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International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019

Prediction of Human Lethality of Psychoactive From

Rodent LD50 Values John C. Dearden, Liverpool John Moores University, UK

ABSTRACT

The number of deaths from the abuse of psychoactive drugs is increasing year after year, and new designer psychoactive drugs of unknown frequently appear on the streets. Human lethal

doses generally do not correlate well with animal LD50 values. In order to investigate whether that

holds for psychoactive drugs, human lethal dose values and rat and mouse LD50 values for several routes of administration for eighteen such drugs were collected from the literature. Quantitative toxicity-toxicity relationship (QTTR) regression correlations of human and rodent lethal doses were poor for both rat and mouse oral and intraperitoneal lethal doses, but both rat and mouse intravenous

LD50 values correlated very well with human lethal doses (r2 = 0.823 and 0.756, respectively). Rat and

mouse intravenous LD50 values predicted from commercial software also correlated reasonably well with human lethal doses (r2 = 0.631 and 0.678, respectively). This means that it should be possible to use these correlations to predict the human lethal doses of new psychoactive drugs.

Keywords

Correlation, Human Lethal Dose, Prediction, Psychoactive Drugs, Rodent LD50

INTRODUCTION

A recent crime survey (Crime Survey for England and Wales, 2016/17) revealed that 19.2% of adults aged 16 to 24 had taken an illicit drug in the past year. According to the Office for National Statistics (Office for National Statistics), deaths related to drug poisoning in England and Wales are increasing year on year, from 2597 in 2012 to 3756 in 2017, an increase of 44.6%. Hence there is a need for the determination of lethal toxicity, based usually on animal experiments, for both and drugs of abuse in order to obtain an estimation of safety and toxicity in humans. It is acknowledged (Gable, 1993) that the determination of the human lethal dose (HLD) of a psychoactive substance is very difficult for a number of reasons, for example whether the substance is taken on its own or together with other substances, whether the person is a new or habitual user, whether the person is alone or in the company of others, and because of the sometimes marked interpersonal variability of rates of metabolism. Gable (1993) stated that ‘the “best-guess lethal dose”

for an average adult human who has not developed tolerance to the substance is probably the LD50

DOI: 10.4018/IJQSPR.2019040101

 Copyright © 2019, IGI Global. Copying or distributing in print or electronic forms without written permission of IGI Global is prohibited. 

1 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 extrapolated from a broad range of laboratory animal studies that falls within the range of lethality cited in clinical or forensic reports’.

The animal LD50 test was developed by Trevan (1927) for the biological standardization of drugs. Like HLD values, it cannot be considered as a biological constant, for it has been pointed out (Zbinden & Flury-Roversi, 1981) that it can vary with animal species, age, sex, weight, health, genetic variability, diet, method of administration, time of assessment after administration, ambient temperature, housing conditions (e.g. isolated or aggregated), time of day/night and time of year.

It is therefore not surprising that correlations between animal LD50 and human toxicity values are generally poor (Abbott, 2005), although a few publications have reported modest results. For example, Hoffmann et al. (2010) found that human acute lethal doses of 30 chemicals correlated with rat oral 2 LD50 values (coefficient of determination (r ) = 0.571); Ekwall et al. (1998) found that human acute lethal doses of 50 chemicals (including a few psychoactive drugs) correlated reasonably well with 2 rat and mouse oral LD50 values (r = 0.607 and 0.653 respectively); Jover et al. (1992) reported correlations between HLDs of 10 chemicals with rat and mouse oral LD50 values (prediction errors 1.04 and 0.68 log unit respectively). Gable (2004) reported median HLD and range values for 20 commonly abused psychoactive substances; for example, he gave the median HLD for as 100 mg, and the lethal range as 20 – 400 mg. He did not, however, examine possible correlations between human and animal lethal doses.

By far the most widely used animals in LD50 testing are rodents, especially rats and mice. It was therefore decided to examine correlations between HLDs and (following the suggestion of Gable

(1993)) a range of rat and mouse LD50 values, with the aim of obtaining one or more valid animal models of human lethality of psychoactive drugs. Such models could then be used to predict the human lethality of new ‘designer’ drugs as they become available. The use of mean LD50 values in the present work hopefully means that many experimental errors and variations in their measurement were cancelled out.

Methods Data HLD values for 18 commonly abused psychoactive substances were taken largely from Gable (2004), who reported them for 20 such substances. However, two of those substances (isobutyl nitrite and ) are gaseous, with different dosage units, and so could not be included in the present study. Where Gable gave only a range of values together with an indication that the median value was ‘> X’, a value only slightly greater than X was used; for example, for methamphetamine Gable (2004) gave the median value as > 150 mg, and the range as 140-1650 mg, so a value of 200 mg was selected as the HLD. Values were converted to mg/kg using a representative human weight of 68 kg (British National Formulary 2017-2018). The 18 psychoactive drugs comprised examples of , , amphetamines, , dibenzylcycloheptenes, morphinans, diphenylpropylamines, tryptamines, , carboxylic acids, phenoxyphenylpropylamines, diphenylpropylamines, arylcyclohexylamines, and dibenzopyrans; their actions included depressant, antidepressant, stimulant, hypnotic, sedative, antitussive, hallucinogenic, anesthetic and analgesic activities. This demonstrates the very wide applicability domain of the drugs used in this work. The physicochemical applicability domain covered a logarithmic octanol-water partition coefficient (log P) range of –0.70 to 7.68, a pKa(base) range of 2.2 to 10.3, a pKa(acid) range of 1.0 to 9.6, and a logarithmic aqueous solubility (log S, with S in mmol/L) of –5.49 to 0.79, as well as ethanol which has infinite solubility in water.

A wide-ranging literature search was performed to find rat and mouse LD50 values obtained via oral, intraperitoneal, sub-cutaneous and intravenous administration, and arithmetic mean LD50 values were calculated, as has been done in previous studies (see, for example, Clothier et al., 1987; Hoffmann et al., 2010). Of the 144 endpoints, for only 28 (mostly involving subcutaneous

2 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019

administration) could no LD50 values be found. Table 1 gives the HLD values and the mean rat and mouse LD50 values. Where a value was reported for the salt of a drug, the value was corrected to that for the corresponding free acid or base using the ratio of molecular weights. Carai et al. (2004) have commented that such a procedure may not give the correct value for the free acid or base; using the example of the sodium salt of γ-hydroxybutyric acid they pointed out that the sodium ion could have contributed to the observed mortality by changing the electrolytic homeostasis. However, there was no way by which such salt effects could be allowed for in data collected from the literature. Tables 1 and 2 of Supplementary Information give all the values found, and their sources; where more than one source gave the same numerical LD50 value, only one source is listed.

It should be noted that during the literature search numerous errors in the reporting of LD50 values came to light. One of the commonest was not stating whether or not an LD50 value for a salt had been corrected to that of the free acid or base; another common error was the misreporting of someone else’s published value(s). Others concerned omission of the route of administration, the strain, sex and/or age of the animals used, the time after administration at which deaths were counted, whether or not animals were housed in isolation, and time of day or time of year when the experiments were performed. Any or all of these factors can significantly alter the measured LD50 value of the compound under investigation. The use of mean LD50 values in the present work should cancel out the effects of such variables, to some extent at least. Modeling Molecular descriptors were calculated from MOE software (Molecular Operating Environment). Quantitative toxicity-toxicity relationships (QTTRs) were obtained using Minitab statistical software v. 18.1 (Minitab) to generate linear regression equations. For modeling purposes HLD and rodent

LD50 values in mg/kg units were firstly converted to mmol/kg units (Dearden et al., 2009). Next, the reciprocals of the values were taken, simply so that a higher number means a higher toxicity.

Finally, the base-10 logarithms of the values were taken, because LD50 values can range over several orders of magnitude, and also QTTRs can be regarded as free energy equations, requiring the use of logarithmic terms; quantitative structure-property relationships were formerly called linear free energy relationships (Wells, 1968).

Only a few software programs offer rodent LD50 prediction. Predicted rat and mouse intravenous (rmivTB) values were obtained from TerraBase Inc. (TerraBase), and mouse intravenous (Miv(ACD)) and subcutaneous (Msc(ACD)) values were from ACD/Labs software (ACD/Labs). These are commercial programs, although online access to the ACD/Labs software is currently available free of charge for academic staff at U.K. universities. Molecular structures were inputted using SMILES nomenclature (Daylight).

Results and Discussion

The HLD values and mean rodent LD50 values of the 18 psychoactive drugs, together with the predicted values for mouse intravenous and subcutaneous and rat intravenous LD50 values, are given in Table 1. The full set of values and their sources are given in Supplementary Information Tables S1 and S2.

The only rodent LD50 values that correlated well with HLD values were rat intravenous (Riv), mouse intravenous (Miv) and mouse subcutaneous (Msc) LD50 values. All five other correlations (mouse oral (Mor), mouse intraperitoneal (Mip), rat oral (Ror), rat intraperitoneal (Rip), and rat subcutaneous (Rsc)) had r2 values < 0.6, and three of them had r2 values < 0.4. The correlations involving Riv, Miv and Msc are shown below:

log (1/HLD) = 0.392 + 1.089 log (1/RivLD50) (1) n = 14 r2 = 0.823 q2 = 0.755 s = 0.473 F = 55.7

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Table 1. Mean human lethal doses (mg/kg) and mean rodent LD50 values (mg/kg) for 18 psychoactive drugs Riv Rsc Rip Ror Miv Msc Mip Mor MW Name Human rmiv(TB) Miv(ACD) Msc(ACD)

Cocaine 303.4 17.6 91.0 80.9 111.7 20.1 - 68.9 170.5 15.1 23 110 39.7

Codeine 299.4 11.8 257.8 110.0 117.9 57.1 311.2 84.6 232.1 57.4 47 160 59.7

Dextromethorphan 271.4 22.1 160.0 72.4 112.1 26.6 192.8 99.5 325.9 21.7 42 110 16.4

N,N-Dimethyltryptamine 188.3 29.4 280.0 47.0 - 37.5 - 140.0 - - 49 580 32.0

Ethanol 46.1 1400 7319 5608 8909 2061 10325 5092 - 1552 1300 5500 1692

Flunitrazepam 313.3 0.44 923 1050 - 13.7 708 1060 - - 56 800 82.6

Fluoxetine 309.3 36.8 342.9 88.5 - 40.3 614.7 121.0 - 31.3 47 330 74.0

Heroin 369.4 1.47 - 245.7 188.5 26.1 150.0 - - 26.7 38 160 22.0

γ-Hydroxybutyric acid 104.1 235.3 3260 3485 4500 3700 4770 1507 - 1400 1500 4100 3694

Ketamine 237.7 39.7 535.0 291.6 - 56.9 387.0 190.3 - 53.7 67 500 76.9

d-Lysergic acid 295.4 1.47 120.0 50.0 - 45.0 - - - 16.5 59 190 26.9 diethylamide

Mescaline 211.3 123.5 756 239.7 534.0 124.0 370.0 184.6 403.5 157.0 94 220 156.6

Methadone 309.5 1.47 102.9 26.4 35.8 19.3 58.6 14.9 39.2 13.1 28 40 14.8

Methamphetamine 149.2 2.94 181.0 51.6 75.7 13.2 787 51.7 13.8 - 15 55 77.5

3,4-Methylenedioxymeth- 193.2 29.4 106.5 85.6 - 56.0 242.5 41.2 25.4 - 46 290 76.0 amphetamine

Phenobarbital 232.2 73.5 254.4 206.7 196.2 213.7 450.7 145.0 178.1 142.5 390 290 211.8

Psilocybin 284.3 88.2 280.0 285.0 - 280.0 280.0 280.0 - 280.0 420 1600 277.8

Δ9-Tetrahydrocannabinol 314.5 30.0 482.0 341.8 - 42.3 823 522.5 - 33.3 49 540 34.9 Note: In the table headings, M = mouse, R = rat, or = oral, ip = intraperitoneal, sc = subcutaneous, iv = intravenous, ACD indicates predicted values from ACD/Labs software, rmiv(TB) indicates combined rat/mouse predicted values from TerraBase software.

log (1/HLD) = 0.545 + 1.074 log (1/MivLD50) (2) n = 18 r2 = 0.756 q2 = 0.658 s = 0.541 F = 49.5

The positive intercepts in Equations (1) and (2) indicate that the psychoactive drugs are more toxic to humans than to rats (by a factor of 2.5) and to mice (by a factor of 3.5). However, the gradients of both correlations are very close to unity (1.089 and 1.074), indicating that the difference between

HLD and rodent intravenous LD50 is more or less constant, and thus is independent of the chemical class and type of medicinal activity of the drugs:

log (1/HLD) = 1.120 + 1.112 log (1/MscLD50) (3) n = 10 r2 = 0.842 q2 = 0.786 s = 0.523 F = 42.5 where n = number of drugs used to derive the model; r2 = coefficient of determination; q2 = cross-validated coefficient of determination (a measure of the robustness and predictivity of the model); s = standard error of the prediction; F = the Fisher statistic (a measure of significance of the correlation).

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Figure 1. Correlation of HLD values predicted from Equation 1 (rat) with observed HLD values

Figure 2. Correlation of HLD values predicted from Equation 2 (mouse) with observed HLD values

It is unfortunate that Msc and Riv LD50 values could not be found for eight and four drugs respectively, despite extensive searches. On the other hand, the TerraBase and ACD/Labs calculated

LD50 values correlate remarkably well with the mean experimental LD50 values (Equations 4-7), raising the possibility that calculated values could if necessary be used in place of the missing experimental values:

log (1/rmivLD50) = - 0.128 + 1.021 log (1/RivLD50) (4)

5 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 n = 14 r2 = 0.964 q2 = 0.946 s = 0.185 F = 321.2

log (1/rmivLD50) = - 0.039 + 0.904 log (1/MivLD50) (5) n = 18 r2 = 0.887 q2 = 0.863 s = 0.285 F = 126.2

log (1/ACDMivLD50) = 0.015 + 0.836 log (1/MivLD50) (6) n = 18 r2 = 0.955 q2 = 0.942 s = 0.160 F = 340.2

log (1/ACDMscLD50) = 0.040 + 0.929 log (1/MscLD50) (7) n = 10 r2 = 0.977 q2 = 0.969 s = 0.156 F = 334.9

New ‘designer’ drugs frequently appear on the street, and the above correlations allow an estimate to be made of their lethal doses to humans. Because only ten Msc LD50 values appear to be available, it is recommended that only Equations 1 or 2 be used to make such estimates.

Because the TerraBase and ACD/Labs calculated rodent LD50 values are so good (Equations

4 – 7) human lethal doses could be estimated using those calculated rodent LD50 values:

log (1/HLD) = 0.654 + 1.040 log (1/rmivLD50) (8) n = 18 r2 = 0.654 q2 = 0.631 s = 0.644 F = 30.1

log (1/HLD) = 0.568 + 1.190 log (1/ACDMivLD50) (9) n = 18 r2 = 0.678 q2 = 0.603 s = 0.621 F = 33.7

log (1/HLD) = 1.294 + 1.124 log (1/ACDMscLD50) (10) n = 18 r2 = 0.596 q2 = 0.513 s = 0.695 F = 23.6

The statistics of Equations 8 and 9, although poorer than those of Equations 1 – 3, are still reasonable, but those of Equation 10 are borderline. It is suggested that the average HLD from Equations 8 and 9 could be taken as the predicted human lethal dose of a new drug of abuse, without the need for measured rodent LD50 values. It should be noted that a drug whose HLD is required to be predicted should have some similarity to one or more of the drugs used to develop the equations, and should not be expected to have a HLD much greater or lower than the range covered by those drugs, otherwise there could be a low level of confidence in the prediction. It is always necessary to test the predictivity of models such as those given above (Dearden et al. (2009), by seeing how well they can predict the human lethal dose of a psychoactive drug that was not used to develop the models. HLD, Riv and Miv values were obtained from published literature for three psychoactive drugs, amitriptyline, amphetamine and dextropropoxyphene (see Supplementary Tables 1 and 2), and predicted Riv and Miv values were obtained from TerraBase Inc. and ACD/Labs software respectively. Equations 1, 2, 8 and 9 were then used to predict HLD values for the three test drugs. The predicted values, together with observed HLD values, are given in Table 2.

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Table 2. Prediction of HLD values (mg/kg) for external test drugs

From From From From Drug Observed Equation 1 Equation 2 Equation 8 Equation 9 Amitriptyline 11.1 3.81 4.02 3.16 4.48 Amphetamine 5.0 6.84 3.65 4.01 5.61 Dextropropoxyphene 9.1 4.11 6.93 7.03 7.20

It can be seen from Table 2 that all predicted HLD values are close to the observed values, being well within one standard deviation. The QTTR models developed here thus have very good predictivity, and can be used even by those with no knowledge of QTTR. Equations 1 and 2 have very good statistics, in contrast to correlations between HLD and rodent oral or intraperitoneal LD50 values. One explanation of that is that little or no metabolism occurs when drugs are administered intravenously, in contrast to oral and intraperitoneal administration. In addition, the data in Supplementary Appendix 2 shows that there is generally more scatter in rodent

LD50 values obtained using oral, intraperitoneal and subcutaneous administration than in those obtained using intravenous administration. Surprisingly, there do not appear to be any published studies of the correlation of human lethal doses versus rodent intravenous LD50 values. One reason for that could be there are relatively few of the latter values in published literature, especially when compared with rodent oral LD50 values (see Supplementary Tables 1 and 2). This work has shown that it is possible, with the use of measured or predicted rat and/or mouse intravenous LD50 values, to obtain good estimates of human lethal doses of psychoactive drugs. Equations 1 and 2 are interspecies correlations, and hence can be used to investigate differences between human and rodent of psychoactive drugs. Equations 11 and 12 show that the ratio of human to rodent lethal doses of psychoactive drugs appears to be a function of dipole moment and solvation energy (E_sol). The descriptors were selected using forward selection step-wise regression in Minitab software. Note that log (RivLD50/HLD) = log (1/HLD) – log (1/ RivLD50):

log (RivLD50/HLD) = – 0.314 + 1.099 dipole – 0.150 AM1_dipole – 0.0294 E_sol (11) n = 14 r2 = 0.854 q2 = 0.676 s = 0.199 F = 19.5

log (MivLD50/HLD) = – 0.138 + 1.314 dipole – 0.254 AM1_dipole – 0.0428 E_sol (12) n = 18 r2 = 0.750 q2 = 0.622 s = 0.292 F = 14.0

The two dipole terms in Equations 11 and 12 are not highly correlated (r2 = 0.733) so it is statistically valid to include both. It is clear that the difference between HLD and rodent intravenous

LD50 values is a function largely of the dipole moments of the drugs, which suggests that a difference in the strength of dipole-dipole interaction at either a or a membrane is responsible. A similar explanation, involving a difference of drug-water interaction strength, could account for the inclusion of the solvation energy term in Equations 11 and 12.

CONCLUSION

Rat and mouse measured and predicted intravenous LD50 values have been shown, using linear regression correlations, to predict the human lethal doses (HLDs) of a diverse data set of 18 psychoactive drugs

7 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 with good accuracy, as well as those of three external test drugs, namely amitriptyline, amphetamine and dextropropoxyphene. This will allow toxicologists to calculate the HLDs of new ‘designer’ drugs quickly from the correlation equations, provided that they are of similar molecular structure and chemical class to one or more of the training set drugs, and that their physicochemical properties are within or close to the ranges encompassed by the training set drugs. It is emphasized, nevertheless, that the diversity of the training set sets is so wide that the requirement of similarity of molecular structure and chemical class should not be unnecessarily restrictive.

CONFLICT OF INTEREST

The author declares no conflict of interests.

SUPPORTING INFORMATION

Appendix A contains all the rat and mouse LD50 values listed by source. Appendix B lists all the rat and mouse LD50 values grouped by drug and route of administration, together with their means.

ACKNOWLEDGMENT

The author is grateful to Dr. Simon Brandt for helpful advice and assistance with data collection, to Dr. Mark Hewitt for the calculation of MOE descriptors, and to the Faculty of Science of Liverpool

John Moores University for a grant for the purchase of software-predicted rat and mouse LD50 values.

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REFERENCES

Abbott, A. (2005). Animal testing: More than a cosmetic change. Nature, 438, 144–146. PMID:16281001 ACD/Labs software. (n..d.). Retrieved from https://www.acdlabs.com/ British National Formulary. (n.d.). Retrieved from https://bnf.nice.org.uk/

Carai, M. A. M., Colombo, G., & Gessa, G. L. (2004). Protection by the GABAB , SCH 50911, of γ-hydroxybutyric acid-induced mortality in mice. European Journal of , 503(1-3), 77–80. PMID:15496299 Clothier, R. H., Hulme, L. M., Smith, M., & Balls, M. (1987). Comparison of the cytotoxicities and acute in vivo toxicities of 59 chemicals. Molecular , 1(4), 571–577. PMID:3509703 Crime Survey for England and Wales. (2017). Retrieved from https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/data/file/642738/drug-misuse-2017-hosb1117.pdf Daylight. http://daylight.com/dayhtml/doc.theory/theory.smiles.html Dearden, J. C., Cronin, M. T. D., & Kaiser, K. L. E. (2009). How not to develop a quantitative structure-activity or structure-property relationship (QSAR/QSPR). SAR and QSAR in Environmental Research, 20(3), 241–266. PMID:19544191 Ekwall, B., Barile, F. A., Castano, A., Clemedson, C., Clothier, R. H., Dierickx, P., & Zucco, F. et al. (1998).

MEIC evaluation of acute systemic toxicity. Part VI. The prediction of human toxicity by rodent LD50 values and results from 61 in vitro methods. Alternatives to Laboratory Animals, 26(Suppl. 2), 617–658. PMID:26042663 Gable, R. S. (1993). Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically. The American Journal of Drug and Abuse, 19(3), 263–281. PMID:8213692 Gable, R. S. (2004). Comparison of acute lethal toxicity of commonly abused psychoactive substances. (Abingdon, England), 99(6), 686–696. PMID:15139867 Hoffmann, S., Kinsner-Ovaskainen, A., Prieto, P., Mangelsdorf, I., Bieler, C., & Cole, T. (2010). Acute oral toxicity: Variability, reliability, relevance and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project. Regulatory Toxicology and Pharmacology, 58(3), 395–407. PMID:20709128 Jover, R., Ponsoda, X., Castell, J. V., & Gómez-Lechón, M. J. (1992). Evaluation of the cytotoxicity of ten chemicals on human cultured hepatocytes: Predictability of human toxicity and comparison with rodent cell culture systems. Toxicology In Vitro, 6(1), 47–52. PMID:20732091 Minitab statistical software. (n.d.). Retrieved from http://www.minitab.com/ Molecular Operating Environment software. (n.d.). Retrieved from https://www.chemcomp.com Office for National Statistics. (n.d.). Retrieved from https://www.ons.gov.uk/peoplepopulationandcommunity/ birthsdeathsandmarriages/deathsrelatedtodrugpoisoninginenglandandwales TerraBase Inc. (n.d.). Retrieved from http://www.terrabase-inc.com/ Trevan, J. W. (1927). The error of determination of toxicity. Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character, 101(712), 483–514. Wells, P. R. (1968). Linear Free Energy Relationships. London: Academic Press.

Zbinden, G., & Flury-Roversi, M. (1981). Significance of the LD50 test for toxicological evaluation of chemical substances. Archives of Toxicology, 47(2), 77–99. PMID:7271444

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APPENDIX A: SUPPLEMENTARY INFORMATION - SOURCES OF LD50 VALUES

Source Abbreviations Gable: Gable, R.S. (2004). Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction, 99, 686-696. CIDP: ChemIdPlus; https://chem.nim.nih.gov/chemidplus/. Sax: Sax’s Dangerous Properties of Industrial Chemicals: 9th edn., (ed. Lewis R.J.), Van Nostrand Reinhold, New York, NY, 1996; 11th edn. (ed. Lewis R.J.), John Wiley & Sons Inc., Hoboken, N.J., 2004; 12th edn. (ed. Lewis R.J.), John Wiley & Sons Inc., Hoboken, N.J., 2012. Cocaine HCl Mip 91 (Gable). Mor 99, Mip 59, Msc 81, Miv 16, Rip 70, Rsc 250, Riv 17.5 (CIDP). Cocaine HCl Mor 96 (corr. 85.7), Mip 68 (corr. 60.7), Msc 30 (corr. 26.8), Miv 15 (corr. 13.4), Rip 78 (corr. 69.6), Rsc 102 (corr. 91.0), Riv 16.38 (corr. 14.6) (CIDP). Cocaine HCl Mip 92.4(f) (corr. 82.5)(f), Mip 93.0(m) (corr. 83.0) (Hearn, W.L., Rose, S., Wagner, J., Ciarleglios, A., & Mash, D.C. (1991). Cocaethylene is more potent than cocaine in mediating lethality. Pharmacology and Behavior, 39(2), 531-533). Cocaine (HCl?)_ Mor 99, Mip 59, Miv 16 (Svennebring, A. (2016). The connection between plasma

protein binding and acute toxicity as determined by the LD50 value. Drug Development Research, 77(1), 3-11). Cocaine HCl Riv 14 mg/kg (corr. 12.5) (Smith, M., Garner, D., & Niemann, J.T. (1991). Pharmacologic

interventions after an LD50 cocaine insult in a chronically instrumented rat model: are beta-blockers contraindicated? Annales of Emergency , 20(7), 768-771). Mip 101.55(m), 90.00(f) (Schechter, M.D., & Meehan, S.M. (1995). The lethal effects of ethanol and cocaine and their combination in mice: implications for cocaethylene formation. Pharmacology Biochemistry & Behavior, 52(1), 245-248). Mip 15.2 (Harbison, R.D., & Evans, M.A. (1978). Teratogenic aspects of drug abuse in pregnancy. In: Rementeria, J.L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects, pp. 233-256. C.V. Mosby Co.: St. Louis, MO). Mip 75, Miv 30 (Sax, 11th edn.). Msc 156 (Graham, J.D.P., & Gurd, M.R. (1940). Effect of ephedrine on the toxicity of local anesthetics. Quarterly Journal of and Pharmacology, 13, 122-129). Cocaine HCl Mip 102(m) (corr. 91(m)) (Heard, K., Krier, S., & Zahniser, N.R. (2008). Administration of ziprasidone for 10 days increases cocaine toxicity in mice. Human and Experimental Toxicology, 27(6), 499-503). Cocaine HCl Mip 95.1 (corr. 84.9) (Bedford, J.A., Turner, C.E., & Elsholy, H.N. (1982). Comparative lethality of coca and cocaine. Pharmacology Biochemistry and Behavior, 17(5), 1087-1088). Cocaine HCl Mip 100.6(m) (corrected 89.8) (Shukla, V.K., Goldfrank, L.R., Turndorf, H., & Banisath, M. (1991). Antagonism of acute cocaine toxicity by buprenorphine. Life Sciences, 49(25), 1887-1893). Cocaine HCl Msc 125 (corr. 111.6) (Benes, L., Borovansky, A., & Kopacova, L. (1972). Local anesthetics. XLI. Basic trans- and cis-cyclohexyl esters of substituted alkoxycarbanilic acids. Archive der Pharmazie, 305(9), 648-654). Cocaine HCl Msc 205 (corr. 183) (Mamedov, S., Tagdisi, D.G., Aminimuaiid, R.A., & Mamedova, E.I. (1966). Efiran-583 as a new local anesthetic. Izvestiya Akademii Nauk Azerbaidzhanskoi SSR, Seriya Biologicheskikh Nauk, (4), 132-135). Cocaine HCl Mip(m) (corr. 98.2) (DeWitt, C.R., Cleveland, N., Dart, R.C.,& Heard, K. (2005). The effect of amiodarone pretreatment on survival of mice with cocaine toxicity. Journal of Medical Toxicology, 1(1), 11-18).

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Cocaine HCl Mip 93 (corr. 83) (Treweek, J.B., Roberts, A.J., & Janda, K.D. (2011). Immunopharmacotherapeutic manifolds and modulation of cocaine overdose. Pharmacology Biochemistry and Behavior, 98(3), 474-484). Cocaine HCl Mip 80.7(m) (corr. 72.0(m)) (housed 6 per cage, and all tested at same period of day) (Ansah, T.A., Wade, L.H., Kopsombut, P., & Shockley, D.C. (2002). Nifedipine potentiates the toxic effects of cocaine in mice. Progress in Neuro- and Biological , 26(2), 357-362). Cocaine HCl Mip 67(m) (corr. 59.8) (Hamilton, H.S., Westfall, B.A., & Ferguson, J.K.W. (1948). A comparison of nine local anesthetics. Journal of Pharmacology and Experimental Therapeutics, 94(3), 299-307). Miv 16, Riv 17.5 (Lachenmeier, D.W., & Rehm, J. (2015). Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports, 5, 8126; DOI: 10.1038/srep8126). Cocaine HCl Rip 79.7(m) (corr. 71.2(m)) (housed in groups of 6) (Witkin, J.M., Goldberg, S.R., & Katz, J.L. (1989). Lethal effects of cocaine are reduced by the -1 receptor antagonist SCH 23390 but not by haloperidol. Life Sciences, 44(18), 1285-1291). Cocaine HCl Rip 82.5 (corr. 73.7) (Witkin, J.M., Goldberg, S.R., Katz, J.L., & Kuhar, M.J. (1989). Modulation of the lethal effects of cocaine by cholinomimetics. Life Sciences, 45(24), 2295-2301).

Rip(f) 55.2 (Glantz, J.C., & Woods, J.R. (1994). Cocaine LD50 in Long-Evans rats is not altered by pregnancy or . Neurotoxicology and Teratology, 16(3), 297-301). Rip 80(m) (Lynch, T.J., Mattes, C.E., Singh, A., Bradley, R.M., Brady, R.O., & Dretchen, K.L. (1997). Cocaine detoxification by human plasma butyrylcholinesterase. Toxicology and Applied Pharmacology, 145, 363-371). Rip 92.6(m) (Hoskins, B., Burton, C.K., & Ho, I.K. (1988). Diabetes potentiation of cocaine toxicity. Research Communications in Substances of Abuse, 9(2), 117-123). Mip for 2 mouse strains: short 100.7; long sleep 107.2 (George, F.R. (1991). Cocaine toxicity: genetic evidence suggests different mechanisms for cocaine-induced seizures and lethality. Psychopharmacology, 104(3), 307-311). Rip(m) for 4 rat strains: ACI 64.3; F344 57.5; LEW 61.4; NBR 34.0 (George, F.R. (1991). Cocaine toxicity: genetic differences in cocaine-induced lethality in rats. Pharmacology Biochemistry and Behavior, 38(4), 893-895). Mip 91, Riv 17.5 (Cunha-Oliveira, T., Rego, A.C., Carvalho, F., & Oliveira, C.R. (2013). Medical toxicology of drugs of abuse. In: Miller, P.M. (ed.). Principles of Addiction: Comprehensive Addictive Behaviors and Disorders, vol. 1, pp. 159-176. Academic Press: San Diego, CA). Mip 95.1 (Domingo, G., Schirmer, K., Brocale, M., & Pomati, F. (2011). Illicit drugs in the environment: implications for ecotoxicology. In: Castiglioni S, Zuccato E, Fanelli R (eds.). Illicit Drugs in the Environment: Occurrence, Analysis, and Fate using Mass Spectrometry, pp. 253-274. John Wiley & Sons: Hoboken, NJ). Mor 99, Mip 75, Miv 30, Rip 70, Riv 17.5 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). Mip 104, Msc 134 (Chabrier, P.R., Giudicelli, R., & Thuillier, J., 1950. Chemical, pharmacological, and clinical study of a new cough sedative – morpholylmorphine. Annales Pharmaceutiques Françaises, 8, 261-273). Codeine phosphate Mor 250 (corr. 188.3), Ror 266 (corrected 200.4) (Gable). Codeine phosphate Mor 237 (corr. 178.6), Mip 110 (corr. 82.9), Msc 80 (corr. 60.3), Miv 62 (corr. 46.7), Ror 85 (corr. 64.0), Rip 104 (corr. 78.4), Rsc 312 (corr. 235.1), Riv 54 (corr. 40.7) (CIDP). Codeine phosphate Mip 185.1 (corr. 139.5) (Kasuya, Y., Watanabe, M., Miyasaka, K., & Ishii, Y. (1977). Potentiation of antitussive effect of codeine by some 1-dimethoxyphenyl-3- alkylaminobutanols in guinea pigs. Arzneimittelforschung, 27(7), 1450-1455).

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Codeine phosphate Mor 550 (corr. 414.4), Msc 191 (corr. 143.9), Miv 87 (corr. 65.5) (Kobayashi, S., Hasegawa, K., Mori, M., & Tagaki, H. (1970). Pharmacological studies on a new specifically potent antitussive agent, 14-hydroxydihydro-6β-thebainol-4-methylether (oxymethebanol). Arzneimittelforschung, 20(1), 43-46). Codeine (taken to be phosphate) Msc 177 (corr. 136.3) (Kito, G., Kase, Y., Takashi, M., Okano, Y., Sato, M., & Ishihara, T. (1974). Pharmacology of 3’-chloro-2’-(N-methyl-N-[(morpholinocarbonyl) methyl]aminomethyl)benzanilide (PB-89, fominoben), a new antitussive possessing respiratory stimulating action. Oyo Yakuri, 8(10), 1491-1513). Codeine (taken to be phosphate) Msc 197 (corr. 148.6) (Kase, Y., Kito, G., Okano, Y., & Sakata, M. (1975). Antitussive action of tolperisone (2,4’-dimethyl-3-piperidinopropiophenone, Muscalm). Oyo Yakuri, 9(5), 809-817). Ror 487.2 (mean of 6) (Hoffmann, S., Kinsner-Ovaskainen, A., Prieto, P., Mangelsdorf, I., Bieler, C., & Cole, T. (2010). Acute oral toxicity: variability, reliability, relevance and interspecies

comparison of rodent LD50 data from literature surveyed for the AcuteTox project. Regulatory Toxicology and Pharmacology, 58(3), 395-407). Codeine (phosphate?) Mor 250, Mip 60, Miv 54 (Svennebring, A. (2016). The connection between

and acute toxicity as determined by the LD50 value. Drug Development Research, 77(1), 3-11). Mor 250, Mip 60, Msc 84.1, Miv 54, Ror 427, Rip 100, Rsc 229, Riv 75 (CIDP). Mor 250, Ror 427 (Volmer, P.A. (2006). “Recreational” drugs. In: Peterson, M.E., Talcott, P.A. (eds). Small Animal Toxicology, pp.273-311. Elsevier Health Sciences, St. Louis, MO). Mor 250, Mip 60, Miv 54, Ror 427, Rip 100, Riv 75 Mor 99, Mip 75, Miv 30, Rip 70, Riv 17.5 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). Mor 210, Ror 350 (Gable). Msc 112, Ror 116, Riv 16.3 (CIDP). Riv 27 (Tortella, F.C., Britton, P., Williams, A., Lu, X.C., & Newman, A.H. (1999). Neuroprotection (focal ischemia) and (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist. Journal of Pharmacology and Experimental Therapeutics, 29(1), 399-408). DXM HBr Mor 165 (corr. 127.1), Msc 125 (corr. 96.3), Miv 34 (corrected 26.2), Ror 350 (corrected 269.6), Rsc 423 (corr. 325.9) (CIDP). DXM HBr Mor 165 (corr. 127), Miv 35 (corr. 27), Ror 350 (corr. 269.6) (Benson, W.M., Stefko, P.L., & Randall, L.O. (1953). Comparative pharmacology of levorphan, racemorphan and and related methyl ethers. Journal of Pharmacology and Experimental Therapeutics, 109(2), 189-200). DXM HBr Mip 94 (corr. 72.4) (Kigoshi, S., & Kokubo, M. (1987). Effect of several d-morphinans on ascites tumors in mice. Japanese Journal of Pharmacology, 44(3), 293-302). DXM HBr monohydrate_Rip 138 (corr. 99.5) (Chen, Y.-W., Chu, K.-S., Lin, C.-N., Tzeng, J.-I., Chu, C.-C., Lin, M.-T., & Wang, J.-J. (2007). Dextromethorphan or dextrorphan have a local anesthetic effect on infiltrative cutaneous analgesia in rats. Anesthesia and Analgesia, 104(5), 1251-1255). DXM (taken to be HBr salt) Msc 147.5 (corr. 113.6) (Kito, G., Kase, Y., Takashi, M., Okano, Y., Sato, M., & Ishihara, T. (1974). Pharmacology of 3’-chloro-2’-(N-methyl-N-[(morpholinocarbonyl) methyl]aminomethyl)benzanilide (PB-89, fominoben), a new antitussive possessing respiratory stimulating action. Oyo Yakuri, 8(10), 1491-1513). DXM (taken to be HBr salt) Msc 164.2 (corr. 126.5) (Kase, Y., Kito, G., Okano, Y., & Sakata, M. (1975). Antitussive action of tolperisone (2,4’-dimethyl-3-piperidinopropiophenone, Muscalm). Oyo Yakuri, 9(5), 809-817). Mor 201 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). N, N-Dimethyltryptamine

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Mor 280, Mip 47 (Gable). Miv 32 (CIDP). Miv 43 (Brimblecombe, R.W., Downing, D.F., Green, D.M., & Hunt, R.R. (1964). Some pharmacological effects of a series of tryptamine derivatives. British Journal of Pharmacology, 23(1), 43-54). DMT HCl Rip 167 (Espamer, V. (1966) . Peripheral physiological and pharmacological actions of indolealkylamines. In: Espamer, V. (ed.). Handbook of Experimental Pharmacology XIX. 5-Hydroxytryptamine and Related Indolealkylamines, pp. 245-359. Springer Verlag: Berlin). Ethanol Mor 6800, Ror 10300 (Gable). Mip 528, Msc 8285, Miv 1973, Rip 3.6 (error – given as 3600 μg/kg instead of 3600 mg/kg), Riv 1440 (CIDP). Ror 8400, Rip 5100 (Ward, C.O., Cam, C.A.L., Tang, A.S.M., Breglia, R.J., & Jarowski, C.I. (1972). Effect of lysine on toxicity and depressant effects of ethanol in rats. Toxicology and Applied Pharmacology, 22(3), 422-426). Ror 7420 (Golovinskaya, L.I. (1976). Water and electrolyte metabolic disturbances in poisoning by home brew and higher alcohols. Sudebno-Meditsinskaya Ekspertiza, 19(1), 33-35). Ror 14990(f) (Youssef, A., Madkour, K., Cox, C., & Weiss, B. (1992). Comparative lethality of , ethanol and mixtures in female rats. Journal of Applied Toxicology, 12(3), 193-197). Ror 21000 (Kennedy, G.L., & Graepel, G.J. (1991). Acute toxicity in the rat following either oral or inhalation exposure. Toxicology Letters, 56(3), 317-326). Ror 7300 (Hillborn, M.E., Sarviharju, M.S., & Lindros, K.O. (1983). Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation. Toxicology and Applied Pharmacology, 70(1), 133-139). Ror 10400 (Hinz, G., Gohlke, R., & Burck, D. (1980). The effect of simultaneous applications of ethanol and styrene. 1. Acute and subacute experiments on rats. Journal of Hygiene, Epidemiology, Microbiology, and , 24(3), 262-270). Mor 7484, Mip 2876 (Dorato, M.A., Lynch, V.D., & Ward, C.O. (1977). Effect of lysine and diethanolamine-rutin on blood levels, withdrawal reaction, and acute toxicity of ethanol in mice. Journal of Pharmaceutical Sciences, 66(1), 35-39). Mor 8709 (mean of 4), Ror 12519.4 (mean of 8) (Hoffmann, S., Kinsner-Ovaskainen, A., Prieto, P., Mangelsdorf, I., Bieler, C., & Cole, T. (2010). Acute oral toxicity: variability, reliability, relevance

and interspecies comparison of rodent LD50 data from literature surveyed for the AcuteTox project. Regulatory Toxicology and Pharmacology, 58(3), 395-407). Mip 8100 (Tsibulsky, V.L., & Amit, Z. (1993). Tolerance to effects of high doses of ethanol: 1. Lethal effects in mice. Pharmacology Biochemistry and Behavior, 45(2), 465-472). Mip 9000 (Hu, J.-H., Ma, Y.-H., Yang, N., Mei, Z.-T., Zhang, M.-H., Fei, J., & Guo, L.-H. (2004). Up- regulation of γ-aminobutyric acid transporter I mediates ethanol sensitivity in mice. , 123(4), 807-812). Mip 6820 (long-sleep mice), 8050 (short-sleep mice) (Baker, R.C., Smolen, A., Smolen, T.N., & Deitrich, R.A. (1987). Relationship between acute ethanol-related responses in long-sleep and short-sleep mice. Alcohol: Clinical and Experimental Research, 11(6), 574-578). Mip 9200 (Ho, A.K.S., Chen, R.C.A., & Ho, C.C. (1978). Interaction toxicity between ethanol and narcotics in mice with reference to alpha-1-acetylmethadol (LAAM). Pharmacology Biochemistry and Behavior, 9(2), 195-200). Mip 7200 (Pietrzak, B., & Kubik-Bogucka, E. (2002). Influence of mianserin on some central effects of ethanol. Pharmacological Research, 46(1), 47-54). Mip 7800 (Gailis, L., Tourigny, A. (1984). Chlorpromazine and dithioerythritol protection against acute ethanol toxicity. Alcohol: Clinical and Experimental Research, 8(3), 308-313).

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Mip 6000 (mean of 5), Ror 13200 (Clothier, R.H., Hulme, L.M., Smith, M., & Balls, M. (1987). Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals. Molecular Toxicology, 1(4), 571-577). Mor 8469 (Mallach, H.J., & Röseler. P. (1961). Observations and research on the combined effects of alcohol and carbon monoxide. Arzneimittelforschung, 11(11), 1004-1008). Mor 8285, Mip 3156, Miv 2209, Ror 10260, Rip 4970, Riv 1815 (Bartsch, W., Sponer, G., Dietmann, K., & Fuchs, G. (1976). Acute toxicity of various solvents in the mouse and rat. Arzneimittelforschung, 26(8), 1581-1583). Mor 7790, Ror 7053 (Ekwall, B., Gómez-Lechón, M.J., Hellberg, S., Bondesson, I., Castell, J.V., Jover, R., Högberg, J., Ponsoda, X., Romert, L., Stenberg, K., & Walum, E. (1990). Preliminary results from the Scandinavian multicentre evaluation of in vitro cytotoxicity (MEIC). Toxicology in Vitro, 4(4-5), 688-691). Mor 8800 (Etzler, K. (1967). Experimental animal investigations on the joint effects of ethyl alcohol and Mogadan® Roche. Inaugural Dissertation, University of Tübingen, Germany). Ror 10600 (3-4 months old), 7060 (10-12 months old); Rip 6710 (3-4 months old), 5100 (10-12 months old) (Wiberg, G.S., Trenholm, H.L., & Coldwell, B.B. (1970). Increased ethanol toxicity

in old rats: changes in LD50, in vivo and in vitro metabolism, and liver alcohol dehydrogenase activity. Toxicology and Applied Pharmacology, 16(3), 718-727). Note: only young rat data used. Ror 10000 (Breglia, R.J., Ward, C.O., & Jarowski, C.I. (1973). Effect of selected amino acids on ethanol toxicity in rats. Journal of Pharmaceutical Sciences, 62(1), 49-55). Ror 14009 (Enslein, K., Tuzzeo, T.M., Borgstedt, H.H., Blake, B.W., & Hart, J.B. (1987). Prediction of

rat oral LD50 from Daphnia magna LC50 and chemical structure. In: Kaiser, K.L.E. (ed.). QSAR in Environmental Toxicology – II, pp. 91-106. D. Reidel Publishing Company, Dordrecht, Holland). Ror 7790 (Gartlon, J., Kinsner, A., Bal-Price, A., Coecke, S., & Clothier, R.H. (2006). Evaluation of a proposed in vitro test strategy using neuronal and non-neuronal cell systems for detecting neurotoxicity. Toxicology in Vitro, 20(8), 1569-1581). Rip 9800 (Jarowski, C.I., & Ward, C.O. (1971). Effect of tryptophan on toxicity and depressant effects of barbiturates and ethanol in rats. Toxicology and Applied Pharmacology, 18(3), 603-606). Rip 7900 (Hollstedt, C., Neri, A., & Rydberg, U. (1981). Ethanol-induced lethality in the developing rat. Blutalkohol: Alcohol, Drugs and Behavior, 18(4), 245-252). Note: This paper determined

LD50 values at rat weights ranging from 25g. to 250g. The value determined for 200g. rats was

used. The Rip LD50 for 100g. rats was 9000. Rip 3367 (Craig, J. (1975). Effects of ethanol and ethionine on DNA synthesis during experimental liver regeneration. Journal of Studies on Alcohol, 36(1), 148-157). Rip 1920 (Lundberg, I., Ekdahl, M., Kronevi, T., Lidums, V., & Lundberg, S. (1986). Relative hepatotoxicity of some industrial solvents after intraperitoneal injection or inhalation exposure in rats. Environmental Research, 40(2), 411-420). Msc 10000 (Thomas, H.M., Trémolières, J., Griffaton, G., & Lowy, R. (1968). Modification of the water-electrolyte balance of mouse tissues by a toxic dose of ethanol. Food and Cosmetics Toxicology, 6(1), 33-38). Msc 8442 (Wagner, K., & Wagner, H.J. (1958). Nil nocere: hazards of medical treatment of accident injuries caused by alcohol (with barbiturates, morphine and polamidone). Münchener Medizinische Wochenschrift, 100(49), 1923-1925). Mor 9490 (Dodson, R.A., Polishak, B.L., Eide, T.J., & Johnson, W.E. (1984). Lethal dose studies with calcium chloride, general CNS depressants, A231878 and verapamil. Proceedings of the Western Pharmacology Society, 27, 511-514). Mor 7830, Ror 6980 (Calleja, M.C., Persoone, G., & Geladi, P. (1994). Human acute toxicity prediction of the first 50 MEIC chemicals by a battery of ecotoxicological tests and physicochemical properties. Food and Chemical Toxicology, 32(2), 173-187).

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Mip 9710(m), 9450(f) (Schechter, M.D., & Meehan, S.M. (1995). The lethal effects of ethanol and cocaine and their combination in mice: implications for cocaethylene formation. Pharmacology Biochemistry and Behavior, 52(1), 245-248). Mor 3450, Mip 933, Miv 1973, Ror 7060, Rip 3750, Riv 1440 (Burdick & Jackson Material Safety Data Sheet; https://research.utdallas.edu/cleanroom/app/uploads/2014/12/ethanol.pdf). Mor 3400, Mip 900, Miv 2000, Ror 7000, Ror 10600, Ror 9900, Rip 3800, Riv 1400 (Toxnet: http:// toxnet.nlm.nih.gov/cgi-bin/sis/search). Mor 700, Ror 1000 (Gable). Mor 1200, Mip 1050, Msc >4000, Ror 415, Rip 1060, Rsc >4000 (CIDP). Mor 1200, Mip 1050, Miv 13.7 (Svennebring, A. (2016). The connection between plasma protein

binding and acute toxicity as determined by the LD50 value. Drug and Development Research, 77(1), 3-11). Mor 870 (Quiñones-Torrelo, C., Sagrado-Vives, S., Villanueva-Camañas, R.M., & Medina-Hernández,

M.J. (2001). An LD50 model for predicting psychotropic drug toxicity using biopartitioning micellar chromatography. Biomedical Chromatography, 15(1), 31-40). Mor 464, Mip 87.5, Ror 825, Rip 121 (CIDP). Fluoxetine HCl Mor 248 (corr. 221.8), Mip 100 (corr. 89.4), Ror 452 (corr. 404.3) (CIDP). Fluoxetine HCl Miv 45 (corr. 40.3), Riv 35 (corr. 31.3) (Ridley, D.S., & Bopp, R.J. (1990). Fluoxetine. In: Florey, K. (ed.). Profiles of Drug Substances, Excipients and Methodology, vol. 19, pp. 193- 217. Academic Press, San Diego, CA). Miv 22, Riv 23 (Gable). Miv 21.8, Riv 22.5 (CIDP). Msc 130 (Dubas, T., Lundy, P., Colhoun, E., & Parker, J.M. (1972). Investigation of mechanisms involved in toxic effects of narcotic analgesics. Internationale Zeitschrift für Klinische, Pharmakologie, Therapie und Toxikologie, 5(4), 397-402). Heroin HCl Mip 240, Msc 262, Miv 38 (CIDP). Heroin HCl Mip 300 (corr. 273) (Guillot, E., de Mazancourt, P., Durigon, M., & Alvarez, J.-C. (2007). Morphine and 6-acetylmorphine concentrations in blood, brain, spinal cord, bone marrow and bone after lethal acute or chronic diacetylmorphine administration to mice. Forensic Science International, 166(2-3), 139-144). Heroin HCl Msc 190.5 (corr. 173.4) (Brands, B., Hirst, M., & Gowdrey, C.W. (1976). Duration of analgesia in mice after heroin by two testing methods. Canadian Journal of and Pharmacology, 54(3), 381-385). Ror 150 (Hogg, J.L. (2014). CHEM2: Chemistry in Your World (2nd edn.), p. 361. Cengage Learning Inc.: Boston, MS). γ-Hydroxybutyric acid Mor 1720, Ror 1540 (Gable). Mor 4800, Mip 4200, Msc 4500, Miv 3700 (CIDP). GHB Na salt Mip 4300 (corr. 3550) (Carai, M.A.M., Colombo, G., & Gessa, G.L. (2004). Protection

by the GABAB receptor antagonist, SCH 50911, of γ-hydroxybutyric acid-induced mortality in mice. European Journal of Pharmacology, 503(1-3), 77-80). GHB Na salt Mip 3300 (corr. 2724), Ror 9690 (corr. 8000), Rip 1650 (corr. 1362) (CIDP). GHB Na salt Mip 4200 (corr. 3467) (Frahm, M. (1973). Pharmacological studies of gamma- hydroxybutyric acid derivatives. In: Bushart, W., Rittmeyer, P. (eds.). Anaesthesie mit Gamma- Hydroxibuttersäure: Experimentelle und klinische Erfahrungen, pp. 5-8. Springer-Verlag: Berlin). Rip (male) 2000, female 1650 (Merck Index, 13th Edn., Royal Society of Chemistry, Cambridge, 2013).

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GHB sodium salt Riv 1700 (corr. 1400) (Laborit, H. (1964). Sodium 4-hydroxybutyrate. International Journal of Neuropharmacology, 3(4), 433-451). Note: not entirely clear whether this is Riv or Rip. Mip 2960-3700, Rip(m) 2000(Na salt) (corr. 1651), Rip(f) 1650(Na salt) (corr. 1362) (Toxnet: http:// toxnet.nlm.nih.gov/cgi-bin/sis/search). Ketamine Ketamine HCl Mip 400 (corr. 346.7) (Gable). Mip 400, Miv 77 (CIDC). Riv 51.2 (Leccese, A.P., Marquis, K.L., Mattia, A., & Morton, J.E. (1986). The convulsant and effects of phencyclidine (PCP) and PCP analogues in the rat. Behavioural Brain Research, 19(2), 163-169). Miv 42.9 (Ben-Shlomo, I., Katz, Y., Rosenbaum, A., & Hadash, O. (2001). Intravenous significantly enhances the lethal effect of thiopental but not that of ketamine in mice. Pharmacology Research, 44(6), 509-512). Rip 148 (Rebuelto, M., Ambros, L., Montoya, L., & Bonafine, R. (2002). Treatment-time- dependent difference of ketamine pharmacological response and toxicity in rats. International, 19(5), 937-945). Riv 58.9 (Harvey, M., Sleigh, J., Voss, L., Jose, J., Gamage, S., Pruijn, F., Liyanage, S., & Denny, W. (2015). Development of rapidly metabolized and ultra-short-acting ketamine analogs. Anesthesia and Analgesia, 121(4), 925-933). Ketamine HCl Mip 259.9 (corr. 225.3) (Wu, T., Zhang, L., Wang, J., Zhou, M., Shao, D., & Dai, T. (2010). Influences of scopolamine on analgesic, hypnotic and of ketamine. Shanghai Yixue, 33(4), 325-328). Ketamine HCl Miv 56.98 (corr. 49.4) (Barak, M., Ben-Shlomo, I., & Katz, Y. (2001). Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice. Journal of Basic and Clinical Physiology and Pharmacology, 12(4), 315-323). Ketamine HCl Mor 617 (corr. 535), Mip 224 (corr. 194), Miv 55.9 (corr. 48.5), Ror 447 (corr. 387), Rip 224 (corr. 194), Riv 58.9 (corr. 51.1) (CIDC). Rip 229 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). d-Lysergic acid diethylamide Miv 46, Riv 17 (Gable). Mip 50, Miv 46, Riv 16 (CIDC). Miv 44 (Sax 12th edn.). Mor 120 (Griffith, R.W., Grauwiler, J., Hodel, Ch., Leist, K.H., & Matter, B. (1978). Toxicologic considerations. In: Berde, B., Schild, H.O., Aellig, W.H. (eds.). Ergot Alkaloids and Related Compounds, pp. 805-851. Springer-Verlag, Berlin). Mescaline Mor 880 (Gable). Mor 880, Mip 315, Msc 534, Miv 157, Rsc 534, Riv 157 (CIDP). Mes HCl Mor 800 (corr. 682), Mip 212 (corr. 181), Miv 110 (corr. 94), Rip 132 (corr. 112.8), Rsc 320 (corr. 273) (CIDP). Mes HCl Mip 212 (corr. 181), Rip 132 (corr. 112.8) (Hardman, H.F., Haavik, C.O., & Seevers, M.H. (1973). Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals. Toxicology and Applied Pharmacology, 25(2), 299-309). Mes HCl Mip 261 (corr. 223) (Walters, G.C., & Cooper, P.D. (1968). Alicyclic analogues of mescaline. Nature, 218(5138), 298-300). Mes sulfate Miv 177.5 (corr. 121) (Delay, J., Gerard, H.P., & Thuillier, J. (1950). Acute toxicity of mescaline sulfate and antidote action of sodium succinate. Comptes Rendus des Séances de la Société de Biologie et de ses Filiales, 144, 163). Ror 370 (https://erowid/psychoactives/health/psychoactives_LD50s.shtml; From (1) Vermont SIRI – Material Safety Data Sheet Collection; (2) Iowa State U. Dept. of Chemistry MSDS Collection).

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Mes HCl Miv 110 (corr. 94), Mor 912 (corr. 778), Rip 270 (corr. 230) (Davis, W.M., Bedford, J.A., Buelke, J.L., Guinn, M.M., Hatoum, H.T., Waters, I.W., Wilson, M.C., & Braude, M.C. (1978). Acute toxicity and gross behavioral effects of amphetamine, four methoxyamphetamines, and mescaline in rodents, dogs, and monkeys. Toxicology and Applied Pharmacology, 45(1), 49-62). Mes sulfate Rip 370 (corr. 253) (Speck, L.B. (1957). Toxicity and effects of increasing doses of mescaline. Journal of Pharmacology and Experimental Therapeutics, 119(1), 78-84). Methadone Methadone HCl_ Mor 124 (corr. 111), Ror 30 (corr. 26.8) (Gable). Mor 70, Mip 35, Msc 35, Rip 18, Rsc 30, Riv 11 (CIDP). Mor 95, Mip 28, Msc 28, Miv 20, Ror 86 (Sax 12th edn.). Mip 15.2 (Harbison, R.D., & Evans, M.A. (1977). Teratogenic aspects of drug abuse in pregnancy. In: Rementeria, J.L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects, pp. 181-194. C.V. Mosby Co. St. Louis, MO). Rsc 74 (Stockhaus, K., & Wick, H. (1969). Toxicity studies in rats of drugs by subcutaneous, intragastric and intraduodenal application. Archives Internationales de Pharmacodynamie et de Thérapie, 180(1), 155-161). Methadone HCl Mor 124 (corr. 111), Mip 8.3 (corr. 7.4), Msc 34 (corr. 30.4), Miv 16 (corr. 14.3), Ror 30 (corr. 26.8), Rip 11 (corr. 9.8), Rsc 12 (corr. 10.7), Riv 9.2 (corr. 8.2) (CIDP). Methadone HCl Rsc 47.2 (corr. 42.2) (Liu, S.J., & Wang, R.I.H. (1975). Increased analgesia and alterations in distribution and metabolism of methadone by desipramine in the rat. Journal of Pharmacology and Experimental Therapeutics, 195(1), 94-104). Methadone HCl Mip 41 (corr. 36.7) (Shannon, H.E., & Holtzman, S.G. (1976). Blockade of the specific lethal effects of narcotic analgesics in the mouse. European Journal of Pharmacology, 39(2), 295-303). Methadone HCl Msc 45 (corr. 40.3) (Ho, I.K., & Berndt, W.O. (1976). Effect of chronic administration of on methadone analgesia and toxicity. Life Sciences, 18(11), 1305-1313). Methadone HCl Msc 33.9 (corr. 30.3) (Richards, R.K. (1975). A study of the effect of d-amphetamine on the toxicity, analgesic and swimming impairment caused by potent analgesics in mice. Archives Internationales de Pharmacodynamie et de Thérapie, 216(2), 225-245). Methadone HCl Msc 57 (corr. 51) (Smits, S.E., & Myers, M.B. (1974). Some comparative effects of racemic methadone and its optical isomers in rodents. Research Communications in Chemical Pathology and Pharmacology, 7(4), 651-662). Methadone HCl Ror 70.3 (mean of 3) (corr. 62.9) (Hoffmann, S., Kinsner-Ovaskainen, A., Prieto, P., Mangelsdorf, I., Bieler, C., & Cole, T. (2010). Acute oral toxicity: variability, reliability, relevance

and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project. Regulatory Toxicology and Pharmacology, 58(3), 395-407). Methadone HCl Mor 178 (corr. 159) (Rosenkrantz, H., & Fleischman, R.W. (1988). In vivo carcinogenesis assay of DL-methadone HCl in rodents. Fundamental and Applied Toxicology, 11(4), 640-651). Methadone HCl Mor 120 (corr. 107), Mor 84 (corr. 75.2), Mip 40 (corr. 35.8) (Masten, L.W., Peterson, G.R., Burkhalter, A., & Way, E.L. (1975). Microsomal induction by methadone and its implications on tolerance to methadone lethality. Nature, 253(5488), 200-202. Methadone HCl Riv 22.5 (corr. 20.1) (Borron, S.W., Monier, C., Risède, P., & Baud, F.J. (2002). Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat. Human and Experimental Toxicology, 21(11), 599-605). Miv 23.45 (Votava, Z., & Horakova, Z. (1952). Comparison of the analgesic effect of morphine, methadone, and demerol. Československá Farmacie, 1, 338-347). Methadone HCl Rip 18.75 (corr. 16.8) (Chevillard, L., Mégarbane, B., Baud, F.J, Risède, P., Declèves, X., Mager, D., Milan, N., & Ricordel, I. (2010). Mechanism of respiratory insufficiency induced by methadone overdose in rats. Addiction Biology, 15(1), 62-80).

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Mor 70, Mip 35, Miv 20 (Svennebring, A. (2016). The connection between plasma protein binding

and acute toxicity as determined by the LD50 value. Drug Development Research, 77(1), 3-11). Mor 70, Ror 86 (Lachenmeier, D.W., & Rehm, J. (2015). Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports 5, 8126; DOI: 10.1038/srep08126). Ror 86, Rip 18, Riv 11 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). l-Methadone Mor 97, Msc 26.5 (Sax 12th edn.). l-Methadone HCl Mip 32 (corr. 28.6), Mip 30 (corr. 26.8), Msc 19 (corr. 17.0), Miv 29 (corr. 25.9), Rip 24 (corr. 21.5), Rsc 44 (corr. 39.4) (Sax 12th edn.). l-Methadone HCl Msc 57 (corr. 51) (Smits, S.E., & Myers, M.B. (1974). Some comparative effects of racemic methadone and its optical isomers in rodents. Research Communications in Chemical Pathology and Pharmacology, 7(4), 651-662). d-Methadone Mip 65, Miv 31, Rip 72 (Sax 12th edn.). d-Methadone HCl 121 (corr. 108.3) (Smits, SE., & Myers, M.B. (1974). Some comparative effects of racemic methadone and its optical isomers in rodents. Research Communications in Chemical Pathology and Pharmacology, 7(4), 651-662). Methamphetamine Methamphetamine HCl Mip 43 (corr. 34.5) (Gable). Rip 10 (CIDP). Methamphetamine HCl Mip 70 (corr. 56.2), Msc 180 (corr. 144.6), Miv 33 (corr. 26.5), Rip 25 (corr. 20.1), Rsc 30 (corr. 24.1) Sax 12th edn.). Methamphetamine HCl Mip 15 (corr. 12.1), Msc 7.56 (corr. 6.1), Miv 6.3 (corr. 5.1) (CIDC). Methamphetamine HCl Mip 67.8 (corr. 54.5) (Numachi, Y., Ohara, A., Yamashita, M. Fukushima, S. Kobayashi, H., Hata, H., Watanabe, H., Hall, F.S., Lesch, K.-P., Murphy, D.L., Uhl, G.R., & Sora, I. (2007). Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and transporters. European Journal of Pharmacology, 572(2-3), 120-128). Methamphetamine HCl Mip 67.8 (corr. 54.5) Nakanishi, H., Okegawa, T., Shimamoto, K. (1966). Comparison of the optical isomers of xylopinine. Japanese Journal of Pharmacology, 16(1), 10-24). Methamphetamine HCl Mip 59 (estimated from graph) (corr. 47.4) (Kataoka, Y., Gomita, Y., Fukuda, T., Eto, K., Araki, Y. (1986). Effects of aggregation on methamphetamine toxicity in mice. Acta Medica Okayama, 40(3), 121-126). Methamphetamine HCl Msc 95 (corr. 76.3) (Funahashi, M., Kohda, H., Shikata, I., & Kimura, H. (1988). Potentiation of lethality and increase in body temperature by combined use of d-methamphetamine and morphine in mice. Forensic Science International, 37(1), 19-26). Methamphetamine HCl_Mip 43.2 (corr. 34.7) (Ginawi, O.T., Al-Shabanah, O.A., & Bakheet, S.A.I., (1997). Increased toxicity of methamphetamine in morphine-dependent mice. General Pharmacology, 28(5), 727-731). Methamphetamine HCl Rsc 10.93 (corr. 8.8) (Witkin, J.M., Ricaurte, G.A., & Katz, J.L. (1990). Behavioral effects of N-methylamphetamine and N, N-dimethylamphetamine in rats and squirrel monkeys. Journal of Pharmacology and Experimental Therapeutics, 253(2), 466-474). Methamphetamine HCl Rsc 10.4 (corr. 8.4) (Bronstein, D.M., & Hong, J.-S. (1995). Effects of sulpiride and SCH 23390 on methamphetamine-induced changes in body temperature and lethality. Journal of Pharmacology and Experimental Therapeutics, 274(2), 943-950). Methamphetamine HCl Rip 50 (corr. 40.2) (Derlet, R.W., Albertson, T.E., & Rice, P. (1990). Antagonism of cocaine, amphetamine, and methamphetamine toxicity. Pharmacology Biochemistry and Behavior, 36(4), 745-749).

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Mip 57 (Yamamoto, H. (1963). The central effects of xylopinine in mice. Japanese Journal of Pharmacology, 13(3), 230-239). Mip 70 (Merck Index, 15th Edition, 2013). Mip 57 (Noggle, F.T., DeRuiter, J., Coker, S.T, & Clark, C.R. (1987). Synthesis, identification, and acute toxicity of some N-alkyl derivatives of 3,4-methylenedioxyamphetamine. Journal of the Association of Official Analytical Chemists, 70(6), 981-986). Rip 55 (Kiyatkin, E.A., & Sharma, H.S. (2009). Acute methamphetamine intoxication, brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. International Review of Neurobiology, 88(1), 65-100. Rip 115 (Heller, B., & Lumbreras, N. (1976). Studies on the role of phenethylamine in methylamphetamine mechanisms. Experientia, 32(2), 210-212). Methamphetamine Mor HCl 300 (corr. 241), Ror 980 (corr. 787) (MSDS of methamphetamine HCl; http://www.chemblink.com/MSDS/MSDSFiles/300-42-5_Clear%20Synth.pdf). Mip 43, Rip 70 (Cunha-Oliveira, T., Rego, A.C., Carvalho, F., & Oliveira, C.R. (2013). Medical toxicology of drugs of abuse. In: Miller, P.M. (ed.). Principles of Addiction: Comprehensive Addictive Behaviors and Disorders, Vol. 1, pp. 159-175. Academic Press, Amsterdam). Mor 232, Mip 15, Miv 10 (Derelanko, M.J., Auletta, C.S. (eds.) (2014). Handbook of Toxicology, 3rd edn., Appendix A, Table A.1. CRC Press, Boca Raton, FL). Mor 70 (Golob, P., 2002. Pest management. In: Golob, P., Farrell, G., & Orchard, J.E. (eds.). Crop Post-Harvest: Science and Technology, Vol. 1. Principles and Practice, pp. 233-320. Blackwell Scientific, Oxford). 3,4-Methylenedioxymethamphetamine (MDMA) Ror 160 (Gable). MDMA HCl Mip 97 (corr. 81.6), Rip 49 (corr. 41.2) (Hardman, H.F., Haavik, C.O., & Seevers, M.H. (1973). Relationship of the structure of mescaline and even analogs to toxicity and behavior in five species of laboratory animals. Toxicology and Applied Pharmacology, 25(2), 299-309). MDMA HCl Mip 106.5(isolated) (corr. 89.6), Mip 30.6(aggregated) (corr. 25.7); note: isolated value used. (Davis, W.M., & Borne, R.F. (1984). Pharmacologic investigation of compounds related to 3,4-methylenedioxyamphetamine (MDA). Substance and Alcohol Actions/Misuse, 5(2), 105-110). MDMA HCl Rsc 18(m) (corr. 15.1(m)), Rsc 42.5(f) (corr. 35.7(f)) (Fonsart, J., Menet, M.-C., Declèves, X., Galons, H., Crété, D., Debray, M., Scherrmann, J.-M, & Noble, F. (2008). Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Toxicology and Applied Pharmacology, 230(1), 117-125). Ror 325 (Lachenmeier, D.W., & Rehm, J. (2015). Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports, 5, 8126; DOI: 10.1038/srep8126). Mip 100 (racemic), 75 (+ enantiomer) (Fantegrossi, W.E., Godlewski, T., Karabenick, R.L,, Stephens, J.M., Ullich, T., Rice, K.C., & Woods, J.H. (2003). Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine (“ecstasy”) and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice. Psychopharmacology, 166(3), 202-211). Miv 97, Riv 49 (Jerome, L. (2007). (+/-)-3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), Investigator’s Brochure, Dec. 2007; (www.maps.org/research-archive/mdma/protocol/ib_mdma_ new08.pdf.) NOTE: these values are for Mip and Rip, NOT Miv and Riv as stated by Jerome. Jerome cites Hardman et al. (1973), who clearly state that their values are for ip, not iv. Also they are for HCl salt. Miv 56 (IACUC Hazardous Chemicals Guide – Safety and Risk Management; https://srm.vcu.edu/.../ IACUC%20Hazardous%20Chemical%20Index%20111517.xls).

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Mor 106.5 (Domingo, G., Schirmer, K., Brocale, M., & Pomati, F., 2011. Illicit drugs in the environment: implications for ecotoxicology. In: Castiglioni, S., Zuccato, E., & Fanelli, R. (eds.). Illicit Drugs in the Environment: Occurrence, Analysis, and Fate using Mass Spectrometry, pp. 253-274. John Wiley & Sons: Hoboken, NJ). Mor 137, Ror 162 (Gable). Mor 137, Mip 88, Msc 228, Miv 218, Ror 162, Rip 110, Rsc 200, Riv 209 (CIDP). Phenobarbital Na salt Mor 200 (corr. 183), Mip 123 (corr. 112), Msc 180 (corr. 164.4), Miv 226 (corr. 206), Ror 150 (corr. 137), Rip 152 (corr. 138.8), Rsc 195 (corr. 178.1), Riv 83 (corr. 76) (CIDP). Phenobarbital Na salt Mor 275 (corr. 251), Mip 250 (corr. 228), Miv 238 (corr. 217) (Lacombe, R., & Brodeur, J. (1974). Effect of pretreatment with dieldrin on certain in vivo parameters of enzyme induction in mice. Toxicology and Applied Pharmacology, 27(1), 70-85). Mor 137, Mip 88, Miv 218 (Svennebring, A. (2016). The connection between plasma protein binding

and acute toxicity as determined by the LD50 value. Drug Development Research, 77(1), 3-11). Mor 180 (Calleja, M.C., Persoone, G., & Geladi, P. (1994). Human acute toxicity prediction of the first 50 MEIC chemicals by a battery of ecotoxicological tests and physicochemical properties. Food and Chemical Toxicology, 32(2), 173-187). Mor 182, Rip 138 (Weiss, M.T., & Sawyer, T.W. (1993). Cytotoxicity of the MEIC test chemicals in primary neurone cultures. Toxicology in Vitro, 7(5), 653-667). Mor 242.0 (mean of 11), Ror 226.7 (mean of 8) (Hoffmann, S., Kinsner-Ovaskainen, A., Prieto, P., Mangelsdorf, I., Bieler, C., & Cole, T. (2010). Acute oral toxicity: variability, reliability, relevance

and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project. Regulatory Toxicology and Pharmacology, 58(3), 395-407). Mip 185 (Nakano, S., Watabe, H., & Ogawa, N. (1979). Circadian rhythm of drug activity on the basis of chronopharmacokinetics. Koen Yoshishu – Yakubutsu Kassei Shinpojumu, 8(1), 53-57). Mip 290 (Wallin, R.F., Blackburn, W.H., & Napoli, M.D. (1970). Pharmacologic interactions of albutoin with other anticonvulsant drugs. Journal of Pharmacology and Experimental Therapeutics, 174(2), 276-282). Mip 231(mean of 4), Ror 349 (mean of 6) (Clothier, R.H., Hulme, L.M., Smith, M., & Balls, M. (1987). Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals. Molecular Toxicology, 1(4), 571-577). Phenobarbital Na salt Mip 240 (corr. 219.2) (Ho, A.K.S., & Ho, C.C. (1979). Toxic interactions of ethanol with other central depressants: antagonism by naloxone to narcosis and lethality. Pharmacology Biochemistry and Behavior, 11(1), 111-114). Mip 223.75 (average over year and times of day) (Bruguerolle, B., Prat, M., Douylliez, C., & Dorfman, P. (1988). Are there circadian and circannual variations in acute toxicity of phenobarbital in mice? Fundamental and , 2(4), 301-304). Mip 325 (Raines, A., Niner, J.M., & Pace, D.G. (1973). A comparison of the anticonvulsant, neurotoxic and lethal effects of diphenylbarbituric acid, phenobarbital and diphenylhydantoin in the mouse. Journal of Pharmacology and Experimental Therapeutics, 186(2), 315-322). Mor 325, Mip 340, Ror 660, Rip 190 (Derelanko, M.J., & Auletta, C.S. (eds.) (2014). Handbook of Toxicology, 3rd edn., Appendix A, Table A.1. CRC Press, Boca Raton, FL). Ror 928 (Kostka, G., Urbanek, K., & Ludwicki, J.K. (2007). The effect of phenobarbital on the methylation level of the p16 promoter region in rat liver. Toxicology, 239(1-2), 127-135). Ror 681 (Zhu, X., Xuan, G., Zheng, Y., Huang, S., & Huang, X. (1998). Detoxication estimated by selective inducers and inhibitors. Weisheng Dulixue Zazhi, 12(1), 26-27). Ror 304 (Boyd, E.M., & Singh, J. (1967). Acute toxicity following rectal thiopental, phenobarbital and leptazol. Anesthesia and Analgesia, 46(4), 395-400).

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Rip 107 (Ashida, H., Kanazawa, K., & Denno, G. (1994). Hepatic phosphoglucomutase activity as a marker of oxidative stress induced by pro-oxidative drugs. Bioscience, Biotechnology, and Biochemistry, 58(1), 55-59). Rip 180 (Krampl, V., Vargová, M., & Vladár, M. (1973). Induction of hepatic enzymes after administration of a combination of heptachlor and phenobarbital. Bulletin of Environmental Contamination and Toxicology, 9(3), 156-162). Mor 137, Mip 128, Mip 340, Miv 218, Ror 162, Ror 660(Na salt) (corr. 603), Rip 151, Riv 209 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). Mip 285, Rip 280 (Gable). Mip 420, Miv 275, Riv 280 (CIDP). Ror 280 (van Amsterdam, J., Opperhuizen, A., & van de Brink, W. (2011). Harm potential of magic mushroom use: a review. Regulatory Toxicology and Pharmacology, 59(3), 423-429). Mor 280 (Smolinske, S.C. (1994). Psilocybin-containing mushrooms. In Spoerke, D.G., & Rumack, B.H. (eds.). Handbook of Mushroom Poisoning: Diagnosis and Treatment, pp. 309-324. CRC Press: Boca Raton, FL). Miv 285 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). Δ9-Tetrahydrocannabinol Mor 22 (Gable). Mor 482, Mip 168, Msc >11,000, Miv 42, Ror 666, Rip 373, Riv 29 (CIDC). Ror 482 (Lachenmeier, D.W., & Rehm, J. (2015). Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports, 5, 8126; DOI: 10.1038/srep8126). Mor 482, Mip 168, Miv 42 (Svennebring, A. (2016). The connection between plasma protein binding

and acute toxicity as determined by the LD50 value. Drug Development Research, 77(1), 3-11). Mip 510 (Sofia, R.D. (1974). The lethal effects of Δ9-tetrahydrocannabinol in mice enhanced by pretreatment with SKF 525A or chloramphenicol. European Journal of Pharmacology, 26(2), 383-385). Mip 300 (Martin, B.R., Montgomery, J., Dewey, W.L., & Harris, L.S. (1978). Alterations in the of 3H-Δ9-tetrahydrocannibinol in mice by bacterial endotoxin. and Disposition, 6(3), 282-287). Mip 454.5, Miv 42.5, Rip 372.9, Riv 28.6 (Phillips, R.N., Turk, R.F., & Forney, R.B. (1971). Acute toxicity of Δ9-tetrahydrocannabinol in rats and mice. Proceedings of the Society for Experimental Biology and Medicine, 136(1), 260-263). Mip 276.3 (for (-)trans-Δ9tetrahydrocannabinol) (Hatoum, N.S., Davis, W.M., Elsohly, M.A., & Turner, C.E. (1981). Cannabichromene and delta 9-tetrahydrocannabinol: interactions relative to lethality, hypothermia and hypnosis. General Pharmacology, 12(5), 357-362). Ror 800(m), Rip 672(m), Riv(m) 35.5, Riv 40 (Rosenkrantz, H., Heyman, I.A., & Braude, M.C. 9 (1974). Inhalation, parenteral and oral LD50 values of Δ -tetrahydrocannabinol in Fischer rats. Toxicology and Applied Pharmacology, 28(1), 18-27). Ror 1015(m), 800(f). (Thompson, G.R., Rosenkrantz, H., Schaeppi, U.H., & Braude, M.C. (1973). Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicology and Applied Pharmacology, 25(3), 363-372). Ror 666, Ror(m) 1270, Ror(m) 800, Ror(f) 730, Rip 373, Rip(m) 35.5, Rip(m) 672, Riv(m) 35.5, Riv 29 (Toxnet: http://toxnet.nlm.nih.gov/cgi-bin/sis/search). Human lethal dose All values taken from Gable (2004) except for ethanol, heroin and Δ9-tetrahydrocannabinol. Ethanol: 1400 mg/kg (Weiss, M.T., & Sawyer, T.W. (1993). Cytotoxicity of the MEIC test chemicals in primary neurone cultures. Toxicology in Vitro, 7(5), 653-667)

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Heroin: 100 mg (1.47 mg/kg) (O’Brien, C.P. (2001). Drug abuse. In: Goodman, L.S., Hardman, J.C., Limbird, L.E., & Gilman, A.G. (eds.). The Pharmacological Basis of Therapeutics, 10th Edn., pp. 621-642. McGraw-Hill: New York, NY). Note: O’Brien gave human lethal dose range 75- 375 mg for a 75 kg male naïve user. Using Gable’s (2004) approach, a value a little above the minimum was taken as being reasonable. Δ9-Tetrahydrocannabinol: 30 mg/kg (Hartung, B., Kauferstein, S., Ritz-Timme, S., & Daldrup, T. (2014). Sudden unexpected death under acute influence of cannabis. Forensic Science International, 237(April), e11-e13; https://doi.org/10.1016/j.forsciint.2014.02.001) Test drugs Amitriptyline Amitriptyline HCl Miv 21 (corr. 18.6), Riv 14 (corr. 12.4) (CIDP). Miv 16 (Svennebring, A. (2016). The connection between plasma protein binding and acute toxicity

as determined by the LD50 value. Drug Development Research, 77, 3-11). Amphetamine Miv 15, Riv 20 (CIDP). Amphetamine HCl Miv 8.4 (corr. 6.6) (CIDP). Amphetamine sulfate Miv 31.8 (corr. 11.7) (CIDP). Miv 18 (Toxnet). Dextropropoxyphene Miv 25 (CIDP). Dextropropoxyphene HCl Miv 25 (corr. 22.6), Riv 15 (corr. 13.5) (CIDP). Dextropropoxyphene HCl Miv 28 (corr. 25.3), Ror 230 (corr. 207.7) (Toxnet). Human lethal dose Amitriptyline HLD 8.8 mg/kg (Bickel M.H. (1975). Poisoning by tricyclis antidepressant drugs. General and pharmacokinetic considerations. International Journal of Clinical Pharmacology and Biopharmacy, 11(2), 145-176). HLD 11.0 mg/kg, 14.0 mg/kg (Woolf A.D., Erdman A.R., Nelson L.S., Caravati E.M., Cobaugh D.J., Booze L.L., Wax P.M., Manoguerra E.S., Scharman E.J., Olson K.R., Chyka P.A., Christianson G., & Troutman W.G. Clinical Toxicology, 45, 203-233). Amitriptyline HCl HLD 11.8 (corr. 10.6) (Toxnet). Amphetamine HLD amphetamine sulfate 13.69 mg/kg (corr. 5.02 mg/kg) (Ekwall, B., Clemedson, C., Crafoord, B., Ekwall, B., Hallander, S., Walum, E., & Bondesson, I. (1998). MEIC evaluation of acute systemic toxicity. Alternatives to Laboratory Animals, 26, 571-616). Dextropropoxyphene HLD 9.1 mg/kg (Ekwall, B., Clemedson, C., Crafoord, B., Ekwall, B., Hallander, S., Walum, E., & Bondesson, I. (1998). MEIC evaluation of acute systemic toxicity. Alternatives to Laboratory Animals, 26, 571-616).

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APPENDIX B: SUPPLEMENTARY INFORMATION - PSYCHOACTIVE DRUGS – DATA COMPARISON

All values corrected where necessary to free drug mg/kg Values in brackets are means; values in italics were not used in the calculation of means Cocaine (salt is HCl) Mor 85.7, 88.4, 99 (91.0) Mip 52.7, 59, 59.8(m), 60.7, 67.0, 72(m), 75, 80.4(f), 81.3, 82.5(f), 83.0(m), 84.9, 89.8(m), 90.0(f), 91(m), 98.2(m), 100.7(short sleep), 101.55(m), 107.2(long sleep) (80.9) Msc 26.8, 81, 111.6, 156, 183 (111.7) Miv 13.4, 14.3, 16, 26.8, 30 (20.1) Ror – Rip NBR 34.0(m); 55.2(f), F344 57.5(m), LEW 61.4(m), 62.5, ACI 64.3(m), 69.7, 70, 71.2, 73.7, 80(m), 92.6(m) (68.9) Rsc 91, 250 (170.5) Riv 12.5, 14.6, 15.6, 17.5 (15.1) Codeine (salt is phosphate) Mor 178.6, 188.3, 250, 414.4 (257.8) Mip 45.2, 60, 75(+ enantiomer), 82.9, 100, 104, 139.5 (86.7) Msc 60.3, 84.1, 134, 136.3, 143.9, 148.6 (117.9) Miv 40.7, 46.7, 54, 87 (57.1) Ror 64.0, 200.4, 321.7, 367, 427, 487.2(mean of 6) (360.7) Rip 75.3, 78.4, 100 (84.6) Rsc 229, 235.1 (232.1) Riv 40.7, 56.5, 75 (57.4) Dextromethorphan (salt is HBr) Mor 102, 127.1, 201, 210 (160) Mip 72.4 Msc 96.3, 112, 113.6, 126.5 (112.1) Miv 26.2, 27 (26.6) Ror 116, 269.6, 350 (Gable: could be HBr salt, hence 269.6) (192.8) Rip 99.5 Rsc 325.9 Riv 16.3, 27 (21.7) N, N-Dimethyltryptamine (salt is HCl) Mor 280 Mip 47 Miv 32, 43 (37.5) Ror – Rip 140 Riv – Ethanol Mor 3400, 3450, 6800, 7484, 7790, 7830, 8285, 8469, 8709(mean of 4), 8800(m), 9490 (7319) Mip 528, 900, 933, 2876, 2876, 3156, 6000, 6820(long-sleep mice), 7200, 7800, 8050 (short-sleep mice), 8100, 9000, 9200, 9450(f), 9710(m) (5608) Msc 8285, 8442, 10000 (8909) Miv 1973, 2000, 2209 (2061) Ror 6980, 7000, 7053, 7060, 7300, 7420, 7790, 8400, 9900, 10000, 10260, 10300, 10400, 10600, 12519.4(mean of 8), 13200, 14009, 14990, 21000 (10325) Rip 1920, 3367, 3600, 3750, 3800, 4970, 5100, 6710, 7900, 9800 (5092)

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Riv 1400, 1440, 1815 (1552) Flunitrazepam Mor 700, 870, 1200 (923) Mip 1050 Msc >4000 Miv 13.7 Ror 415, 1000 (708) Rip 1060 Riv – Fluoxetine (salt is HCl) Mor 221.8, 464 (342.9) Mip 87.5, 89.4 (88.5) Miv 40.3 Ror 404.3, 825 (614.7) Rip 121 Riv 31.3 Heroin (salt is HCl) Mor – Mip 218.4, 273 (245.7) Msc 130, 173.4, 262 (188.5) Miv 21.8, 22, 34.6 (26.1) Ror 150 Rip – Riv 22.5, 23, 34.6 (26.7) γ-Hydroxybutyrate (salt is Na+) Mor 1720, 4800 (3260) Mip 2724, 2960-3700, 3467, 3550, 4200 (3485) Msc 4500 Miv 3700 Ror 1540, 8000 (4770) Rip 1362(f), 1651(m) (1507) Riv 1400 Ketamine (salt is HCl) Mor 535 Mip 194.2, 225.3, 347, 400 (291.6) Miv 42.9, 48.5, 49.4, 66.8, 77 (56.9) Ror 387 Rip 148, 194, 229 (190.3) Riv 51.1, 51.2, 58.9 (53.7) d-Lysergic acid diethylamide Mor 120 Mip 50 Miv 44, 46 (45.0) Ror – Rip – Riv 16, 17 (16.5) Mescaline Mor 682, 683, 778, 880 (756) Mip 181, 223, 315 (239.7) Msc 534

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Miv 94, 121, 157 (124.0) Ror 370 Rip 112.8, 211, 230 (184.6) Rsc 273, 534 (403.5) Riv 157 Methadone Mor 70, 75.2, 95, 107, 111, 159 (102.9) Mip 7.4, 15.2, 28, 35, 35.8, 36.7 (26.4) Msc 28, 30.3, 30.4, 35, 40.3, 51 (35.8) Miv 14.3, 20, 23.45 (19.3) Ror 26.8, 62.9, 86 (58.6) Rip 9.8, 16.8, 18 (14.9) Rsc 10.7, 30, 42.2, 74 (39.2) Riv 8.2, 11, 20.1 (13.1) l-Methadone Mor 97 Mip 28.6 Msc 26.5, 51 d-Methadone Mip 65 Msc 108.3 Miv 31 Rip 72 Methamphetamine (salt is HCl) Mor 70, 232, 241 (181.0) Mip 12.1, 34.5, 34.7, 43, 47.4, 54.5, 54.6, 56.2, 57, 70 (51.6) Msc 6.1, 76.3, 144.6 (75.7) Miv 5.1, 8.0, 26.5 (13.2) Ror 787 Rip 10, 20.1, 40.2, 55, 70, 115 (51.7) Rsc 8.4, 8.8, 24.1 (13.8) Riv – 3,4-Methylenedioxymethamphetamine Mor 106.5 Mip 81.6, 89.6 (85.6) Miv 56 Ror 160, 325 (242.5) Rip 41.2 Rsc 15.1(m), 35.7(f) (25.4) Riv – Phenobarbital Mor 137, 180, 182, 183, 187, 242.0(mean of 11), 251, 325, 603 (254.4) Mip 88, 112, 128, 219.2, 223.75, 228, 231(mean of 4), 290, 340 (206.7) Msc 164.4, 228 (196.2) Miv 206, 217, 218 (213.7) Ror 137, 162, 226.7(mean of 8), 304, 349(mean of 6), 609, 660, 681, 928 (450.7) Rip 107, 110, 138, 138.8, 151, 180, 190 (145.0) Rsc 178.1 Riv 76, 209 (142.5) Psilocybin

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Mor 280 Mip 285, 420 (285) Miv 275, 285 (280) Ror 280 Rip 280 Riv 280 Δ9-Tetrahydrocannabinol Mor 22, 482 (482) Mip 168, 276.3, 300, 454.5, 510 (341.8) Msc >11,000 Miv 42, 42.47, 42.5 (42.3) Ror 482, 666, 730(f), 800(m), 800(f), 1015(m), 1270(m) (823.3) Rip 35.5(m), 372.9, 672(m) (522.5) Riv 28.6, 29, 35.5(m), 40 (33.3) Human lethal doses Cocaine 17.6 Codeine 11.8 Dextromethorphan 22.1 N,N-Dimethyltryptamine 29.4 Ethanol 1400 Flunitrazepam 0.44 Fluoxetine 36.8 Heroin 1.47 γ-Hydroxybutyrate 235.3 Ketamine 39.7 Lysergic acid diethylamide 1.47 Mescaline 123.5 Methadone 1.47 Methamphetamine 2.94 3,4-Methylenedioxymethamphetamine 29.4 Phenobarbital 73.5 Psilocybin 88.2 Δ9-Tetrahydrocannabinol 30 Test drugs Amitriptyline Miv 16, 18.6 (17.3) Riv 12.4 Amphetamine Miv 6.4, 11.7, 15, 18 (12.8) Riv 20 Dextropropoxyphene Miv 22.6, 25, 25.3 (24.3) Riv 13.5 Human lethal doses Amitriptyline 8.8, 10.6, 11, 14 (11.1) Amphetamine 5.02 Dextropropoxyphene 9.1

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John C. Dearden is Emeritus Professor of at Liverpool John Moores University. He has published over 270 peer-reviewed papers and book chapters, mostly in the field of QSAR and QSPR. He was the 2004 recipient of the International QSAR Award for significant contributions on QSAR in the human health and environmental sciences.

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