated anabolic steroids as a class of drugs under Schedule III of the CSA. As a result, a new anabolic steroid is not scheduled according to the procedures set out in 21 U.S.C. 811, but can be administratively classified as an anabolic steroid through the rulemaking process by adding the steroid to the regulatory definition of an anabolic steroid in 21 CFR 1300.01(b)(4).
On October 22, 2004, the President signed into law the Anabolic Steroid Control Act of 2004 (Pub. L. 108-358), which became effective on January 20, 2005. Section 2(a) of the Anabolic Steroid Control Act of 2004 amended 21 U.S.C. 802(41)(A) by replacing the existing definition of "anabolic steroid." The Anabolic Steroid Control Act of 2004 classifies a drug or hormonal substance as an anabolic steroid if the following four criteria are met: (A) The substance is chemically related to testosterone; (B) the substance is pharmacologically related to testosterone; (C) the substance is not an estrogen, progestin, or a corticosteroid; and (D) the substance is not dehydroepiandrosterone (DHEA). Any substance that meets the criteria is considered an anabolic steroid and must be listed as a Schedule III controlled substance. DEA believes that prostanozol (17[beta]-hydroxy-5[alpha]-androstano[3,2- c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]- androstan-17[beta]-ol-3-one) meet this definition of "anabolic steroid," and is proposing that they be added to the list of anabolic steroids in 21 CFR 1300.01(b)(4).
Anabolic steroids are a class of drugs structurally related to the endogenous hormone testosterone that exert androgenic (masculinizing) as well as anabolic (body building) effects. These effects are mediated primarily through binding of the anabolic steroid to the androgen receptor in target tissues (Evans, 2004). Anabolic effects include promotion of protein synthesis in skeletal muscle and bone, while the androgenic effects are characterized by the development of male secondary sexual characteristics such as hair growth, deepening of the voice, glandular activity, thickening of the skin, and central nervous system effects, to name a few (Kicman, 2008). Anabolic efficacy is characterized by positive nitrogen balance and protein metabolism, resulting in increases in protein synthesis and lean body mass (Evans, 2004). These effects often come at a cost to the healthy individual who experiences clear physical and psychological complications (Trenton and Currier, 2005; Brower, 2002; Hall et al., 2005).
In the United States, only a small number of anabolic steroids are approved for either human or veterinary use. Approved medical uses for anabolic steroids include treatment of androgen deficiency in hypogonadal males, adjunctive therapy to offset protein catabolism associated with prolonged administration of corticosteroids, treatment of delayed puberty in boys, treatment of metastatic breast cancer in women, and treatment of anemia associated with specific diseases (e.g., anemia of chronic renal failure, Fanconi's anemia, and acquired aplastic anemia). However, with the exception of the treatment of male hypogonadism, anabolic steroids are not the first-line treatment due to the availability of other preferred treatment options. DEA is not aware of any legitimate medical use or New Drug Applications (NDA) for the two substances that DEA is proposing to classify by this NPRM as anabolic steroids under the definition set forth under 21 U.S.C. 802(41)(A). Moreover, DEA has not been able to identify any chemical manufacturers currently using these substances as intermediates in their manufacturing process(es).
Adverse health effects are associated with abuse of anabolic steroids and
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depend on several factors (e.g., age, sex, anabolic steroid used, the amount used, and the duration of use) (Hall and Hall, 2005; Quaglio et al., 2009). These include cardiovascular, dermatological, behavioral, hepatic, and gender specific endocrine side effects. Anabolic steroids have direct and indirect impact on the developing adolescent brain and behavior (Sato et al., 2008). Furthermore, adolescent abuse of anabolic steroids may result in stunted growth due to premature closure of the growth plates in long bones. In adolescent boys, anabolic steroid abuse can cause precocious sexual development. In both girls and women, anabolic steroid abuse induces permanent physical changes such as deepening of the voice, increased facial and body hair growth, menstrual irregularities, and clitoral hypertrophy. In men, anabolic steroid abuse can cause testicular atrophy, decreased sperm count, and sterility. Gynecomastia (i.e., enlargement of the male breast tissue) can develop with the abuse of those anabolic steroids with estrogenic actions. In both men and women, anabolic steroid abuse can damage the liver and may result in high cholesterol levels, which may increase the risk of strokes and cardiovascular heart attacks. Furthermore, anabolic steroid abuse is purported to induce psychological effects such as aggression, increased feelings of hostility, and psychological dependence and addiction (Brower, 2002; Kanayama et al., 2008). Upon abrupt termination of long-term anabolic steroid abuse, a withdrawal syndrome may appear including severe depression. Additionally, polysubstance abuse is routinely associated with anabolic steroid abuse, where ancillary drugs, including recreational and prescription drugs, are abused in response to unwanted side effects (Hall et al., 2005; Parkinson et al., 2005; Skarberg et al., 2009).
A review of the scientific literature finds adverse health effects including liver toxicity with renal failure reported in conjunction with methasterone abuse (Shah et al., 2008; Jasiurkowski et al., 2006; Singh et al., 2009; Nasr and Ahmad, 2008; and Krishnan et al., 2009). In March 2006, the U.S. Food and Drug Administration (FDA) issued a Warning Letter in response to adverse health effects associated with the product Superdrol (methasterone). In July 2009, FDA issued a warning regarding bodybuilding products containing steroid or steroid- like substances. In this warning, a product containing the THP ether derivative of prostanozol was named in conjunction with other products presenting safety concerns.
Evaluation of Statutory Factors for Classification as an Anabolic Steroid
DEA is proposing by this NPRM to classify prostanozol (17[beta]- hydroxy-5[alpha]-androstano[3,2-c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]-ol-3-one) as anabolic steroids under the definition set forth under 21 U.S.C. 802(41)(A). As noted previously, a drug or hormonal substance is classified as an anabolic steroid by meeting the following four definitional requirements: (A) The substance is chemically related to testosterone; (B) the substance is pharmacologically related to testosterone; (C) the substance is not an estrogen, progestin, or corticosteroid; and (D) the substance is not DHEA.
(A) Chemically Related to Testosterone
To classify a substance as an anabolic steroid, a substance must be chemically related to testosterone. A structure activity relationship (SAR) evaluation for each substance compared the chemical structure of the steroid to that of testosterone. Substances with a structure similar to that of testosterone are predicted to possess comparable pharmacological and biological activity.
Prostanozol is also known by the following name: 17[beta]-hydroxy- 5[alpha]-androstano[3,2-c]pyrazole. DEA determined that the chemical structure of prostanozol is similar to testosterone, differing by only the attachment of a pyrazole ring at carbon 2 (C2) and carbon 3 (C3) positions of the androstane skeleton, replacing the C3-keto group and the lack of a double bond between carbon 4 (C4) and carbon 5 (C5) positions. Similar modifications to testosterone's chemical structure have been documented and, in general, they have been found to be well tolerated, displaying both anabolic and androgenic activity (Fragkaki et al., 2009; Vida, 1969). Clinton and coworkers, in their synthesis of prostanozol, described the modification as a fusion of a pyrazole ring to the androstane steroidal nucleus at C2 and C3 (Clinton et al., 1961). Further analysis finds the chemical structure of prostanozol to be very similar to the anabolic steroid stanozolol. The two structures differ only about a 17[alpha]-methyl group (alpha methyl group attached to carbon 17).
Methasterone is known by the following chemical names: 2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]-ol-3-one; 2[alpha],17[alpha]-dimethyl-17[beta]-hydroxy-5[alpha]-androstan-3-one; 17[alpha]-methyl-drostanolone; methasteron; methyldrostanolone; 2[alpha],17[alpha]-dimethyldihydrotestosterone; and 2[alpha],17[alpha]- dimethyl-etiocholan-17[beta]-ol-3-one. DEA has determined that the chemical structure of methasterone is chemically related to testosterone. The chemical structure of methasterone differs from testosterone by the following three chemical groups: an alpha methyl group at carbon 17 (C17), an alpha methyl group at C2, and the lack of a double bond between spanning C4 and C5. Removal of the C4-C5 double bond (A-ring) and methylation at the C2 and C17 positions has been shown to increase anabolic activity (Zaffroni, 1960; Fragkaki et al., 2009). Furthermore, methyl group substitution at the C2 and C17 has been reported to impair aromatization, thus, prolonging the anabolic effect (Fragkaki et al., 2009).
(B) Pharmacologically Related to Testosterone
A substance must also be pharmacologically related to testosterone (i.e., produce similar biological effects) to be classified as a Schedule III anabolic steroid. The pharmacology of a steroid, as related to testosterone, can be established by performing one or more of the following androgenic and anabolic activity assays: ventral prostate assay, seminal vesicle assay, levator ani assay, and androgen receptor binding and efficacy assays. These assays are described below.
Ventral Prostate Assay, Seminal Vesicle Assay, and Levator Ani Assay: The classic scientific procedure for evaluating androgenic (masculinizing) and anabolic (muscularizing) effects of a steroid is the ventral prostate assay, seminal vesicle assay, and levator ani assay. This testing paradigm allows for the direct comparison to testosterone. Select male accessory tissues (i.e., the ventral prostate, seminal vesicles, and levator ani muscle) are testosterone sensitive, specifically requiring testosterone to grow and remain healthy. Upon the removal of the testes (i.e., castration), the primary endogenous source of testosterone is eliminated causing the atrophy of the ventral prostate, seminal vesicles, and levator ani muscle (Eisenberg et al., 1949; Nelson et al., 1940; Scow, 1952; Wainman and Shipounoff, 1941). Numerous scientific studies have demonstrated the ability of exogenous testosterone or a pharmacologically similar steroid administered to rats following castration to maintain the normal weight and size of all three testosterone sensitive organs (Biskind and Meyer, 1941; Dorfman and
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Dorfman, 1963; Dorfman and Kincl, 1963; Kincl and Dorfman, 1964; Nelson et al., 1940; Scow, 1952; Wainman and Shipounoff, 1941). Thus, a steroid with testosterone-like activity will also prevent the atrophy of these three testosterone-dependent organs in castrated rats.
Castrated male rats are administered the steroid for a number of days, then the rats are euthanized and the previously described tissues are excised and weighed. Tissue weights from the three animal test groups are compared, castrated animals alone, castrated animals receiving the steroid, and healthy intact animals (control), to assess anabolic and androgenic activity. A reduction in tissue weights relative to the control group suggests a lack of androgenic and/or anabolic activity. An increase in tissue weights relative to the castrated rats receiving no steroid suggests an androgenic and/or anabolic effect.
Androgen Receptor Binding and Efficacy Assay: Anabolic steroids bind with the androgen receptor to exert their biological effect. Affinity for the receptor is evaluated in the receptor binding assay, while the transactivation (functional) assay provides additional information as to both affinity and ability to activate the receptor. Receptor binding and transactivation studies are valuable tools in evaluating pharmacological activity and drawing comparisons to other substances. A steroid displaying affinity for the androgen receptor and properties of being an agonist in transactivation studies is determined to be pharmacologically similar to testosterone.
Studies used to evaluate anabolic steroids are the androgen receptor binding assay and the androgen receptor transactivation assay. Both are well-established and provide significant utility in evaluating steroids for affinity to their biological target and the modulation of activity. The androgen receptor binding assay provides specific detail as to the affinity of a steroid for the androgen receptor (biological target of anabolic steroids). To assess further whether the steroid is capable of activating the androgen receptor, the androgen receptor transactivation assay evaluates the binding of a steroid to the androgen receptor and subsequent interaction with DNA. In this study, transcription of a reporter gene provides information as to a steroid's ability to modulate a biological event. This activity measurement provides information as to the potency of a steroid to bind to a receptor and either initiate or inhibit the transcription of the reporter gene. The androgen receptor binding assay and androgen receptor transactivation assay are highly valuable tools in assessing the potential activity of a steroid and comparing the activity to testosterone.
Results of the Androgenic and Anabolic Activity Assays
DEA reviewed the published scientific literature, and pharmacological studies were undertaken to collect additional information on prostanozol and methasterone in several different androgenic and anabolic activity assays.
Findings from these studies indicate that in addition to being structurally similar to testosterone, prostanozol and methasterone have similar pharmacological activity as testosterone.
Prostanozol
The chemical synthesis and anabolic and androgenic effects of prostanozol (17[beta]-hydroxy-5[alpha]-androstano[3,2-c]pyrazole) were published in 1961 (Clinton et al., 1961). Clinton and coworkers evaluated the anabolic activity by means of nitrogen balance and androgenic activity based on weight changes of the ventral prostrate of prostanozol upon subcutaneous administration to rats with the reference standard testosterone propionate. The potency ratio of anabolic activity to androgenic activity for prostanozol was reported to be eight (Clinton et al., 1961). In another study, prostanozol was reported to have approximately the same relative binding affinity for human sex steroid binding protein as testosterone (Cunningham et al., 1981).
To build on these findings, a pharmacological study \1\ was conducted to evaluate the anabolic and androgenic effects of prostanozol in castrated male rats. Results were compared to testosterone by a similar protocol. Administration of prostanozol to castrated male rats by subcutaneous injection prevented the atrophy (loss in weight) of the ventral prostate, seminal vesicles, and levator ani muscle.\1\ These testosterone sensitive tissues experienced increases in weight comparable to testosterone in castrated male rats. Results from this study support that prostanozol possesses both androgenic and anabolic activity. Additional studies were conducted to further assess prostanozol's anabolic effect. In a competitive binding assay, prostanozol was found to possess affinity for the androgen receptor comparable to testosterone.\1\ In the androgen receptor transactivation assay, prostanozol displayed increased activity relative to testosterone.\1\ Effects elicited by prostanozol in this transactivation assay were consistent and comparable to those of testosterone. Taken together, data from in vitro and in vivo assays indicate the pharmacology of prostanozol to be similar to testosterone.
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\1\ 2009 BIOQUAL, Inc. study commissioned by the National Institutes of Health on behalf of DEA.
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Methasterone
The synthesis of methasterone (2[alpha],17[alpha]-dimethyl- 5[alpha]-androstan-17[beta]-ol-3-one) was reported in 1956 and the anabolic activity in 1959 (Ringold and Rosenkranz, 1956; Ringold et al., 1959). Methasterone was described as a potent anabolic agent exhibiting weak androgenic activity in the castrated male rat (Ringold et al., 1959). Zaffaroni and coworkers reported methasterone possessed one-fifth the androgenic activity and four times the anabolic activity of the anabolic steroid methyltestosterone, when administered orally to the experimental animal (Zaffaroni et al., 1960).
Additional pharmacological studies were undertaken to further evaluate the androgenic and anabolic effects of methasterone. \1\ Methasterone was administered subcutaneously and orally to castrated male rats. By both routes of administration, methasterone prevented the atrophy (loss in weight) of ventral prostate, seminal vesicles, and levator ani muscle. Tissue weight increases for the castrated methasterone-treated animals were comparable to the castrated rats treated with testosterone and methyltestosterone. These results were consistent with earlier findings that methasterone is anabolic and androgenic (Zaffaroni, 1960; Ringold et al., 1959). Functional assays were also undertaken to further evaluate methasterone.\1\ Methasterone displayed affinity for the androgen receptor comparable to testosterone in a competitive binding assay.\1\ In the androgen receptor transactivation assay, methasterone displayed increased activity relative to testosterone.\1\ Effects elicited by methasterone in the androgen transactivation assay were consistent and comparable to those of testosterone. Collectively, in vivo and in vitro results indicate that the pharmacology of methasterone is similar to testosterone.
(C) Not Estrogens, Progestins, and Corticosteroids
DEA has determined that prostanozol and methasterone are unrelated to estrogens, progestins, and corticosteroids. DEA evaluated the SAR for each of the substances. The chemical structure of each substance was
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compared to that of estrogens, progestins, and corticosteroids, since chemical structure can be related to its pharmacological and biological activity. DEA found that these two substances lack the necessary chemical structures to impart significant estrogenic activity (e.g., aromatic A ring) (Duax et al., 1988; Jordan et al., 1985; Williams and Stancel, 1996), progestational activity (e.g., 17[beta]-alkyl group) (Williams and Stancel, 1996), or corticosteroidal activity (e.g., 17[beta]-ketone group or 11[beta]-hydroxyl group) (Miller et al., 2002). Furthermore, methasterone was reported to display anti- estrogenic activity in mouse assay to assess estrogen stimulated uterine growth (Dorfman et al., 1961). To assess the estrogenic, progestational, and corticosteroid activity of prostanozol and methasterone, these substances were evaluated in receptor binding and functional transactivation assays. Prostanozol and methasterone showed low binding affinity for the estrogen, progesterone, and glucocorticoid receptors. Furthermore, these steroids displayed low to no transactivation mediated by the estrogen receptors, progesterone receptors, or glucocorticoid receptors. Therefore, based on these data, prostanozol and methasterone are not estrogens, progestins, or corticosteroids and these anabolic steroids are not exempt from control on this basis.
(D) Not Dehydroepiandrosterone
Dehydroepiandrosterone, also known as DHEA, is exempt from control as an anabolic steroid by definition (21 U.S.C. 802(41)(A)). Prostanozol and methasterone are not dehydroepiandrosterone and therefore, are not exempt from control on this basis.
Conclusion
Therefore, based on the above, DEA concludes that prostanozol and methasterone meet the CSA definition of "anabolic steroid" because each substance is: (A) Chemically related to testosterone; (B) pharmacologically related to testosterone; (C) not an estrogen, progestin, or a corticosteroid; and (D) not DHEA (21 U.S.C. 802(41)). All anabolic steroids are classified as Schedule III controlled substances (21 U.S.C. 812). Once a substance is determined to be an anabolic steroid, DEA has no discretion regarding the scheduling of these substances. As discussed further below, all requirements pertaining to controlled substances in Schedule III would pertain to these substances.
Impact of Proposed Rule and Effect of Classifying These Substances as Anabolic Steroids
If this rulemaking is finalized as proposed, DEA will classify prostanozol (17[beta]-hydroxy-5[alpha]-androstano[3,2-c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]- ol-3-one) as Schedule III anabolic steroids. If classified as Schedule III anabolic steroids, any person who manufactures, distributes, dispenses, imports, or exports prostanozol or methasterone or who engages in research or conducts instructional activities with respect to these two substances would be required to obtain a Schedule III registration in accordance with the CSA and its implementing regulations. Manufacturers and importers of these two substances would be required to register with DEA and would be permitted to distribute these substances only to other DEA registrants. Only persons registered as dispensers would be allowed to dispense these substances to end users. The CSA defines a practitioner as "a physician, dentist, veterinarian, scientific investigator, pharmacy, hospital, or other person licensed, registered, or otherwise permitted, by the United States or the jurisdiction in which he practices or does research, to distribute, dispense, conduct research with respect to, administer, or use in teaching or chemical analysis, a controlled substance in the course of professional practice or research." 21 U.S.C. 802(21). At present, there are no approved medical uses for these two substances. Until a manufacturer applies to the FDA and gains approval for products containing these substances, no person may dispense them in response to a prescription.
Manufacture, import, export, distribution, or sale of prostanozol (17[beta]-hydroxy-5[alpha]-androstano[3,2-c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]-ol-3-one) except by DEA registrants, would become a violation of the CSA that may result in imprisonment and fines (see, e.g., 21 U.S.C. 841, 960). Possession of these two steroids, unless legally obtained, would also become subject to criminal penalties (21 U.S.C. 844).
In addition, under the CSA, these two substances could be imported only for medical, scientific, or other legitimate uses (21 U.S.C. 952(b)) under an import declaration filed with DEA (21 CFR 1312.18). Importation of these substances would be illegal unless the person importing these substances is registered with DEA as an importer or researcher and files the required declaration for each shipment. An individual who purchases either of these substances directly from foreign companies and has them shipped to the United States will be considered to be importing even if the steroids are intended for personal use. Illegal importation of these substances would be a violation of the CSA that may result in imprisonment and fines (21 U.S.C. 960).
